OWNER ON BEHALF OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEYL. Füsun Saygılı, MD

MANAGING CLERICAL DIRECTORNilgün Başkal, MD

ADRESS FOR MANAGEMENTThe Society of Endocrinology and Metabolism of TurkeyMeşrutiyet Caddesi No: 29/12 Kızılay, Ankara, TURKEYPhone: +90 312 425 20 72Fax: +90 312 425 20 98web: www.turkjem.orgE-mail: president@temd.org.tr

Publication Type and PeriodsTurkish Journal of Endocrinology and Metabolism is published 4 (March, June, September and December) times a year.

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Publication Date: 20.03.2019

ISSN: 1301-2193E-ISSN: 1308-9846

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

Owner on Behalf of the Society ofEndocrinology and Metabolism of TurkeyL. Füsun Saygılı, Ege University Faculty of Medicine, İzmir, Türkiye

Editor-In-ChiefNilgün Başkal, Ankara University Faculty of Medicine Retired Lecturer,Ankara, Turkey

Deputy EditorMurat Faik Erdoğan, Ankara University Faculty of Medicine, Ankara, Turkey

Associate EditorsHasan Ali Altunbaş, Akdeniz University Faculty of Medicine, Antalya, TurkeyDilek Gogas Yavuz, Marmara University Faculty of Medicine, İstanbul, TurkeyNeslihan Başçıl Tütüncü, Başkent University Faculty of Medicine, Ankara, Turkey

Statistical ConsultantAtilla Halil Elhan, Ankara, TurkeyLevent Dönmez, Antalya, TurkeyDerya Öztuna, Ankara, TurkeyCan Ateş, Van, Turkey

Language EditorJennifer Gabriel, California, USA

Honorary BoardSema Akalın, Marmara University Faculty of Medicine Retired Lecturer, İstanbul, TurkeyMetin Arslan, Gazi University Faculty of Medicine Retired Lecturer, Ankara, TurkeyGürbüz Erdoğan, Ufuk University Faculty of Medicine, Ankara, TurkeyOlcay Gedik, Hacettepe University Faculty of Medicine Retired Lecturer, Ankara, TurkeySadi Güngoğdu, Istanbul University Cerrahpaşa Faculty of Medicine Retired Lecturer, İstanbul, Turkey

Hüsrev Hatemi, İstanbul, TurkeyŞazi İmamoğlu, Uludağ University Faculty of Medicine Retired Lecturer, Bursa, TurkeyTaylan Kabalak, Ege University Faculty of Medicine Retired Lecturer, İzmir, TurkeySenay Molvalılar, İstanbul, TurkeyCandeğer Yılmaz, Ege University Faculty of Medicine Retired Lecturer, İzmir, Turkey

Editorial BoardErsin Akarsu, Gaziantep University Faculty of Medicine, Gaziantep, TurkeyMüjde Aktürk, Gazi University Faculty of Medicine, Ankara, TurkeyFaruk Alagöl, Koç University Faculty of Medicine, İstanbul, Turkeyİnan Anaforoğlu, Medical Park International Trabzon Hospital, Trabzon, TurkeyYalçın Aral, Bozok University Institute of Health Sciences, Yozgat, TurkeyAyşegül Atmaca, Ondokuz Mayıs University Faculty of Medicine, Samsun, TurkeyGöksun Ayvaz, Liv Hospital, Ankara, TurkeyÖmer Azal, Gulhane Education and Research Hospital, Ankara, TurkeyMustafa Kemal Balcı, Akdeniz University Faculty of Medicine, Antalya, TurkeyDavid Baylink, Loma Linda University, California, USAFahri Bayram, Erciyes University Faculty of Medicine, Kayseri, TurkeyErol Bolu, Memorial Atasehir Hospital, İstanbul, TurkeyBekir Çakır, Yıldırım Beyazıt University Faculty of Medicine, Ankara, TurkeyMehtap Çakır, Kent Hospital, İzmir, TurkeyBerrin Çetinarslan, Kocaeli University Faculty of Medicine, Kocaeli, TurkeyAhmet Çorakçı, Ufuk University Faculty of Medicine, Ankara, TurkeyAbdurrahman Çömlekci, Dokuz Eylül University Faculty of Medicine, İzmir, TurkeySelçuk Dağdelen, Hacettepe University Faculty of Medicine, Ankara, TurkeyHatice Sebila Dökmetaş, Istanbul Medipol University Faculty of Medicine, İstanbul, TurkeyBelgin Efe, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, TurkeySevinç Eraslan, Dokuz Eylul University Faculty of Medicine, İzmir, TurkeyTomris Erbaş, Hacettepe University Faculty of Medicine, Ankara, TurkeyMehmet Erdoğan, Ege University Faculty of Medicine İzmir, TurkeyEda Ertörer, Başkent University Adana Dr. Turgut Noyan Hospital, Adana, TurkeyJohn W. Funder, Monash University, Victoria, AustraliaHossein Gharib, Mayo Clinic, Minnesota, USASait Gönen, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey

Nilgün Güvener, Okan University Faculty of Medicine, İstanbul, TurkeySerdar Güler, Liv Hospital, Ankara, TurkeySevim Güllü, Ankara University Faculty of Medicine, Ankara, TurkeyAlptekin Gürsoy, Ankara Güven Hospital, Ankara, TurkeyZeliha Hekimsoy, Celal Bayar University Faculty of Medicine, Manisa, TurkeyLarry Jameson, Perelman School of Medicine Univ. Of Pennsylvania, Philadelphia, UsaPınar Kadıoğlu, İstanbul University Cerrahpasa Faculty of Medicine, İstanbul, TurkeyAhmet Kaya, Selcuk University Meram Faculty of Medicine, Konya, TurkeyFahrettin Keleştimur, Health Institutes of Turkey, Ankara, TurkeyMustafa Kutlu, Gulhane Education and Research Hospital, Ankara, TurkeyPierre J. Lefebvre, University of Liege Faculty of Medicine, Liege, BelgiumMesut Özkaya, Dr.Ersin Arslan Training and Research Hospital, Gaziantep, TurkeyTae Sun Park,Chonbuk National University Medical School, Jeonju, Koreaİlhan Satman, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyFüsun Saygılı, Ege University Faculty of Medicine, İzmir, TurkeyAlper Sönmez, Gulhane Education and Research Hospital, Ankara, TurkeyTümay Sözen, Hacettepe University Faculty of Medicine, Ankara, Turkeyİbrahim Şahin, İnönü University Faculty of Medicine, Malatya, TurkeyMustafa Şahin, Ankara University Faculty of Medicine, Ankara, TurkeyRefik Tanakol, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyKubilay Ükinç, Gayrettepe Florence Nightingale Hospital, İstanbul, TurkeyBetül Uğur Altun, Başkent University İstanbul Hospital, İstanbul, TurkeyAli Rıza Uysal, Ankara University Faculty of Medicine, Ankara, TurkeyKürşad Ünlühızarcı, Erciyes University Faculty of Medicine, Kayseri, TurkeyAyşe Kubat Üzüm, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyAnthony Weetman, The University of Sheffield, Sheffield, UKSema Yarman, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyBülent Okan Yıldız, Hacettepe University Faculty of Medicine, Ankara, Turkey

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

AIMS AND SCOPE

The Turkish Journal of Endocrinology and Metabolism is thepeer-reviewed periodical on clinical and experimental en-docrinology and metabolism diseases and related fields. It isthe official journal of the Society of Endocrinology and Meta-bolism of Turkey and is published quarterly (March, June,September and December) as hardcopy and an electronic jo-urnal at www.turkjem.org. The manuscripts are published inEnglish language.The journal publishes original research papers, reviews andcase reports which primarily focus on clinical endocrinology.The journal's aim is to be the essential reading for both en-docrinologists and clinical practitioners.

Open Access PolicyThe Turkish Journal of Endocrinology and Metabolism is anopen access journal. This journal provides immediate openaccess to its content on the principle that making researchfreely available to the public supports a greater global exc-hange of knowledge.Open Access Policy is based on rules of Budapest Open AccessInitiative (BOAI) http://www.budapestopenaccessinitiative.org/.Instructions for online manuscript submission, current issuesand archives of the journal can be found at www.turkjem.org.Please do not send manuscripts to the editorial office. Forother related issues you may contact the editorial office:

Subscription informationThe Turkish Journal of Endocrinology and Metabolism is dis-tributed free of charge to all endocrinology academicians andinstructors serving in our country. Access to full-text articlesof all issues of the journal is free at the journal's websitewww.turkjem.org

Instructions for authorsInstructions for authors are published in the journal pagesand can be accessed at the web site of the journalwww.turkjem.org

Material DisclaimerStatements or opinions expressed in the manuscripts publis-hed in the Turkish Journal of Endocrinology and Metabolismreflect the views of the author(s) and are not the opinions ofthe editors, the editorial board and the publisher. The editors,editorial board and the publisher disclaim any responsibility orliability for such materials.

Advertising PolicyThe Turkish Journal of Endocrinology and Metabolismis Turkish Journal of Endocrinology and Metabolism receivesadvertising support for its print and electronic editions andmaintains editorial integrity through policies that define theEditorial/Advertiser relationship:

Print and electronic advertising does not influence editorialdecisions, and advertising is not an endorsement by the Pub-lisher, Editor, or the Editorial Board.

Turkish Journal of Endocrinology and Metabolism reservesthe right to refuse any advertising for any reason preservingthe conditions consistent with the journal’s high standards ofhealthcare editorial.

Editors have full and final authority for approving print and elect-ronic advertisements and for enforcing the advertising policy.

Print advertisements are interspersed throughout the jour-nal but do not interrupt the flow articles. The journal websitecontains online banner advertising.

To avoid implied endorsement by the Journal, the article, orthe authors of the article; advertisements are not adjacent toarticles addressing the product or its disease state.

The Publisher reserves the right to print the word “Advertise-ment” on any advertisement where it may not be clear, so rea-ders can distinguish readily between advertising and editorial.It is the responsibility of the advertiser and its agencies toadhere to appropriate legal requirements and regulationsFor all advertising information, please contact reklam@turki-yeklinikleri.com

The journal is printed on acid-free paper.

All rights are reserved. Rights to the use and reproduction, including in the electronic media, of all communications, papers, photographs and illustrations appea-ring in this journal belong to the Turkish Journal of Endocrinology and Metabolism. Reproduction without prior written permission of part or all of any material isforbidden. The journal complies with the Professional Principles of the Press.

The paper used the print this journal conforms to ISO 9706: 1994 standard (Requirements for Permanence). The National Library of medicine suggests that bio-medical publications be printed on acid free paper (alkaline paper).

Reviewing the articles’ conformity to the publishing standards of the Journal, typesetting, reviewing and editing and editing the manuscripts and abstracts in En-glish and publishing process are realized by Türkiye Klinikleri.

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

INSTRUCTIONS FOR AUTHORSTurkish Journal of Endocrinology and Metabolism (Turk J Endocrinol Metab) is-sues papers on all aspects of endocrinology. The journal is the scientific pub-lishing organ of the Society of Endocrinology and Metabolism of Turkey and hasbeen published quarterly (March, June, September and December) since1997.In addition to original articles, case reports, review articles, letters tothe editor, educational articles, sections of question and answers, abstractsfrom literature and announcements of congresses/meetings are also pub-lished. Turkish Language Institution dictionary and orthography guide shouldbe taken as basic for literary. The idioms used should be checked.The scien-tific and ethical liability of the manuscripts belongs to the authors and thecopyright of the manuscripts belongs to the Turkish Journal of Endocrinologyand Metabolism. The authors should submit the signed copyright transfer formtogether with their manuscripts. Authors are responsible for the contents ofthe manuscript and accuracy of the references.The authors should guaranteethat their manuscripts has not been published and/or is not under considera-tion for publication in any other periodical. This requirement does not apply topapers presented in scientific meetings and whose summaries, not exceeding250 words, are published. In this case, however, the name, date and place ofthe meeting in which the paper was presented should be stated. The signedstatement of scientific contributions and responsibilities of all authors is re-quired.The Turkish Journal of Endocrinology and Metabolism does not charge any ar-ticle submission or processing charges.

Peer-reviewEditorial policies of the journal are conducted according to the rules advisedby Council of Science Editors and reflected in the Uniform Requirements forManuscripts Submitted to Biomedical Journals: Writing and Editing for Bio-medical Publication (http://www.icmje.org/).Submitted manuscripts are subjected for double-blind peer-review. The sci-entific board guiding the selection of the papers to be published in the Jour-nal consists of elected experts of the Journal and if necessary, selected fromnational and international experts in the relevant field of research. All manu-scripts are reviewed by the editor, section associate editors and at least threeinternal and external expert referees. All research articles undergo review bystatistical editor as well.Submitted manuscripts are also subjected for the evaluation of plagiarism, dupli-cate publication by automatic software. Authors are obliged to acknowledge if theypublished study results in full or in part in form of abstracts.The authors of the accepted manuscripts should be in consent that the editorand associate editors could make corrections without changing the main textof the paper.Manuscript format should be in accordance with Uniform Re-quirements for Manuscripts Submitted to Biomedical Journals: Writing and Ed-iting for Biomedical Publication (http://www.icmje.org/).For details: http://www.turkjem.org/pages/peer-review-ethic-5

General GuidelinesManuscripts can only be submitted electronically through the web site(http://www.turkjem.org) after creating an account. This system allows onlinesubmission and peer-review.The manuscripts are archived according to ICMJE-www.icmje.org, Index Medicus (Medline/PubMed) and Ulakbim-Turkish Medi-cine Index Rules. Rejected manuscripts, except artwork are not returned.For the experimental, clinical and drug human studies, approval by ethical com-mittee and statement on the adherence of the study protocol to the internationalagreements (Helsinki Declaration revised 2013 (https://www.wma.net/wp-con-tent/uploads/2016/11/DoH-Oct2013-JAMA.pdf) are required. In experimental an-imal studies, the authors should indicate that the procedures followed were inaccordance with animal rights (Guide for the care and use of laboratory animals,

https://www.nap.edu/read/12910/chapter/1) and they should obtain animal ethiccommittee approval. The Ethic Committee approval document should be sub-mitted to the Turkish Journal of Endocrinology and Metabolism together withthe manuscript.The approval of the ethic committee, statement on the adherence to internationalguidelines mentioned above and that the patients` informed consent is obtainedshould be indicated in the `Material and Method` section and is required for casereports whenever data/media used could reveal identity of the patient. The dec-laration of the conflict of interest between authors, institutions, acknowledge-ment of any financial or material support, aid is mandatory for authors submittingmanuscript and the statement should appear at the end of manuscript. Review-ers are required to report if any potential conflict of interest exists between re-viewer and authors, institutions.

Original ArticlesClinical research should comprise clinical observation, new techniques or labo-ratory studies. Provided that these manuscripts are written with lower-case let-ters, they should include the title in Turkish/English, the background and the keywords in Turkish/English, introduction, materials and methods, results (findings),discussion, references, tables, charts, pictures and they should be written in ac-cordance with Journal Agent rules. They should not exceed sixteen (A4) pages.It is recommended to present research articles and meta-analysis/systematic re-views article according to the guidelines on specific design of the study: random-ized studies (CONSORT), observational studies (STROBE), studies on diagnosticaccuracy (STARD), meta- analysis and systematic review (PRISMA, MOOSE) andother study designs (www.equator-network.org).

Author InformationThe name and the surname of the authors should be written without abbrevi-ation. The academic titles, the affiliations and the addresses of these affilia-tions should be clearly declared. Furthermore, the contact information of thecorresponding author should be entered to the system. Since e-mail will beused primarily for the contact with the authors, the e-mail of the correspon-ding author should be indicated. In addition the phone and the fax numbersshould be also indicated.

Title PageThis page should include the titles of the manuscript, key words and running ti-tles. In Turkish manuscripts the title in English should also take place. Likely,Turkish title should be mentioned for articles in foreign language. If the contentof the paper has been previously presented or its abstract has been published,an explanation should be made in this page about this issue. If there are anygrants and other financial supports by any institutions or firms for the study, in-formation must be provided by the authors.

AbstractTurkish and English summaries of the manuscript should take place in a man-ner that it will not exceed 250 words. The keywords should be written at theend of the summary. The references should not be cited in the summary sec-tion. As far as possible, use of abbreviations is to be avoided. If any abbrevi-ations are used, they must be taken into consideration independently of theabbreviations used in the text. The summary should be written with four run-ning titles.Purpose: The goal of the study should be clearly stated.Material and Method: The study should be defined, the standard criteria; itshould be also indicated whether the study is randomized or not, whether it isretrospective or prospective, the statistical method, if any, should be indicated.Results (Findings): The detailed result of the study should be given and thestatistical significance level should be indicated.

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

INSTRUCTIONS FOR AUTHORSDiscussion: It should reflect the results of the study, the favorable and un-favorable aspects should be declared.Key words: At least three and maximum eight key words. (in English and inTurkish) Do not use abbreviations in the key words. Turkish key words will beprovided by the editorial office for the authors who are not Turkish speakers. Ifyou are not a native Turkish speaker, please re-enter your English keywords to thearea provided for the Turkish keywords. English key words should be providedfrom Medical Subject Headings (http://www.nlm.nih.gov/mesh/) while Turkishkey words should be provided from http://www.bilimterimleri.com.Original researches should have the following sections;IntroductionBrief explanation about the topic should be done, the objective of the studyshould be indicated and these should be supported by the literature informa-tion.Materials and MethodsThe study design should be described, it should be indicated whetherit is interventional randomized or observational, whether it is retrospective orprospective, the number of trials, the characteristics, studied variables and spe-cific methods, the used statistical methods should be indicated. If any, it shouldbe indicated that the results should be scrutinized.Results (Findings)The results should be given, the tables and the pictures should be given innumerical order and, the results should be indicated as % and/or p-values.DiscussionThe obtained values should be discussed with its favorable and unfavorable as-pects and, they should be compared with literature.Study Limitations: Study Limitations and strengths, and directions for fur-ther research or implication must be discussed.Conclusion: The conclusion of the study should be highlighted.Authors contributions, Declaration of conflict of interest and Acknowledge-ments should appear at the end of the main text of manuscript.ReferencesAccuracy of reference data is the author’s responsibility. References shouldbe numbered according to the consecutive citation in the text. Referencesshould be indicated by parenthesis in the text. If there is Turkish Reference,attention should be paid to indicate this. Journal titles should be abbreviatedaccording to the style used in the Index Medicus. All the references, books,papers and similar articles should be cited as references should be writtenaccording to the rules of the International Committee of Medical Journal Ed-itors Uniform Requirements for Manuscripts Submitted to Biomedical Jour-nals (http://www.nlm.nih.gov/bsd/uniform_requirements.html).Journal: The surnames of the authors and the initial of authors’ names, thetitle of the paper, the title of the journal (the original abbreviation stated in thejournal), year, volume and the page numbers.Example: Collin JR, Rathbun JE. Involutional entropion: a review with evalu-ation of a procedure. Arch Ophthalmol. 1978;96:1058-1064.Book with a Single Author: The surname and the initial of the author, thetitle, chapter and section, the name of the editor, title of the book, place ofpublication, name of the printing house, year of print, page numbers.Example: Herbert L. Conjunctivitis, keratitis and infections of periorbital struc-tures. In: Armstrong D, Cohen J, eds. The Infectious Diseases (1st ed).Philadelphia; Mosby Harcourt; 1999;11;1-8.

Book Chapter: The surname and the initial of the author, chapter and section,name of the editor, title of the book, place of publication, name of the print-ing house, year of print, page numbers.Example: O’Brien TP, Green WR. Periocular Infections. In: Feigin RD, CherryJD, eds. Textbook of Pediatric Infectious Diseases (4th ed). Philadelphia; W.B.Saunders Company;1998:1273-1278.Visual Materials (Tables, Graphics, Figures, and Pictures): All tables,graphics or figures should be enumerated according to the sequence within thetext and a brief descriptive caption should be written. The abbreviations usedshould be definitely explained in the figure’s legend. Especially, the text of tablesshould be easily understandable and should not repeat the data of the main text.Illustrations that already published are acceptable if supplied by permission ofauthors for publication. The details of the pictures should be distinguishable andthey should be recorded in JPEG format and in 500 pixels per inch at least.Case ReportsIt should consist of the title, summary, key words, summary in English, key-words, introduction, case report, discussion and references, the case or thecases should be worth to be presented, it should contribute to literature, andall of them should not exceed 5 papers in (A4) sizes.ReviewIt should include new topics, the own experiences of the author, if possible,and the references also. It should consist of the title in Turkish, the summary,the keywords, the title in English, the summary in English and the keywordsin English.Letters to the EditorThey should be assays in the “review” manner in various topics or the assaysconcerning the articles published in the Turkish Journal of Endocrinology andMetabolism with the contributive content or contents as questions that do notexceed 200 words.Scientific LettersThe manuscripts should be error-free in the summaries compiled from the ar-ticles in other journals, the author names (surname, name) should be written,the journal title should be written with its original abbreviation, its year shouldbe indicated and, the name and he surname of the translator should be indi-cated under the manuscript.Open Access PolicyThis journal provides immediate open access to its content on the principlethat making research freely available to the public supports a greater globalexchange of knowledge.

CorrespondenceAll correspondences can be done to the following postal address or to the fol-lowing e-mail address, where the journal editorial resides:Address: Ankara University Faculty of Medicine, Department of Endocrinologyand Metabolism, Ankara, TurkeyPhone: +90 312 508 21 00Fax: +90 312 309 45 05E-mail: nilgun.baskal@temd.org.tr

“This journal licenced under the terms of the Creative Commons 4.0 Interna-tional Licence (CC BY 4.0)”

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

CONTENTS

Original Articles1 Evaluation of the Circulating Betatrophin Concentration and

its Possible Correlations Among Diabetic Patients with DyslipidemiaDislipidemi Diyabetik Hastalarda Dolaşımdaki Betatrofin Konsantrasyonunun veMuhtemel Korelasyonlarının DeğerlendirilmesiRasha M. Hussein

8 Physical Activity, Insulin Sensitivity, and Metabolic Control in Type 1 Diabetes MellitusTip 1 Diabetes Mellitusta Fiziksel Aktivite, İnsülin Duyarlılığı ve Metabolik KontrolNizameddin Koca, Metin Güçlü, İrfan Esen, Gamze Emlek, Sinem Kıyıcı, Gürcan Kısakol

19 Determination of Serum Thyroid Hormones and Electrolytesin Hypothyroid and Hyperthyroid Females-A Case Control Study in Lahore, PakistanHipotiroid ve Hipertiroid Kadınlarda Serum Tiroid Hormonları veElektrolitlerinin Belirlenmesi-Lahor, Pakistan’da Bir Vaka Kontrol ÇalışmasıBushra Mubarak, Sohail Ashraf, Raheela Aslam

25 Migraine is Strongly Associated with Central Obesity Than with General Obesity: A Case-Control StudyMigren Genel Obeziteden Daha Fazla ve Güçlü Şekilde Santral Obezite ile İlişkilidir: Bir Vaka-Kontrol ÇalışmasıBilal Natiq Nuaman, Asaad M. Sadik

33 A Bibliometric Analysis of Turkey’s Contribution to Bone Health Literature from an Endocrinologist PerspectiveTürkiye’nin Kemik Hastalıkları Literatürüne Katkısını Endokrinolojik Çerçeveden DeğerlendirenBibliyometrik Bir BakışCeyla Konca Değertekin, Özlem Turhan İyidir, Dilek Gogas Yavuz

38 The Effect of Treatment of Iron Deficiency Anemia on Thyroid VolumeDemir Eksikliği Tedavisinin Tiroid Volümü Üzerine EtkisiDiğdem Öze Etik, Murat Faik Erdoğan

Review Article47 Relationship Between Sarcopenia and Type 2 Diabetes Mellitus in Elderly Patients

Yaşlı Hastalarda Sarkopeni ve Tip 2 Diabetes Mellitus Arasındaki İlişkiZeynel Abidin Sayiner, Zeynel Abidin Öztürk

March 2019 Volume: 23 Issue: 1

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

Case Reports53 Overlapping Between Thymus Neuroendocrine Carcinoma

as an Ectopic Cushing Syndrome and Exogenous Cushing’s Syndrome: A Case ReportEktopik Cushing Sendromu Olan Timus Nöroendokrin Karsinomu ileEkzojen Cushing Sendromu Örtüşmesi: Bir Olgu SunumuEsmail Faraji, Sepideh Tahsini Tekantapeh

58 Critical Role of Ga-68 DOTATATE PET-CT in a Patient with Neuroendocrine Tumor andSecond Primary CancerNöroendokrin Tümörlü ve İkincil Primer Tümörü Olan Hastada Ga-68 DOTATATE PET-BT’nin Kritik RolüTuğçe Telli, Murat Tuncel, Saadettin Kılıçkap

64 Case Report: Fixed Drug Eruption Caused by DapagliflozinVaka Sunumu: Dapagliflozine Bağlı Fiks İlaç ErüpsiyonuMüge Keskin, Özlem Tekin, Arzu Or Koca, Murat Dağdeviren, Gülçin Güler Şimşek,Mustafa Altay, Derun Taner Ertuğrul

68 Transient Elevation of CA 19-9 Due to Cessation of Levothyroxine in a Patient with Hashimoto’s ThyroiditisHashimoto Tiroiditi Olan Bir Hastada Levotiroksinin Kesilmesi Nedeni ile Geçici CA 19-9 YükselmesiArzu Or Koca, Mustafa Altay

72 Hypoglycemia Due to the Presence of Anti-insulin Antibodies: A Case ReportAnti-insülin Antikorlarının Varlığına Bağlı Hipoglisemi: Bir Olgu SunumuElif Sevil Alagüney, Belgin Efe, Göknur Yorulmaz, Berat Acu, İnsaf Durmuş

Erratum76 Expression Level of Circulating miR-93 in Serum of Patients with Diabetic Nephropathy

Masoume Akhbari, Maryam Shahrabi-Farahani, Alireza Biglari, Mitra Khalili, Fatemeh Bandarian

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

EDITORIAL

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Quality of life with extended life span is more under discussion than ever. This term largely accepted as very confusing andeven esoteric depending on the intention of measurement. In early times being alive was accepted as having quality of life.Harvard Universities seventy five year lasting research on Study of Adult Development convey some interesting findings.From a much diversified control group of 724 men findings are very striking. Good relations keep us happy and healthy.Strong social relations improves happiness and health while loneliness kills. Another community-based study by SaravananP., Chau W.F., Roberts N., Vedhara K., Greenwood R., Dayan C.M. have the evidence that patients with thyroxinereplacement even with a normal TSH display significant impairment in psychological wellbeing compared to controls ofsimilar age and sex. Another study by Paul W.Ladenson puts forward that, practiced clinicians understand that the linkbetween thyroid hormone deficiency and constitutional and neuropsychiatric symptoms is complex and sometimes tenuous.Complaints such as fatigue, poor memory, slow thinking, depressed mood, cold intolerance, dry skin and constipation arecertainly more common in hypothyroid than euthyroid individuals, a fact well documented by both clinical trials involvingshort-term hypothyroidism. All these findings reminds what Plato has quoted centuries back: “That as you ought not toattempt to cure the eyes without the head, or the head without the body, so neither ought you to cure the body withoutthe soul”, and this he said “is the reason why the cure of many diseases is unknown to the physicians of Hellas, becausethey are ignorant of the whole, which ought to be studied also; for the part can never be well unless the whole is well.”

Science of medicine is interdisciplinary by nature, endocrinology and metabolism system as a whole seems to contributeto the wellbeing and extended life if we adopt a holistic approach.Through developing research literature our journal alsofollows impressive research by scholars frame our March issue with:“Evaluation of the circulating betatrophin concentrationand its possible correlations among diabetic patients with dyslipidemia”, “Physical activity, insulin sensitivity and metaboliccontrol in type 1 diabetes mellitus”,“Determination of serum thyroid hormones and electrolytes in hypothyroid andhyperthyroid females”,“Migraine is strongly associated with central obesity than with general obesity”,“A bibliometricanalysis of Turkey's contribution to bone health literature from an endocrinologist perspective”,“The effect of treatment ofiron deficiency anemia on thyroid volume”,“Relationship between sarcopenia and type 2 diabetes mellitus in elderlypatients”,“Overlapping between thymus neuroendocrine carcinoma as an ectopic Cushing syndrome and exogenousCushing’s syndrome”, “Critical role of Ga-68 DOTATATE PET-CT in a patient with neuroendocrine tumor and secondprimary cancer”,“Fixed drug eruption caused by dapagliflozin”,“Transient elevation of CA 19-9 due to cessation oflevothyroxine in a patient with Hashimoto’s thyroiditis”, and “Hypoglycemia due to the presence of anti-insulin antibodies”.

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JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

Original ResearchTurk J Endocrinol Metab 2019;23:1-7

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Address for Correspondence: Rasha M. Hussein, Department of Biochemistry, Faculty of Pharmacy,Beni-Suef University, Salah Salem Street, 62514, Beni-Suef, Egypt

Phone: 002 01200136515 E-mail: rasha.hussein@pharm.bsu.edu.egReceived: 27/09/2018 Received in revised form: 03/12/2018 Accepted: 16/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Evaluation of the Circulating BetatrophinConcentration and its Possible Correlations Among

Diabetic Patients with DyslipidemiaDislipidemili Diyabetik Hastalarda

Dolaşımdaki Betatrofin Konsantrasyonunun veMuhtemel Korelasyonlarının Değerlendirilmesi

*Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, 62514 Beni-Suef, Egypt**Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, Karak, Jordan

IntroductionDiabetes mellitus (DM) is a complex diseasecharacterized by chronic hyperglycemia thathas become increasingly prevalent duringthe last decades (1). It is broadly classifiedinto type 1 and type 2 DM; while type 1 di-abetic patients do not produce insulin due tothe autoimmune destruction of the pancre-

atic beta cells, type 2 DM is a result of meta-bolic syndrome and insulin resistance (2).However, recent discoveries regarding themolecular pathophysiology of DM advocatea more stringent disease classification basedon patient genotypes and phenotypes (2, 3).Both types are associated with a gradualloss of pancreatic beta cell function, which

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Objective: The circulating betatrophin levels in diabetic pa-tients, treated with insulin or with oral hypoglycemic agents,were measured. The correlation between betatrophin levelsand the glucose/lipid variables was also analyzed.Material and Methods: Thirty-six diabetic patients (18 in-sulin-treated and 18 oral hypoglycemics-treated) and 16age-and sex-matched non-diabetic controls were enrolled.The serum levels of betatrophin, glucose, and lipids weremeasured.Results: The serum betatrophin levels were significantlylower in both the insulin-treated and oral hypoglycemics-treated diabetics compared to the controls (32.8±3.6 and48.4±5.2 vs. 54.4±3.7, respectively, p<0.001). Pearson’sbivariate correlation analysis showed that betatrophin waspositively correlated with total cholesterol (r=0.303,p=0.029), LDL-cholesterol (r=0.339, p=0.014) and triglyc-eride (r=0.562, p=0.015) levels.Conclusion: The circulating betatrophin levels were re-duced in diabetic patients compared to the non-diabeticcontrols, and positively correlated with lipid parameters butnot with glucose levels.

Keywords: ANGPTL8; betatrophin; Diabetes mellitus;glucose; lipids

Amaç: İnsülin veya oral hipoglisemik ajanlarla tedavi edilendiyabetik hastalarda dolaşımdaki betatrofin seviyeleri öl-çüldü. Ayrıca, betatrofin seviyeleri ile glukoz/lipit değişken-leri arasındaki korelasyon analiz edildi.Gereç ve Yöntemler: Otuz altı diyabetik hasta (insülinletedavi edilen 18 ve oral hipoglisemik ile tedavi edilen 18),yaş ve cinsiyeti eşleştirilmiş 16 diyabetik olmayan kontrolçalışmaya dâhil edildi. Serum betatrofin, glukoz ve lipit se-viyeleri ölçüldü.Bulgular: Serum betatrofin düzeyleri hem insülinle hem deoral hipoglisemikle tedavi edilen diyabetiklerde kontrollerekıyasla anlamlı derecede düşük bulundu (sırasıyla 32,8±3,6ve 48,4±5,2’ye karşı 54,4±3,7, p<0,001). Pearson iki de-ğişkenli korelasyon analizi, betatrofinin total kolesterol(r=0,303, p=0,029), LDL-kolesterol (r=0,339, p=0,014) vetrigliserid (r=0,562, p=0,015) düzeyleri ile pozitif korelas-yon gösterdiğini ortaya koydu.Sonuç: Dolaşımdaki betatrofin seviyeleri diyabetik hasta-larda diyabetik olmayan kontrollere göre azaldı ve lipit pa-rametreleriyle pozitif korelasyon gösterdi, ancak glukozseviyeleri ile göstermedi.

Anahtar kelimeler: ANGPTL8; betatrofin; Diabetes mellitus;glukoz; lipidler

may persist for several decades (4), andcannot be attenuated by the current thera-pies (5). In addition, DM is also associatedwith serious complications such as athero-sclerosis, retinopathy, and nephropathy, aswell as high mortality (1).Betatrophin, also known as lipasin, refeed-ing induced in fat and liver (RIFL) and an-giopoietin-like protein 8 (ANGPTL8), is a 22kDa hormone produced mainly in the liverand adipose tissues. Its levels increase inthe liver after feeding and decrease uponfasting (6). Since betatrophin stimulates theproliferation of pancreatic beta cells (7), it isa promising option for regenerative therapyagainst diabetes (8). Betatrophin is alsoclosely associated with lipid metabolism viainhibition of lipoprotein lipase activity (9),and its overexpression in mice increasestriglyceride levels by modulating hepaticVLDL secretion (6, 10, 11). However, the be-tatrophin levels in either type 1 or type 2 DMpatients are still ambiguous. While somestudies have reported an increase in betat-rophin concentration in both type 1 and type2 diabetic patients (12-14), Gómez-Ambrosiet al. found lower betatrophin levels in pa-tients with type 2 DM (15). Some studies onthe other hand report lack of any correlationbetween betatrophin concentration and glu-cose tolerance (10, 16).Moreover, only a few studies have evaluatedthe effects of anti-diabetic treatments on thecirculating betatrophin levels. For example,Espes et al. found that diabetic patientstreated with metformin had higher serumbetatrophin levels compared to the controls(14). Another study on a Japanese cohortdemonstrated that betatrophin concentra-tion was elevated in type 1 diabetic patientsreceiving insulin therapy and in type 2 dia-betic patients receiving oral hypoglycemicagents (17). However, Fenzl et al. found thattype 2 diabetic patients treated with met-formin, either alone or in combination with asulfonylurea, showed similar circulating be-tatrophin levels compared to the normalcontrols (16). Taken together, any potentialcorrelation between betatrophin concentra-tion and anti-diabetic therapies is at presentunclear (18).In this study, the circulating betatrophin lev-els in diabetic patients treated with either in-sulin injection or with oral hypoglycemic

agents, and in healthy controls were meas-ured. In addition, the correlation betweenbetatrophin levels with that of glucose andlipids were tested.

Material and Methods

SubjectsA total of 52 Egyptian subjects aged 40-60years (24 males, 28 females) were includedin this study, of which 36 subjects were di-agnosed with DM and 16 were age- and sex-matched healthy controls. The averagedisease duration was 7.5±1.8 years, and thepatients were classified into the insulin-treated (N=18), and oral hypoglycemic-treated (N=18) groups based on therespective monotherapies. In addition, 15patients received metformin monotherapyand 3 were treated with metformin in com-bination with the sulfonylurea glimepiride.The subjects with liver, heart, and lung dis-eases or Cushing syndrome were excluded.The Ethics Committee of the Faculty of Med-icine, Beni-Suef University (FM-BSU-REC)approved the study (declaration no:FWA00015574, approval date:22/01/2017), which was performed in ac-cordance with the declaration of Helsinkiprinciples revised in 2000. All subjects pro-vided written informed consent.

Evaluation of serum biochemical indicesBlood samples were drawn from all subjectsafter overnight fasting, and 2 h after a meal.The sera were separated and fasting/post-prandial blood glucose, total cholesterol,HDL-cholesterol and triglycerides weremeasured (19) using commercially availablekits (Bio-diagnostics, Giza, Egypt). The LDL-cholesterol levels were calculated as totalcholesterol–HDL cholesterol–(triglyc-erides/5).

Betatrophin measurementSerum betatrophin content was measuredafter overnight fasting by enzyme linked im-munosorbent assay (human BetatrophinELISA kit, Cat. No E3381Hu, Bioassay Tech-nology Laboratory, China) according to themanufacturer’s instructions. Briefly, 40 µL ofserum samples was added to each well of a96-well plate, and then 10 µL biotin-conju-gated anti-human betatrophin antibody and

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50 µL streptavidin-HRP were added. Afterincubating for 60 min at 37°C, the wellswere washed 5 times for 5 min each and 50µL each of the substrate solution A and so-lution B were added each well. Following a10 min incubation at 37°C, 50 µL stop solu-tion was added and the absorbance of theblue colored solution was measured at 450nm by an ELISA plate reader. The sensitivityof the kit was 0.23 ng/mL, inter-assay pre-cision CV<10%, and intra-assay precisionwas CV<8% (CV%= SD/mean × 100).

Statistical analysisThe statistical analysis was conducted usingSPSS software version 22 (SPSS Inc.,Chicago, Illinois). Normal distribution of thedata was determined by the Kolmogorov-Smirnov test. Multiple groups were com-pared using the one way analysis of variance(ANOVA) followed by Tukey’s post Hoc test.Correlations between betatrophin and othervariables were determined using Pearson’sbivariate correlation analysis followed by lin-ear regression analysis. Data are expressedas mean±SE, and p values <0.05 were con-sidered statistically significant.

Results

Demographic and biochemical characteristicsOut of the 36 diabetic patients, 18 were in-sulin-treated (7 males and 11 females, meanage 51.1±3.6 years) and 18 received oral

hypoglycemics (10 males and 8 females,mean age 55.8±3.3 years). In addition, 16age- and sex-matched non-diabetic controls(7 males and 9 females, mean age 49.6±5.3years) were also included. There were nosignificant differences between the two pa-tient subgroups in terms of age or diseaseduration. However, the insulin-treated pa-tients showed a mean disease duration of7.4±2.1 years and mean age of 51.1±3.6years, which largely excludes the possibilityof type 1 DM. Interestingly, no significant dif-ferences were observed in the age, and inthe HDL-cholesterol, LDL-cholesterol, totalcholesterol and triglyceride levels betweenthe patients and controls, regardless of thetherapeutic regimen in the former (p>0.05).In fact, all subjects showed high LDL-choles-terol levels (158.3±9.7 for normal, 127±9.7for insulin-treated patients and 146±12.3 fororal hypoglycemics-treated patients), andthe controls had borderline high total cho-lesterol (205.5±11.1 mg/dL), indicating dys-lipidemia among all subjects. Furthermore,none of the established parameters of glu-cose or lipid metabolism showed significantdifferences between the two therapeuticsubgroups among the diabetic patients, ex-cept HDL-cholesterol that was significantlylower in the oral hypoglycemics-treated pa-tients compared to the insulin-treated pa-tients (45.9±1.2 vs. 54.4±2.6, p=0.027).The biochemical characters of all groups aresummarized in Table 1.

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M: Male; F: female; y.: year.Data are presented as mean±SE. One Way Analysis of Variance (ANOVA) followed by Tukey’s post Hoc test was used to compare the diffe-rences among groups.*: significant value when insulin-treated diabetics or oral hypoglycemics-treated diabetics were compared to normal non-diabetics (p<0.001).a: significant value when insulin-treated diabetics were compared to oral hypoglycemics-treated diabetics (p<0.05).

Oral hypoglycemics-

Normal non-diabetics Insulin-treated diabetics treated diabetics

M: F 7:9 7:11 10:8

Age (y.) 49.6±5.3 51.1±3.6 55.8±3.3

Disease duration (y.) - 7.4±2.1 7.3±1.7

Fasting blood glucose (mg/dl) 83.8±2.5 158.6±18.3* 188.1±17 *

2 h. postprandial blood glucose (mg/dl) 98.2±1.2 226.6±18.3* 257.5±17.5 *

Total cholesterol (mg/dl) 205.5±11.1 181.4±9.5 191.9±12.3

HDL- cholesterol (mg/dl) 47.1±2.9 54.4±2.6 45.9±1.2a

LDL- cholesterol (mg/dl) 133.9±9.9 105.2±8.8 124.2±11.3

Triacylglycerol (mg/dl) 122.3±11.8 113.3±14.6 119.9±6.4

Table 1. The biochemical characters of the studied groups.

Circulating betatrophin levelsThe serum betatrophin levels were signifi-cantly lower in the diabetics compared tothe normal subjects (40.61±3.3 vs.54.4±3.7, p=0.02). Furthermore, both in-sulin-treated (32.8±3.6) and oral-hypo-glycemics-treated (48.4±5.2) patients hadlower betatrophin levels compared to thehealthy controls, and that in the insulin-treated subgroup was significantly lowercompared to the oral hypoglycemic sub-group (p=0.016). However, the hormonelevels were similar between male and fe-male patients (p=0.76). The results aresummarized in Figure 1.

The correlation between betatrophin andlipid variablesThe relationship between the circulating be-tatrophin levels and various biochemical pa-rameters were evaluated by Pearson’sbivariate correlation analysis. Betatrophinlevels showed a significant positive correla-tion with total cholesterol (r=0.303,p=0.029) (Figure 2A) and LDL-cholesterol(r=0.339, p=0.014) (Figure 2B) levels in allsubjects. However, no significant correlationwas observed between betatrophin and fast-ing glucose, postprandial glucose, triglyc-erides, HDL-cholesterol or age (p>0.05). Inthe oral hypoglycemics-treated group, thebetatrophin levels were positively correlated

with that of triglycerides (r=0.562,p=0.015; Figure 2C). Multiple linear regres-sion analysis showed that total cholesterol(B=0.131; SE=0.058; β=0.303, t=2.248,p=0.029), LDL-cholesterol (B=0.148;SE=0.058; β=0.39, t=2.5; p=0.014) andtriglyceride (B=0.452; SE=0.166; β=0.562;t=2.7; p=0.015) levels are independent fac-tors affecting circulating betatrophin levels.

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Figure 1: The circulating betatrophin concentrationsamong the studied groups.Box plot shows the serum betatrophin concentrations in nor-mal, insulin-treated DM and oral hypoglycemics-treated DMsubjects. Box represents the first and third quartiles and me-dian. Whiskers represents minimum and maximum values.*: significant value when compared to normal subjects (p<0.001).a: significant difference when insulin treated patients compa-red to oral hypoglycemic treated patients (p<0.05)

Figure 2: The correlations between circulating betatrophin and lipid parameters.Scatter diagram shows the significant correlations between betatrophin and lipid parameters.(A) Correlation between betatrophin and total cholesterol in all subjects; (B) Correlation between betatrophin and LDL-cholesterol in all subjects; (C) Correlation between betatrophin and triglycerides in normal, insulin treated DM and oralhypoglycemics- treated DM groups. Pearson’s correlation coefficient and p values are indicated in each figure.

DiscussionThis study found that circulating betatrophinlevels were significantly lower in diabetic pa-tients regardless of the therapeutic regimen,and positively correlated with various lipidsbut not glucose. The reports on betatrophinlevels in DM are ambiguous at present (20).For example, several studies have shownhigher concentrations in only type 1 (12),only type 2 (13, 14, 21, 22), and both type 1and 2 DM (17), as well as in pregnant womenwith gestational diabetes (23, 24). Gómez-Ambrosi et al. measured the serum betat-rophin levels in non-diabetic, glucoseintolerant and type 2 diabetic obese individ-uals, and found an overall 40% reduction inthe obese subjects compared to the non-obese controls, which was further reduced inthose with impaired glucose tolerance or type2 DM by 59% and 70%, respectively (15).However, Fenzl et al. found no difference inbetatrophin levels between type 2 diabeticsand non-diabetics, or between lean and mor-bidly obese individuals (16). Furthermore,Guo et al. found that excess body weight, andnot diabetes was associated with high betat-rophin levels in a cohort of type 2 DM patients(25). It is noteworthy that most studies thatshowed increased betatrophin levels in DMwere conducted in animal models, and there-fore might not be applicable to humans. Forinstance, Jiao et al. found that human pan-creatic beta cells did not expand in vitro inthe presence of murine betatrophin (26).The relevance of the increased betatrophinlevels in diabetes is still unknown (12). Obe-sity is a major driving factor of type 2 DM,with most patients exhibiting hypertriglyc-eridemia (27). Betatrophin has a regulatoryrole in triglycerides metabolism, and Angptl8knockout mice showed decreased plasmatriglyceride levels after re-feeding (10). Inaddition, several studies have shown that be-tatrophin levels are positively correlated tothat of triglycerides, HDL-cholesterol (1, 15),apolipoprotein B, total cholesterol, and LDL-cholesterol in type 2 diabetic patients (16).This study found a significant positive corre-lation of betatrophin with a lipid variable onlyin the oral hypoglycemics-treated patients.Based on these findings, the increase in be-tatrophin levels is likely a compensatorymechanism against hyperlipidemia and actsby reducing the plasma lipoprotein levels

(15). In contrast, our and others’ studiesshow lack of any correlation between betat-rophin and lipid variables and/or glucosemetabolic parameters (12, 25). In addition,Wang et al. found no change in glucose me-tabolism or insulin levels in Angptl8 knock-out mice (10). Finally, this study found nosignificant differences in betatrophin levelsbetween males and females, in contrast tothe findings of Gómez-Ambrosi et al., (15).To summarize, betatrophin levels were sig-nificantly lower in both insulin and oral hy-poglycemics-treated patients compared tothe normal controls, and not correlated withblood glucose levels. There were severallimitations in the present study, such as thesmall cohort and lack of newly-diagnosed di-abetic patients. In addition, the postprandialbetatrophin levels should also be measuredsince it is known to be a nutritionally regu-lated factor and thereby affected by fast-ing/re-feeding, along with the HbA1c levels.

ConclusionThe circulating betatrophin levels were re-duced in the DM patients compared to non-diabetic controls regardless of the therapy,and was positively correlated with total cho-lesterol, LDL-cholesterol, and triglyceridesbut not with the blood glucose level. There-fore, betatrophin is a potential clinical pa-rameter for both diabetes and obesity thatneeds to be further investigated.

EthicsResearch involving Human Participantsand/or Animals:This study was approvedby the Ethics Committee of Faculty of Medi-cine, Beni-Suef University (FM-BSU-REC),declaration no: FWA00015574. Approvaldate: 22/01/2017.Informed consent: ll participants gave awritten informed consent.Funding: This research did not receive a fund.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

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Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsRasha M. Hussein designed the experi-ments, measured the biochemical indices,analyzed the data and wrote the manu-script.

References1. Gao T, Jin K, Chen P, Jin H, Yang L, Xie X, Yang M,

Hu C, Yu X. Circulating betatrophin correlates withtriglycerides and postprandial glucose among dif-ferent glucose tolerance statuses--a case-controlstudy. PLoS One. 2015;10:e0133640. [Crossref][PubMed]

2. Zaccardi F, Webb DR, Yates T, Davies MJ. Patho-physiology of type 1 and type 2 diabetes mellitus: a90-year perspective. Postgrad Med J. 2015;92:63-69. [Crossref] [PubMed]

3. Tuomi T, Santoro N, Caprio S, Cai M, Weng J, GroopL. The many faces of diabetes: a disease with in-creasing heterogeneity. Lancet. 2014;383:1084-1094. [Crossref]

4. Keenan HA, Sun JK, Levine J, Doria A, Aiello LP,Eisenbarth G, Bonner-Weir S, King GL. Residual in-sulin production and pancreatic β-cell turnover after50 years of diabetes: Joslin Medalist Study. Dia-betes. 2010;59:2846-2853. [Crossref] [PubMed]

5. Bagust A, Beale S. Deteriorating beta‐cell functionin type 2 diabetes: a long‐term model. QJM.2003;96:281-288. [Crossref] [PubMed]

6. Zhang R. Lipasin, a novel nutritionally-regulatedliver-enriched factor that regulates serum triglyc-eride levels. Biochem Biophys Res Commun.2012;424:786-792. [Crossref] [PubMed]

7. Kugelberg E. Diabetes: betatrophin--inducing β-cellexpansion to treat diabetes mellitus? Nat Rev En-docrinol. 2013;9:379. [Crossref] [PubMed]

8. Lickert H. Betatrophin fuels β cell proliferation: firststep toward regenerative therapy? Cell Metab.2013;18:5-6. [Crossref] [PubMed]

9. Quagliarini F, Wang Y, Kozlitina J, Grishin NV, HydeR, Boerwinkle E, Valenzuela DM, Murphy AJ, CohenJC, Hobbs HH. Atypical angiopoietin-like protein thatregulates ANGPTL3. Proc Natl Acad Sci U S A.2012;109:19751-19756. [Crossref] [PubMed][PMC]

10.Wang Y, Quagliarini F, Gusarova V, Gromada J, Valen-zuela DM, Cohen JC, Hobbs HH. Mice lackingANGPTL8 (Betatrophin) manifest disrupted triglyc-eride metabolism without impaired glucose home-ostasis. Proc Natl Acad Sci U S A. 2013;110:16109-16114. [Crossref] [PubMed] [PMC]

11.Tang T, Li L, Tang J, Li Y, Lin WY, Martin F, Grant D,Solloway M, Parker L, Ye W, Forrest W, Ghilardi N,

Oravecz T, Platt KA, Rice DS, Hansen GM, Abuin A,Eberhart DE, Godowski P, Holt KH, Peterson A,Zambrowicz BP, de Sauvage FJ. A mouse knockoutlibrary for secreted and transmembrane proteins.Nat Biotechnol. 2010;28:749-755. [Crossref][PubMed]

12.Espes D, Lau J, Carlsson PO. Increased circulatinglevels of betatrophin in individuals with long-stand-ing type 1 diabetes. Diabetologia. 2014;57:50-53.[Crossref] [PubMed] [PMC]

13.Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB,Zhang R. Elevated circulating lipasin/betatrophin inhuman type 2 diabetes and obesity. Sci Rep.2014;4:5013. [Crossref] [PubMed] [PMC]

14.Espes D, Martinell M, Carlsson PO. Increased circu-lating betatrophin concentrations in patients withtype 2 diabetes. Int J Endocrinol. 2014;2014:323407. [Crossref] [PubMed] [PMC]

15.Gómez-Ambrosi J, Pascual E, Catalán V, RodríguezA, Ramírez B, Silva C, Gil MJ, Salvador J, FrühbeckG. Circulating betatrophin concentrations are de-creased in human obesity and type 2 diabetes. JClin Endocrinol Metab. 2014;99:E2004-E2009.[Crossref] [PubMed]

16.Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M,Kautzky-Willer A, Stulnig TM, Kiefer FW. Circulatingbetatrophin correlates with atherogenic lipid profilesbut not with glucose and insulin levels in insulin-re-sistant individuals. Diabetologia. 2014;57:1204-1208. [Crossref] [PubMed]

17.Yamada H, Saito T, Aoki A, Asano T, Yoshida M,Ikoma A, Kusaka I, Toyoshima H, Kakei M, IshikawaSE. Circulating betatrophin is elevated in patientswith type 1 and type 2 diabetes. Endocr J.2015;62:417-421. [Crossref] [PubMed]

18.Li S, Liu D, Li L, Li Y, Li Q, An Z, Sun X, Tian H. Cir-culating betatrophin in patients with type 2 dia-betes: a meta-analysis. J Diabetes Res.2016;2016:6194750. [Crossref] [PubMed] [PMC]

19.Hussein RM. Biochemical relationships betweenbone turnover markers and blood glucose in pa-tients with type 2 diabetes mellitus. Diabetes MetabSyndr. 2017;11:S369-372. [Crossref] [PubMed]

20.Cox AR, Barrandon O, Cai EP, Rios JS, Chavez J,Bonnyman CW, Lam CJ, Yi P, Melton DA, KushnerJA. Resolving discrepant findings on ANGPTL8 in β-cell proliferation: a collaborative approach to re-solving the betatrophin controversy. PloS One.2016;11:e0159276. [Crossref] [PubMed] [PMC]

21.Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, WangD, Yang L, Wang J, Mao C, Zhou L, Yuan G. In-creased circulating levels of betatrophin in newly di-agnosed type 2 diabetic patients. Diabetes Care.2014;37:2718-2722. [Crossref] [PubMed]

22.Chen X, Lu P, He W, Zhang J, Liu L, Yang Y, Liu Z, XieJ, Shao S, Du T, Su X, Zhou X, Hu S, Yuan G, ZhangM, Zhang H, Liu L, Wang D, Yu X. Circulatingbetatrophin levels are increased in patients withtype 2 diabetes and associated with insulin resist-ance. J Clin Endocrinol Metab. 2014;100:E96-E100.[Crossref] [PubMed]

23.Erol O, Ellidağ HY, Ayık H, Özel MK, Derbent AU, Yıl-maz N. Evaluation of circulating betatrophin levelsin gestational diabetes mellitus. Gynecol Endocrinol.2015;31:652-656. [Crossref]

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Hussein Turk J Endocrinol MetabCirculating Betatrophin and Diabetes 2019;23:1-7

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24.Ebert T, Kralisch S, Wurst U, Lössner U, Kratzsch J,Blüher M, Stumvoll M, Tönjes A, Fasshauer M. Be-tatrophin levels are increased in women with ges-tational diabetes mellitus compared to healthypregnant controls. Eur J Endocrinol. 2015;173:1-7.[Crossref] [PubMed]

25.Guo K, Lu J, Yu H, Zhao F, Pan P, Zhang L, Chen H,Bao Y, Jia W. Serum betatrophin concentrationsare significantly increased in overweight but not inobese or type 2 diabetic individuals. Obesity (Sil-

ver Spring). 2015;23:793-797. [Crossref] [Pub-Med]

26.Jiao Y, Le Lay J, Yu M, Naji A, Kaestner KH. Elevatedmouse hepatic betatrophin expression does not in-crease human β-cell replication in the transplantsetting. Diabetes. 2014;63:1283-1288. [Crossref][PubMed] [PMC]

27.Hossain P, Kawar B, El Nahas M. Obesity and diabetesin the developing world--a growing challenge. N EnglJ Med. 2007;356:213-215. [Crossref] [PubMed]

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Original ArticleTurk J Endocrinol Metab 2019;23:8-18

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Address for Correspondence: Nizameddin Koca, University of Health Sciences,Bursa Yüksek İhtisas Research and Training Hospital, Department of Internal Medicine, Bursa, Turkey

Phone: +90 224 295 50 00 E-mail: nizameddin.koca@sbu.edu.trReceived: 21/06/2018 Received in revised form: 19/12/2018 Accepted: 08/01/2019 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Physical Activity, Insulin Sensitivity,and Metabolic Control in Type 1 Diabetes Mellitus

Tip 1 Diabetes Mellitusta Fiziksel Aktivite,İnsülin Duyarlılığı ve Metabolik Kontrol

Department of Internal Medicine, University of Health Sciences, Bursa Yüksek İhtisas Research and Training Hospital, Bursa, Turkey*Department of Endocrinology and Metabolism, University of Health Sciences, Bursa Yüksek İhtisas Research and Training Hospital, Bursa, Turkey

IntroductionSedentary lifestyle, lack of exercise, inade-quate diet, and poor treatment compliance

are considered the main causative factorsfor obesity, insulin resistance, and ultimatelyincreased cardiometabolic risk in patients

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Objective: To assess insulin sensitivity and physical acti-vity level (PAL) and their relationship with demographic,clinical, and laboratory parameters in patients with Type 1diabetes mellitus (T1DM).Material and Methods: We evaluated 150 adults withT1DM using the International Physical Activity Questionnaire(IPAQ) to determine PAL and estimated glucose disposalrate (eGDR) for insulin sensitivity. The patients were dividedinto three groups according to PAL [inactive (n=48),moderately active (n=55), and highly active (n=47)] andinto two groups according to eGDR [<8.16 mg·kg–1·min–1

[n=67] and ≥8.16 mg·kg–1·min–1 (n=83)].Results: According to eGDR values, 44.6% of 150 patientswere insulin resistant. Insulin resistant patients were olderand heavier and had higher body mass index, waist cir-cumference, blood pressure, and serum glycemic and lipidparameters than insulin sensitive patients, and hadnephropathy and a family history of DM. No significantdifferences in PAL were found according to insulin sensitivitybetween the groups. According to eGDR values, high-density lipoprotein cholesterol and glomerular filtrationrate were positively correlated. In terms of clinical andmetabolic parameters, except for gender distribution, nodifferences were found among the PAL groups.Conclusion: The prevalence of insulin resistance was highin Turkish adults with T1DM and a meaningful correlationwas evident between eGDR and disease control parameters.PAL assessed by the IPAQ was similar between insulin-re-sistant and insulin-sensitive patients.

Keywords: Type 1 diabetes mellitus; physical activity;insulin sensitivity; metabolic control;estimated glucose disposal rate

Amaç: Tip 1 diabetes mellitus (Tip 1 DM) lu hastalarda in-sülin duyarlılığı ve fiziksel aktivite düzeyi (PAL) ile bunlarındemografik, klinik ve laboratuvar parametreleri ile ilişkisinideğerlendirmektedir.Gereç ve Yöntemler: PAL ve insülin duyarlılığı için tahminiglukoz atılım oranı (eGDR) nı belirlemek amacıyla Uluslar-arası Fiziksel Aktivite Anketi (IPAQ) kullanılarak 150 erişkinTip 1 DM'li hasta değerlendirildi. Hastalar PAL’ye göre 3gruba [inaktif (n=48), orta derecede aktif (n=55) ve yüksekderecede aktif (n=47)] ve eGDR'ye göre iki gruba [<8.16mg·kg–1·min–1 (n=67) ve ≥8.16 mg·kg–1·min–1 (n=83)] ay-rıldı.Bulgular: eGDR değerlerine göre, 150 hastanın %44,6'sıinsülin dirençli idi. İnsülin dirençli hastalar; daha yaşlıve kiloluydu, insülin duyarlı hastalardan daha yüksekbeden kitle indeksi, bel çevresi, kan basıncı ve serum gli-semik ve lipit parametrelerine sahipti ve diyabet aile öy-küsü ve nefropatileri mevcuttu. Gruplar arasında insülinduyarlılığına göre PAL'de anlamlı farklılık bulunmadı. eGDRdeğerlerine göre; yüksek yoğunluklu lipoprotein, koleste-rol ve glomerüler filtrasyon hızı ile pozitif korelasyon ol-duğu gösterildi. Klinik ve metabolik parametreler açısın-dan cinsiyet dağılımı dışında PAL grupları arasında fark bu-lunamadı.Sonuç: Tip 1 DM'li Türk erişkinlerde, insülin direnci preva-lansı yüksek idi ve eGDR ile hastalık kontrol parametreleriarasında anlamlı bir ilişki olduğu görüldü. IPAQ ile değer-lendirilen PAL’nin insülin dirençli ve insülin duyarlı hastalardabenzer olduğu gözlendi.

Anahtar kelimeler: Tip 1 diabetes mellitus; fiziksel aktivite;insülin duyarlılığı; metabolik kontrol;tahmini glukoz atılım oranı

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with type 1 diabetes mellitus (T1DM) (1-3).Most patients with T1DM are characterizedby varying degrees of insulin resistance,which is characterized by limited stimulationof glucose metabolism in muscles and theliver. Approximately 30-50% reduction in in-sulin-mediated glucose uptake has beendemonstrated in such patients (4-8). Someinsulin-dependent patients may have phe-notypic features that are associated withtype 2 DM. The term “double diabetes” hasbeen used to describe such patients. Thesepatients are more prone to developmacrovascular and microvascular complica-tions. They have a higher incidence ofmorbidity and mortality rates than insulin-sensitive and lean patients (4).Regular physical activity has several benefitssuch as a decrease in cardiovascular risk andmortality and better quality of life. Physicalexercise may act as a powerful stimulus forhomeostasis, and physical exercise distrib-utes the energy balance and enhances pe-ripheral insulin sensitivity (9-13). Hormonaland metabolic responses to exercise dependon the intensity, duration, and individualtraining status. Skeletal muscles are not sim-ply a movement organ, but also an endocrineorgan producing and releasing numerousmyokines, growth factors, and metallopepti-dases in response to contraction (14). Se-creted myokines can influence metabolism.Muscle contraction increases glucose uptakeby itself and results in the recruitment of glu-cose transporters to the cell membrane inde-pendent of insulin (14-20).In our daily practice, the number of uncon-trolled diabetic patients is quite high despitethe intensive insulin treatment and close fol-low-up. In this study, we assess the reasonsthat could lead to this situation. We hypoth-esized that daily physical activity affects in-sulin resistance and required insulin dose inT1DM. In this study, we aimed to investigatethe relationship between calculated insulinresistance and exercise questionnaire withdemographic, clinical features and labora-tory results in patients with poorly controlleddiabetes.

Material and MethodsThis is a cross-sectional, single-center studyamong Turkish patients with T1DM being fol-lowed in a tertiary hospital. The study was

conducted between March 2014 and March2015, following the Ethics Committee ap-proval from the University of Health Sci-ences, Bursa Yuksek Ihtisas Training &Research Hospital (formerly Sevket YilmazTraining & Research Hospital).During the study period, 185 patients withT1DM were screened and 35 of them wereexcluded because they did not meet the in-clusion criteria or because of lack of sufficientdata. In total, 150 outpatient clinic patientsbetween 18 and 65 years of age, capable ofphysical exercise and having a diagnosis ofT1DM with a minimum duration of one yearwere included after providing written in-formed consent. T1DM was diagnosed withpatients’ clinical and laboratory evaluationsaccording to the American Diabetes Associa-tion criteria (21). Prior weight loss, sympto-matic acute hyperglycemia, the presence ofinitial ketosis, and permanent requirement ofinsulin treatment after six months of diagno-sis were accepted as clinical criteria. Lowc-peptide and insulin levels despite concomi-tant hyperglycemia and positive serumauto-antibodies were used as laboratory cri-teria. Estimated Glucose Disposal Rate(eGDR), which can be calculated by usingroutine clinical measures such as waist cir-cumference (WC) or waist-to-hip ratio, gly-cosylated hemoglobin (HbA1c) levels, andpresence of hypertension, was derived tomeasure insulin resistance. As an insulin sen-sitivity index, eGDR is well correlated withthe results obtained from a euglycemichyper-insulinemic clamp study which is thegold standard for the measurement of insulinsensitivity in patients with T1DM. In an eGDRvalidation study, the clamp-measured glucosedisposal rate was 3.8-13.4 mg·kg-1·min-1,with a range of ~9-11 mg·kg-1·min-1 in thosewith normal IR (22) and it should be empha-sized that lower eGDR levels indicate greaterinsulin resistance (23-26).International physical activity questionnaire(IPAQ), which is generally accepted survey,using a simplified questionnaire to assessthe physical activity level (PAL). It is vali-dated for different societies and an instru-ment designed primarily for adult populationsurveillance. Also, it has been shown thatthis test is appropriate and reliable foryoung Turkish population similar to ourstudy population (27, 28).

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Patients with severe retinopathy, end-stagerenal disease, established cardiovasculardiseases, and physical disability were ex-cluded to reduce the disease-related exer-cise intolerance bias. In addition, patientswith a history of taking medications thatmight affect glucose metabolism and insulinsensitivity were excluded.Body weight (kg) and height (cm) weremeasured in suitable conditions. Body massindex (BMI) was calculated as weight di-vided by height in meters squared (kg·m-2).WC was measured at the midpoint betweenthe lowest rib and the anterior iliac. Bloodpressure (BP) was measured in a seated po-sition using an automated BP monitor. Indi-viduals using antihypertensive medicationsand/or those with a systolic BP (SBP) of≥140 mmHg and/or diastolic BP (DBP) ≥90mmHg were considered hypertensive.T1DM duration, educational level, maritalstatus, family history of DM, and daily usedinsulin dose (U/day) were obtained from theclinical history.

Assessments of physical activityFreely available (www.ipaq.ki.se) short formof the IPAQ (26, 27) was employed for deter-mining PAL. The short form of the IPAQ asksabout the frequency (days/week) and dura-tion (min/day) of walking, moderate intensityactivities, and vigorous intensity activities. Ametabolic equivalent-min (MET-min) is com-puted by multiplying the MET score by theminutes of an activity. An average MET scorewas derived for each type of activity:■ Walking MET-min/week= 3.3×duration×frequency■ Moderate MET-min/week= 4.0×duration×frequency■ Vigorous MET-min/week= 8.0×duration×frequency■ Total Physical Activity= Walking+Moderate+ Vigorous MET-min/weekAccording to their PAL, patients were dividedas follows: inactive (n=48) (<600MET-min/week), moderately active (n=55) (601-3000 MET-min/week), and highly active(n=47) (>3000 MET-min/week).

Insulin sensitivityThe eGDR was calculated as follows:21.158+(-0.009×WC)+(-3.407×HTN)+(-0.51×HbA1c),

HTN indicates hypertension and is expressedas 0 (no) or 1 (yes or still on antihyperten-sive medications). Patients were divided ac-cording to their eGDR values using 8.16mg·kg-1·min-1 as the cutoff level as previ-ously described by Chillaron et al. (28), whofound a strong correlation between thiseGDR value and all types of diabetes-relatedcomplications. Patients with eGDR values<8.16 mg·kg-1·min-1 (n=67) were recog-nized as insulin resistant, whereas patientswith eGDR values ≥8.16 mg·kg-1·min-1

(n=83) were recognized as insulin sensitive.

Laboratory methodsBlood samples were analyzed for fastingplasma glucose (FPG), blood urea nitrogen(BUN), creatinine, aspartate aminotrans-ferase (AST), alanine aminotransferase(ALT), total cholesterol, high-densitylipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and triglyc-erides (TGs) using an autoanalyzer (AbbottAeroset System; Abbott Laboratories, Ab-bott Park, IL, USA). LDL-C levels in patientswith TG values <400 mg/dL were calculatedusing the Friedewald formula:LDL-C=total cholesterol-[(TG/5)-HDL-C]HbA1c levels were measured using high-performance liquid chromatography (HPLC;Bio-Rad Diagnostic Group, Hercules, CA,USA), and 24-hour urine albumin excretionwas measured by a chemiluminescence im-munoassay (Immulite 2500 analyzer;Siemens, Los Angeles, CA, USA).The solid-phase enzyme-linked immunosor-bent assay method was used with a HighSensitivity CRP Enzyme Immunoassay (DRGInternational Inc., Mountainside, NJ, USA)for measuring high-sensitivity C-reactiveprotein (h-CRP). The measurable range was<0.1-10 mg/L, and intra- and interassay co-efficients of variation were 2.5% and 2.3%,respectively.

Statistical analysisStatistical analyses were performed usingthe IBM-Statistical Package for the SocialSciences version 21.0 (SPSS Inc., Chicago,IL, USA). The Shapiro-Wilk test was used todetermine the normality of data. Compar-isons between groups were performed usingAnalysis of variance for normally distributedvariables, and the Mann-Whitney and

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Kruskal-Wallis tests for non-normal vari-ables. The Mann-Whitney U test was used tocompare means and medians of continuousvariables, and Pearson’s c2 test was used forcomparing proportions of insulin resistancebetween or among categorical variables (orFisher’s exact test for 2×2 tables when c2

test assumptions were not satisfied). Inde-pendent samples t-tests were used for com-paring insulin-resistant and non-insulin-resistant subjects with respect to discrete orcontinuous variables. Spearman’s correla-tion coefficient was used to evaluate the cor-relation between eGDR and PAL and clinicalfindings, laboratory parameters, and familyhistory of any types of DM. Continuous vari-ables are expressed as the mean ±standarddeviation or median (minimum-maximum),as appropriate; categorical variables are ex-pressed as frequencies (n,%). The signifi-cance level was considered as p<0.05.

ResultsDuring the study period, a total of 185patients with T1DM were screened and 35patients were excluded. Of the 150 partici-pants, 85 were women and 65 were men.Mean disease duration was 10.7±6.9 years.All the patients were literate and approxi-mately two-thirds of patients had a high edu-cational degree. Sixty-two percent of thepatients were married. Furthermore, 75(50%) patients did not have a family historyof DM, 21 (14%) had T1DM, and 54 (36%)had a family history of type 2 diabetes melli-tus (T2DM). Mean FPG was 229.1±120.6mg/dL and HbA1c was 9.3%±2.3% which in-dicated uncontrolled diabetic disease. Bodymeasurements reflected a lean body structure,mean weight was 65.1±10.5 kg, WC was67.6±10.8 cm, and BMI was 23.8±4.1 kg·m-2.Mean eGDR was 8.22±2.09 mg·kg-1·min-1 thatis higher than our cut-off value of 8.16mg·kg-1·min-1 for describing insulin sensitiv-ity. All the participants, except 22 patientswho were using an insulin pump, were re-ceiving intensive subcutaneous insulin ther-apy. Demographic, clinical, and somelaboratory data are listed in Table 1.On the basis of eGDR values, patients weredivided as insulin resistant and insulin sensi-tive. Gender distribution and mean diseaseduration were similar in both groups, but pa-tients in the insulin-resistant group were

older and had higher blood pressure (SBPand DBP) than patients in the insulin-sensi-tive group. Body weight, BMI, and WC werealso significantly higher in insulin-resistantpatients and strongly reflected insulin resist-ance (p<0.001). Although the mean totaldose of insulin used was higher in the insulin-resistant group than in the insulin-sensitivegroup, the difference was insignificant(p=0.809). Patients in the insulin-resistantgroup had higher FPG and HbA1c levels com-pared with patients in the insulin-sensitivegroup (p>0.001). Serum AST (p=0.580) andALT (p=0.512) levels were similar in bothgroups. The kidney function of insulin-resis-tant patients was worse than that of insulin-sensitive patients (Table 2). The mean totalcholesterol, LDL cholesterol, and TGs were

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Parameter Data (n=150)

Age (years) 31.07±8.83

Women/men, n 85/65

Disease duration (years) 10.7±6.9

Educational level, n (%)

Elementary school 47 (31.3%)

High school 62 (41.3%)

University 41 (27.3%)

Family history of DM, n (%)

None 75 (50%)

T1DM 21 (14%)

T2DM 54 (36%)

Marital status

Unmarried 57 (38%)

Married 93 (62%)

Total daily insulin dose (U/day) 55.7±21.5

Body weight (kg) 65.1±10.5

BMI (kg/m2) 23.8±4.1

WC (cm) 87.6±10.8

FPG (mg/dL) 229.1±120.6

HbA1c (%) 9.3±2.3

eGDR (mg∙kg-1•min-1) 8.22±2.09

PAL, n (%)

Low 47 (31.3%)

Moderate 54 (36.1%)

High 49 (32.6%)

Table 1. Patients’ demographic characteristics and cli-nical and laboratory data.

BMI: body mass index; DM: diabetes mellitus; eGDR: estima-ted glucose disposal rate; FPG: fasting plasma glucose; HbA1c:glycosylated hemoglobin; PAL: physical activity level; WC:waist circumference.

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significantly higher and HDL cholesterol wassignificantly lower in the insulin-resistantgroup than in the insulin-sensitive group(p<0.001). Patients in both groups had sim-ilar exercise habits (Table 2).We also divided our patients into threegroups according to their PALs determinedusing the IPAQ survey. The distribution ac-cording to sex was the only significant differ-ence between the groups, with a significantlyhigher proportion of women in the low and

moderately active groups and a higher pro-portion of men in the high activity group.With respect to clinical and metabolic param-eters, there were no significant differencesbetween the groups, except for GFR that wassignificantly different between the low andhighly active groups (p=0.015, Table 3).Although significant positive correlationswere observed among eGDR, AST, HDL cho-lesterol, and GFR, significant negative cor-relations were observed among eGDR, age,

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; BUN: blood urea nitrogen; C: choleste-rol; DBP: diastolic blood pressure; eGDR: estimated glucose disposal rate; FPG: fasting plasma glucose; GFR: glomerular filtrationrate; HbA1c: glycosylated hemoglobin; Hct: hematocrit; HDL: high-density lipoprotein; Hb: hemoglobin; hs-CRP: high-sensitivityC-reactive protein; LDL: low density lipoprotein; PAL; physical activity level; PLT: platelet count; SBP: systolic blood pressure; TG:triglycerides; WBC: white blood cell count; WC: waist circumference. Significant differences are shown in bold.

Low-eGDR group High-eGDR group

(n = 67, 41.9%) (n = 83, 58.1%) p

Women/men 34/33 31/52 0.227

Age (years) 33.2±9.3 29.5±8.1 0.016

Family history of diabetes (n, %) 49 (73.1%) 26 (31.2%) <0.05

Type 1 DM (n, %) 13 (19.4%) 8 (9.6%) <0.01

Type 2 DM (n, %) 36 (53.7%) 18 (21.6%) <0.001

Disease duration (years) 10.37±7.6 10.96±6.4 0.335

Insulin dose (U/day) 61.03±26.3 51.95±16.4 0.809

SBP (mmHg) 118.5±18.7 106.9±12.9 <0.001

DBP (mmHg) 75.6±12.3 70.0±9.15 0.007

Body weight (kg) 69.9±10.5 61.5±9.1 <0.001

BMI (kg/m2) 25.6±4.0 22.5±3.6 <0.001

WC (cm) 93.9±9.3 83.0±9.5 <0.001

FPG (mg/dL) 274.6±125.4 196.2±106.2 <0.001

HbA1c (%) 10.9±2.46 8.17±1.3 <0.001

AST (U/L) 21.4±13.5 19.4±10.3 0.580

ALT (U/L) 20.1±10.8 20.7±11.4 0.512

BUN (mg/dL) 15.1±7.4 11.69±3.5 0.002

Creatinine (mg/dL) 0.87±0.34 0.77±0.14 0.048

Total C (mg/dL) 212.9±50.6 181.5±45.8 <0.001

HDL-C (mg/dL) 50.9±13.2 61.5±15.1 <0.001

LDL-C (mg/dL) 125.5±35.0 99.1±34.8 <0.001

TG (mg/dL) 179.7±117.5 100.8±71.6 <0.001

hs-CRP (mg/dL) 5.05±3.7 5.3±6.7 0.017

Microalbuminuria (mg/24 h) 186.2±560.1 98.4±340.7 0.014

GFR (mL∙min-1∙1.73 m-2) 93.0±24.3 104.0±20.1 0.008

eGDR (mg∙kg-1∙min-1) 6.35±1.77 9.59±0.91 <0.001

PAL, n

Low (n) 22 25 0.875

Moderate (n) 24 30 0.874

High (n) 21 28 0.609

Table 2. Demographic and metabolic characteristics according to eGDR.

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disease duration, insulin dose, SBP, DBP,body weight, WC, FPG, HbA1c, total choles-terol, LDL cholesterol, and TGs. There wereno significant correlations among eGDR, ALT,BUN, creatinine, h-CRP, and microalbumin-uria. Regarding PAL, we found a positivecorrelation only between PAL and GFR and anegative correlation between PAL and FPG.Correlation analyses among eGDR, PAL, andmetabolic and clinical parameters are shownin Table 4.

DiscussionIn T1DM, insulin production by the b-cells di-minishes long before the clinical onset of hy-perglycemia, and this process is marked bythe loss of pulsatile secretion and the first-phase insulin response to intravenous glu-

cose. Decreased insulin efficiency results inprogressive glucose intolerance and reducedinsulin sensitivity by the time they are diag-nosed with overt diabetes (29-32). The totaldaily insulin dose reflects insulin sensitivity,and, clinically, insulin resistance in patientswith T1DM is often recognized by high insulinrequirements. It is difficult to recognizewhether insulin dose is normal and until nowthere are no age- and gender-specific nor-mative data on daily insulin doses. Althoughthe relationship between insulin dose and in-sulin resistance has been shown in previousstudies (33-35), it was not so obvious in ourstudy. Despite the higher insulin level ob-served in the insulin-resistant group, the dif-ference was not significant (61.03±26.3U/day vs. 51.95±16.4 U/day, p=0.809).

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; BUN: blood urea nitrogen; C: choleste-rol; DBP: diastolic blood pressure; eGDR: estimated glucose disposal rate; FPG: fasting plasma glucose; GFR: glomerular filtrationrate; HbA1c: glycosylated hemoglobin; Hct: hematocrit; HDL: high-density lipoprotein; Hb: hemoglobin; hs-CRP: high-sensitivityC-reactive protein; LDL: low density lipoprotein; PAL; physical activity level; PLT: platelet count; SBP: systolic blood pressure; TG:triglycerides; WBC: white blood cell count; WC: waist circumference.

Low-activity group Moderate-activity group High-activity group

(n=47) (n=54) (n=49) p

Women/men 32/15 35/19 21/28 0.026

Age (years) 30.7±8.2 31.2±9.0 31.1±9.2 0.972

Disease duration (years) 10.7±6.4 11.3±7.7 10.0±6.6 0.689

Insulin dose (U/day) 52.23±21.5 58.35±22.5 50.6±20.5 0.192

SBP (mmHg) 114.85±17.9 108.85±15.6 112.6±16.2 0.537

DBP (mmHg) 72.05±11.17 72.15±10.55 73.15±11.3 0.882

Body weight (kg) 65.34±10.7 65.85±11.01 64.09±10.1 0.207

BMI (kg/m2) 24.4±3.9 24.1±4.8 23.0±3.2 0.256

WC (cm) 89.3±10.9 88.2±12.0 85.3±9.0 0.269

FPG (mg/dL) 251.1±140.2 237.0±115.1 198.6±100.9 0.150

HbA1c (%) 9.69±2.90 9.16±1.82 9.18±2.26 0.934

AST (U/L) 21.5±14.3 20.3±10.0 19.0±10.6 0.636

ALT (U/L) 19.64±9.5 20.5±13.8 20.1± 19.2 0.887

BUN (mg/dL) 13.2±7.3 13.1±5.1 13.0±4.6 0.382

Creatinine (mg/dL) 0.87±0.38 0.79±0.16 0.79±0.13 0.831

Total C (mg/dL) 188.5±47.0 193.7±45.9 202.6±57.5 0.601

HDL-C (mg/dL) 54.8±16.1 58.6±16.1 57.4±13.2 0.470

LDL-C (mg/dL) 104.1±33.3 110.8±35.7 115.4±41.9 0.456

TG (mg/dL) 144.1±121.8 123.4±88.7 137.0±92.6 0.767

hs-CRP (mg/dL) 5.81±6.98 4.96±4.81 4.93±5.27 0.394

Microalbuminuria (mg/24 h) 260.8±107 54.2±170.1 111.7±400 0.632

GFR (mL∙min-1∙1.73 m-2) 93.7±27.2 98.2±21.2 106.1±17.1 0.590

eGDR (mg∙kg-1∙min-1) 7.71±2.59 8.52±1.49 8.31±2.10 0.530

Table 3. Demographic and metabolic characteristics according to PAL.

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Calculation of eGDR as an insulin sensitivityindex is practical, and the results correlatewell with the results obtained from glucoseclamp studies. eGDR has first described inPittsburgh epidemiological studies, and alow eGDR reflects a high resistance to in-sulin (23, 26, 33-35). Kilpatrick et al. (9)showed that patients with the highest in-sulin resistance at their baseline visit havemore microvascular and macrovascularcomplication development risk independ-ently of their assigned treatment group.Several studies have investigated insulinsensitivity according to eGDR and its differ-

ent cut-off values in patients with T1DM(36-41). Similar to the determination of op-timal HbA1c levels, Chillarón et al. (28) de-termined 8.16 mg·kg-1·min-1 as a cut-off valuefor developing microvascular complications.They found that patients with microvascularcomplications had quite low levels of eGDRsuch as 5.97±1.2 mg/kg-1.min-1 for diabeticretinopathy, 5.06±0.4 mg/kg-1.min-1 for dia-betic neuropathy and 5.79±1.5 mg/kg-1.min-1

for diabetic nephropathy. Because of thecross-sectional nature of our study, we useda single cut-off point to establish differentgroups. Despite the single cut-off point, there

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; BUN: blood urea nitrogen; C: choleste-rol; DBP: diastolic blood pressure; eGDR: estimated glucose disposal rate; FPG: fasting plasma glucose; GFR: glomerular filtrationrate; HbA1c: glycosylated hemoglobin; Hct: hematocrit; HDL: high-density lipoprotein; Hb: hemoglobin; hs-CRP: high-sensitivityC-reactive protein; LDL: low density lipoprotein; PAL; physical activity level; PLT: platelet count; SBP: systolic blood pressure; TGs:triglycerides; WBC: white blood cell count; WC: waist circumference.Significant differences are shown in bold.

eGDR PAL

r p value r p value

Women/men 0.074 0.383 -0.207 0.013

Age (years) 0.532 <0.001 -0.144 0.114

Disease duration (years) -0.296 0.001 -0.041 0.626

Educational level 0.229 0.006 -0.022 0.790

Family history of DM -0.244 0.003 0.051 0.547

Marital status -0.207 0.013 -0.011 0.892

Insulin dose (U/day) -0.265 0.001 0.074 0.380

SBP (mmHg) -0.529 <0.001 -0.045 0.598

DBP (mmHg) -0.404 <0.001 -0.041 0.631

Body weight (kg) -0.489 <0.001 -0.048 0.571

BMI (kg/m2) -0.489 <0.001 -0.137 0.105

WC (cm) -0.589 <0.001 -0.147 0.081

FPG (mg/dL) -0.276 0.001 -0.174 0.037

HbA1c (%) -0.663 <0.001 -0.086 0.305

AST (U/L) 0.226 0.007 -0.071 0.402

ALT (U/L) -0.047 0.580 0.016 0.848

BUN (mg/dL) 0.020 0.819 -0.140 0.096

Creatinine (mg/dL) -0.024 0.781 -0.071 0.402

Total C (mg/dL) -0.342 <0.001 0.113 0.184

HDL-C (mg/dL) 0.290 0.001 0.068 0.421

LDL-C (mg/dL) -0.340 <0.001 0.121 0.158

TG (mg/dL) -0.418 <0.001 -0.028 0.741

hs-CRP (mg/dL) -0.067 0.430 -0.620 0.463

Microalbuminuria (mg/24 h) -0.154 0.082 -0.128 0.147

GFR (mL∙min-1∙1.73 m-2) 0.196 0.021 0.221 0.009

eGDR (mg∙kg-1∙min-1) - - 0.103 0.222

Table 4. Correlation analyses between eGDR and PAL and other patient data.

were significantly meaningful correlations be-tween the levels of 8.16 mg·kg-1·min-1 foreGDR and metabolic parameters reflectinginsulin resistance. This is the first suchstudy in a Turkish population and we iden-tified an acceptable eGDR value for describ-ing insulin resistance. Unlike total dailyinsulin dose, the eGDR showed a strongcorrelation with most of the parameters in-vestigated in our study, such as family his-tory of T2DM, longer diabetes duration,older age, poor glycemic control, a greateramount of fat, and increased lipid levels(42-45). As shown in Table 2 and Table 4,insulin-resistant patients were older andhad higher body weight, WC, BMI, SBP,DBP, total cholesterol, LDL-C, TG, FPG,HbA1c, and lower HDL-C than insulin-sensi-tive patients in the present study. Moreover,although the disease duration was similar inboth groups, insulin-resistant patients hadlower GFR and higher Urinary albumin ex-cretion rate (UAER) than patients in the in-sulin-sensitive patients. With respect torenal parameters, our results were similarto those of Bulum et al. (36), where the au-thors found a strong correlation betweeneGDR and the markers of renal function,such as UAER, creatinine level, and creati-nine clearance.Teixeirra et al. (37) used two parameters fordescribing insulin resistance, eGDR and in-sulin sensitivity score (ISS). In addition to amoderate correlation between eGDR and ISS(r=0.612), the authors also found a positivecorrelation between BMI, body fat distribu-tion, waist-to-height ratio, total daily dose ofinsulin, age, diabetes duration, and both for-mulas. As shown in Table 1, our study partic-ipants had acceptable mean body weight,BMI, and WC, reflecting healthy individualsmeasurements, and an eGDR value of8.22±2.09 mg·kg-1·min-1. Mean body weightwas 65.1±10.5 kg, mean BMI was 23.8±4.1kg·m-2, and mean WC was 87.6±10.8 cm.Thus, our patients were lean and insulin sen-sitive according to our cut-off value. How-ever, when patients were grouped accordingto eGDR, patients with low eGDR had higherbody weight (69.9±10.5 vs. 61.5±9.1 kg),BMI (25.6±4.0 vs. 22.5±3.6 kg·m-2), and WC(93.9±9.3 vs. 83.0±9.5 cm) compared withpatients with high eGDR. There were signifi-cant differences between the groups with p-

values <0.001 for all those measurements.These results were similar to those presentedby Teixeirra et al. There were 13 hyperten-sive patients (21.7%) in the low eGDR group,but no hypertensive patients in thehigh eGDR group. Patients with low eGDRhad higher levels of total cholesterol, LDLcholesterol, and TGs but a lower level of HDLcholesterol.In the Pittsburgh Epidemiology of DiabetesComplications Study experience, in patientswith T1DM, Pambianco et al. (38) reportedthat having had more metabolic syndromeparameters initially is associated with devel-oping of more chronic microvascular compli-cation rates. The relation between eGDR andmetabolic syndrome parameters was alsoconsistent in our study and we found astrong correlation between low eGDR andworse metabolic and anthropometric pa-rameters.A family history of T2DM and chronic hyper-glycemia during the clinical phase of T1DMare associated with decreased peripheralglucose uptake and insulin resistance. Thisrelationship has been supported in numer-ous studies (46-50) and this was a promi-nent finding in our study. There was ameaningful correlation between some demo-graphics such as educational level, familyhistory of DM, and marital status. Patientswith a family history of DM had a lowereGDR, reflecting insulin resistance(p=0.003). There was a higher proportion ofpatients with a family history of T2DM in theinsulin-resistant group than in the in-sulin-sensitive group (53.7% [36 of 67] vs.21.6% [18 of 83]). The proportion of pa-tients with a family history of T1DM was19.4% (13 of 67) in the insulin-resistantgroup and 9.6% (8 of 83) in the insulin-sen-sitive group. There were significant differ-ences between the two groups in terms offamily history of DM (p<0.005, for all types).In addition, the proportion of patients whohad high educational levels and who weremarried was higher in the insulin-sensitivegroup (p=0.006, r=0.229 for educationallevel; and p=0.013, r=-0.207 for maritalstatus). We cannot explain these relation-ships as these may have been a coincidence.A high education level and being marriedmay lead to a more regular lifestyle toachieve and sustain better glycemic control.

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Turk J Endocrinol Metab Koca et al.2019;23:8-18 Physical Activity and Insulin Sensitivity in Type 1 DM

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Exercise is one of the important corner-stones of diabetes management. Exercisecan improve body weight control, cardiovas-cular disease risk, and insulin sensitivity. Inaddition, the frequency and severity of com-plications in individuals with T1DM aregreater among those reporting little exercise(10-13, 15, 51-53). From the perspective ofPAL, as assessed using IPAQ, we did not findsuch clear results in our study. We found nocorrelation between PAL and parameters re-flecting good disease control (HbA1c levels,lipid parameters, BP, and anthropometricmeasurements).In diabetic patients, exercise increases theprevalence of hypoglycemia. Hypoglycemiais the most important factor for the physi-cal activity (54). The fear of hypoglycemiaresults in a serious limitation to the inten-sive glycemic control and exercise imple-mentation. In addition, activation ofcounter-regulatory hormones, especiallyduring intense activity, may be another pos-sible explanation (55, 56). A recently pub-lished meta-analysis showed no evidence ofimprovement in HbA1c with exercise (13).Increased calorie intake, insulin dose reduc-tion, and weakness are concluded as thereasons for this finding. In our study, menreported more intense activity than womenand it may be associated with our sociolog-ical structure. Besides a negative correlationwith FPG, there was a positive correlationbetween GFR and PAL, reflecting the physi-ological effects of exercise on glomerular fil-tration. All these results appear complex andsomewhat contradictory, which may be re-lated to our assessment methods. Exercisereduces cardiovascular disease and mortal-ity by improving endothelial function withdecreasing insulin requirement and lipid lev-els and promoting well-being in patientswith T1DM (3). Although we did not observea glycemic benefit in our study, we suggestexercise because of its well-defined benefits.In conclusion, Turkish adults with T1DMhave high insulin resistance prevalence.Older age, high WC, body weight, BMI, BP,lipid levels, glycemic parameters, BUN, cre-atinine, UAER, and low GFR and HDL cho-lesterol were the more common featuresamong T1DM patients with insulin resist-ance. The effects of physical activity werenot consistent with respect to metabolic

control parameters in patients with T1DM inour study population. This consistency per-sisted when analyses were done accordingto eGDR groups.

Learning PointsAccording to the estimated glucose disposalrate, 44.6% of 150 Type 1 DM patients wereinsulin-resistant.Insulin resistant patients were older, heavierand have higher body mass index, waist cir-cumference, blood pressure, serumglycemic and lipid parameters than insulinsensitive patients, and had nephropathy andfamily history of DM.No significant differences were found in thephysical activity level between the insulinsensitive and resistant groups.Prevalence of insulin resistance was high inTurkish type 1 diabetic adults and the mean-ingful correlation was evident between theestimated glucose disposal rate and diseasecontrol parameters.The IPAQ alone was not sufficient to assessthe exercise levels of type 1 diabetic pa-tients.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Nizameddin Koca, MetinGüçlü; Design: Nizameddin Koca, MetinGüçlü; Control/Supervision: Metin Güçlü,Nizameddin Koca; Data Collection and/or Pro-cessing: Nizameddin Koca, İrfan Esen, GamzeEmlek, Sinem Kıyıcı; Analysis and/or Inter-pretation: Metin Güçlü, Nizameddin Koca; Lit-

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Koca et al. Turk J Endocrinol MetabPhysical Activity and Insulin Sensitivity in Type 1 DM 2019;23:8-18

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erature Review: Metin Güçlü, Sinem Kıyıcı;Writing the Article: Metin Güçlü, NizameddinKoca; Critical Review: Metin Güçlü, Nizamed-din Koca; References and Fundings: MetinGüçlü, Nizameddin Koca; Materials: GamzeEmlek, Gürcan Kısakol, İrfan Esen.

References1. Kavookjian J, Elswick BM, Whetsel T. Interventions for

being active among individuals with diabetes: a sys-tematic review of the literature. Diabetes Educ.2007;33:962-988. [Crossref] [PubMed]

2. Peirce NS. Diabetes and exercise. Br J Sports Med.1999;33:161-172. [Crossref] [PubMed] [PMC]

3. Chimen M, Kennedy A, Nirantharakumar K, Pang TT, An-drews R, Narendran P. What are the health benefits ofphysical activity in type 1 diabetes mellitus? A literaturereview. Diabetologia. 2012;55:542-551. [Crossref][PubMed]

4. Kennedy A, Nirantharakumar K, Chimen M, Pang TT,Hemming K, Andrews RC, Narendran P. Does exerciseimprove glycaemic control in type 1 diabetes? A sys-tematic review and meta-analysis. PLoS One.2013;8:e58861. [Crossref] [PubMed] [PMC]

5. Wadén J, Forsblom C, Thorn LM, Saraheimo M, Rosen-gård-Bärlund M, Heikkilä O, Lakka TA, Tikkanen H,Groop PH; FinnDiane Study Group. Physical activity anddiabetes complications in patients with type 1 diabetes:the Finnish Diabetic Nephropathy (FinnDiane) Study. Di-abetes Care. 2008;31:230-232. [Crossref] [PubMed]

6. Ramalho AC, de Lourdes Lima M, Nunes F, Cambuí Z,Barbosa C, Andrade A, Viana A, Martins M, Abrantes V,Aragão C, Temístocles M. The effect of resistance versusaerobic training on metabolic control in patients withtype-1 diabetes mellitus. Diabetes Res Clin Pract.2006;72:271-276. [Crossref] [PubMed]

7. Durak EP, Jovanovic-Peterson L, Peterson CM. Random-ized crossover study of effect of resistance training onglycemic control, muscular strength, and cholesterol intype I diabetic men. Diabetes Care. 1990;13:1039-1043. [Crossref] [PubMed]

8. Duzova H. Skeletal muscle, myokines and health. Med-icine Science. 2012;1:211-231. [Crossref]

9. Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, themetabolic syndrome, and complication risk in type 1 di-abetes: "double diabetes" in the diabetes control andcomplications trial. Diabetes Care. 2007;30:707-712.[Crossref] [PubMed]

10. DeFronzo RA, Hendler R, Simonson D. Insulin resistanceis a prominent feature of insulin-dependent diabetes.Diabetes. 1982;31:795-801. [Crossref] [PubMed]

11. Vuorinen-Markkola H, Koivisto VA, Yki-Jarvinen H. Mech-anisms of hyperglycemia-induced insulin resistance inwhole body and skeletal muscle of type I diabetic pa-tients. Diabetes. 1992;41:571-580. [Crossref] [PubMed]

12. Yki-Järvinen H, Koivisto VA. Natural course of insulin re-sistance in type I diabetes. N Engl J Med.1986;315:224-230. [Crossref] [PubMed]

13. DeFronzo RA, Tobin JD, Andres R. Glucose clamptechnique: a method for quantifying insulin secretionand resistance. Am J Physiol. 1979;237:E214-223.[PubMed]

14. Leroux C, Gingras V, Desjardins K, Brazeau AS, Ott-Braschi S, Strychar I, Rabasa-Lhoret R. In adult patientswith type 1 diabetes healthy lifestyle associates with a

better cardiometabolic profile. Nutr Metab CardiovascDis. 2015;25:444-451. [Crossref] [PubMed]

15. DeFronzo RA, Simonson D, Ferrannini E. Hepatic andperipheral insulin resistance: a common feature of type2 (non-insulin-dependent) and type 1 (insulin-depen-dent) diabetes mellitus. Diabetologia. 1982;23:313-319. [Crossref] [PubMed]

16. Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY,Smithline Kinder L, Ellis D, Becker DJ. Insulin resist-ance-related factors, but not glycemia, predict coronaryartery disease in type 1 diabetes: 10-year follow-updata from the Pittsburgh Epidemiology of Diabetes Com-plications Study. Diabetes Care. 2003;26:1374-1379.[Crossref] [PubMed]

17. Del Prato S, Nosadini R, Tiengo A, Tessari P, Avogaro A,Trevisan R, Valerio A, Muggeo M, Cobelli C, Toffolo G.Insulin-mediated glucose disposal in type I diabetes:evidence for insulin resistance. J Clin Endocrinol Metab.1983;57:904-910. [Crossref] [PubMed]

18. Nijs HGT, Radder JK, Frölich M, Krans HMJ. The courseand determinants of insulin action in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1989;32.[Crossref]

19. Wadén J, Tikkanen H, Forsblom C, Fagerudd J, Petters-son-Fernholm K, Lakka T, Riska M, Groop PH; FinnDianeStudy Group. Leisure time physical activity is associatedwith poor glycemic control in type 1 diabetic women:the FinnDiane study. Diabetes Care. 2005;28:777-782.[Crossref] [PubMed]

20. Franc S, Dardari D, Biedzinski M, Requeda E, Canipel L,Hochberg G, Boucherie B, Charpentier G. Type 1 dia-betes: dealing with physical activity. Diabetes Metab.2012;38:466-469. [Crossref] [PubMed]

21. American Diabetes Association. 2. Classification and Di-agnosis of Diabetes: Standards of Medical Care in Dia-betes-2018. Diabetes Care. 2017;41:S13-S27.

22. Karaca A, Ergen E, Koruc Z. The reliability and the validityof the physical activity assessment questionnaire (PAAO).Hacettepe Journal of Sport Sciences. 2000;11:17-28.

23. Pedersen BK. Muscular interleukin-6 and its role as anenergy sensor. Med Sci Sports Exerc. 2012;44:392-396.[Crossref] [PubMed]

24. Ploug T, Galbo H, Richter EA. Increased muscle glucoseuptake during contractions: no need for insulin. Am JPhysiol. 1984;247:E726-731. [PubMed]

25. Peltoniemi P, Yki-Järvinen H, Oikonen V, Oksanen A,Takala TO, Rönnemaa T, Erkinjuntti M, Knuuti MJ, Nuu-tila P. Resistance to exercise-induced increase in glucoseuptake during hyperinsulinemia in insulin-resistantskeletal muscle of patients with type 1 diabetes. Dia-betes. 2001;50:1371-1377. [Crossref] [PubMed]

26. Craig CL, Marshall AL, Sjöström M, Bauman AE, BoothML, Ainsworth BE, Pratt M, Ekelund U, Yngve A, SallisJF, Oja P. International physical activity questionnaire:12-country reliability and validity. Med Sci Sports Exerc.2003;35:1381-1395. [Crossref] [PubMed]

27. The International Physical Activity Questionnaire (IPAQ).[Link]

28. Chillarón JJ, Goday A, Flores-Le-Roux JA, Benaiges D,Carrera MJ, Puig J, Cano-Pérez JF, Pedro-Botet J. Esti-mated glucose disposal rate in assessment of the meta-bolic syndrome and microvascular complications inpatients with type 1 diabetes. J Clin Endocrinol Metab.2009;94:3530-3534. [Crossref] [PubMed]

29. Mäkimattila S, Virkamäki A, Malmström R, Utriainen T, Yki-Jarvinen H. Insulin resistance in type I diabetes mellitus: amajor role for reduced glucose extraction. J Clin EndocrinolMetab. 1996;81:707-712. [Crossref] [PubMed]

17

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17

18

Koca et al. Turk J Endocrinol MetabPhysical Activity and Insulin Sensitivity in Type 1 DM 2019;23:8-18

18

30. Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR.Insulin resistance in type 1 diabetes: what is 'double di-abetes' and what are the risks? Diabetologia.2013;56:1462-1470. [Crossref] [PubMed] [PMC]

31. Greenbaum CJ. Insulin resistance in type 1 diabetes. Di-abetes Metab Res Rev. 2002;18:192-200. [Crossref][PubMed]

32. Gray RS, Cowan P, Duncan LJ, Clarke BF. Reversal of in-sulin resistance in type 1 diabetes following initiation ofinsulin treatment. Diabetic Medicine. 1986;3:18-23.[Crossref] [PubMed]

33. Araszkiewicz A, Uruska A, Zozulinska-Ziolkiewicz D, Pi-lacinski S, Wierusz-Wysocka B. Factors related to insulinresistance in type 1 diabetic patients treated with in-tensive insulin therapy from the onset of the disease.Diabetes Res Clin Pract. 2010;90:e23-24. [Crossref][PubMed]

34. Wiegand S, Raile K, Reinehr T, Hofer S, Näke A, Rabl W,Holl RW. Daily insulin requirement of children and ado-lescents with type 1 diabetes: effect of age, gender,body mass index and mode of therapy. Eur J Endocrinol.2008;158:543-549. [Crossref] [PubMed]

35. Muis MJ, Bots ML, Bilo HJ, Hoogma RP, Hoekstra JB,Grobbee DE, Stolk RP. Determinants of daily insulin usein Type 1 diabetes. J Diabetes Complications.2006;20:356-360. [Crossref] [PubMed]

36. Bulum T, Duvnjak L. Insulin resistance in patients withtype 1 diabetes: relationship with metabolic and in-flammatory parameters. Acta Clin Croat. 2013;52:43-51. [PubMed]

37. Teixeira MM, Diniz Mde F, Reis JS, Ferrari TC, de CastroMG, Teixeira BP, Arantes IC, Bicalho DM, Foscolo RB. In-sulin resistance and associated factors in patients withType 1 Diabetes. Diabetol Metab Syndr. 2014;6:131.[Crossref] [PubMed] [PMC]

38. Pambianco G, Costacou T, Orchard TJ. The prediction ofmajor outcomes of type 1 diabetes: a 12-year prospec-tive evaluation of three separate definitions of the meta-bolic syndrome and their components and estimatedglucose disposal rate: the Pittsburgh Epidemiology ofDiabetes Complications Study experience. DiabetesCare. 2007;30:1248-1254. [Crossref] [PubMed]

39. Danielson KK, Drum ML, Estrada CL, Lipton RB. Racialand ethnic differences in an estimated measure of in-sulin resistance among individuals with type 1 diabetes.Diabetes Care. 2010;33:614-619. [Crossref] [PubMed][PMC]

40. Palomo Atance E, Ballester Herrera MJ, Giralt Muiña P,Ruiz Cano R, León Martín A, Giralt Muina J. [Estimatedglucose disposal rate in patients under 18 years of agewith type 1 diabetes mellitus and overweight or obe-sity]. Endocrinol Nutr. 2013;60:379-385. [Crossref][PubMed]

41. Epstein EJ, Osman JL, Cohen HW, Rajpathak SN, LewisO, Crandall JP. Use of the estimated glucose disposalrate as a measure of insulin resistance in an urban mul-tiethnic population with type 1 diabetes. Diabetes Care.2013;36:2280-2285. [Crossref] [PubMed] [PMC]

42. Thorn LM, Forsblom C, Fagerudd J, Thomas MC, Pet-tersson-Fernholm K, Saraheimo M, Wadén J, RönnbackM, Rosengård-Bärlund M, Björkesten CG, Taskinen MR,Groop PH; FinnDiane Study Group. Metabolic syndromein type 1 diabetes: association with diabetic nephropa-thy and glycemic control (the FinnDiane study). Dia-betes Care. 2005;28:2019-2024. [Crossref]

43. Greenfield JR, Samaras K, Chisholm DJ. Insulin resist-ance, intra-abdominal fat, cardiovascular risk factors,

and androgens in healthy young women with type 1diabetes mellitus. J Clin Endocrinol Metab. 2002;87:1036-1040. [Crossref] [PubMed]

44. Caravaca F, Cerezo I, Macías R, García de Vinuesa E,Martínez del Viejo C, Villa J, Martínez Gallardo R, Fer-reira F, Hernández-Gallego R. [Insulin resistance inchronic kidney disease: its clinical characteristics andprognosis significance]. Nefrologia. 2010;30:661-668.[PubMed]

45. Nadeau KJ, Regensteiner JG, Bauer TA, Brown MS,Dorosz JL, Hull A, Zeitler P, Draznin B, Reusch JE. In-sulin resistance in adolescents with type 1 diabetes andits relationship to cardiovascular function. J Clin En-docrinol Metab. 2010;95:513-521. [Crossref] [PubMed][PMC]

46. Roglic G, Colhoun HM, Stevens LK, Lemkes HH, ManesC, Fuller JH. Parental history of hypertension andparental history of diabetes and microvascular compli-cations in insulin-dependent diabetes mellitus: the EU-RODIAB IDDM Complications Study. Diabet Med.1998;15:418-426. [Crossref]

47. Erbey JR, Kuller LH, Becker DJ, Orchard TJ. The associ-ation between a family history of type 2 diabetes andcoronary artery disease in a type 1 diabetes population.Diabetes Care. 1998;21:610-614. [Crossref] [PubMed]

48. Purnell JQ, Dev RK, Steffes MW, Cleary PA, Palmer JP,Hirsch IB, Hokanson JE, Brunzell JD. Relationship offamily history of type 2 diabetes, hypoglycemia, andautoantibodies to weight gain and lipids with intensiveand conventional therapy in the Diabetes Control andComplications Trial. Diabetes. 2003;52:2623-2629.[Crossref] [PubMed] [PMC]

49. Hadjadj S, Péan F, Gallois Y, Passa P, Aubert R, WeekersL, Rigalleau V, Bauduceau B, Bekherraz A, Roussel R,Dussol B, Rodier M, Marechaud R, Lefebvre PJ, Marre M;Genesis France-Belgium Study. Different patterns of in-sulin resistance in relatives of type 1 diabetic patientswith retinopathy or nephropathy: the Genesis France-Belgium Study. Diabetes Care. 2004;27:2661-2668.[Crossref] [PubMed]

50. Ghosh S, Collier A, Hair M, Malik I, Elhadd T. Metabolicsyndrome in type 1 diabetes. Int J Diabetes Mellit.2010;2:38-42. [Crossref]

51. Gulve EA. Exercise and glycemic control in diabetes: ben-efits, challenges, and adjustments to pharmacotherapy.Phys Ther. 2008;88:1297-1321. [Crossref] [PubMed]

52. Hayashi T, Wojtaszewski JF, Goodyear LJ. Exercise reg-ulation of glucose transport in skeletal muscle. Am JPhysiol. 1997;273:E1039-1051. [PubMed]

53. Kriketos AD, Gan SK, Poynten AM, Furler SM, ChisholmDJ, Campbell LV. Exercise increases adiponectin levelsand insulin sensitivity in humans. Diabetes Care.2004;27:629-630. [Crossref] [PubMed]

54. Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H.Barriers to physical activity among patients with type 1diabetes. Diabetes Care. 2008;31:2108-2109. [Cros-sref] [PubMed] [PMC]

55. Sandoval DA, Guy DL, Richardson MA, Ertl AC, DavisSN. Effects of low and moderate antecedent exercise oncounterregulatory responses to subsequent hypo-glycemia in type 1 diabetes. Diabetes. 2004;53:1798-1806. [Crossref] [PubMed]

56. Davey RJ, Howe W, Paramalingam N, Ferreira LD, DavisEA, Fournier PA, Jones TW. The effect of midday mod-erate-intensity exercise on postexercise hypoglycemiarisk in individuals with type 1 diabetes. J Clin EndocrinolMetab. 2013;98:2908-2914. [Crossref] [PubMed]

Address for Correspondence: Bushra Mubarak, University Institute of Medical Laboratory Technology,The University of Lahore, Lahore, Pakistan

Phone: 00923224118145 E-mail: Bushra.mubarik@yahoo.comReceived: 31/10/2018 Received in revised form: 20/12/2018 Accepted: 29/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Determination of Serum Thyroid Hormonesand Electrolytes in Hypothyroid and

Hyperthyroid Females-A Case Control Studyin Lahore, Pakistan

Hipotiroid ve Hipertiroid Kadınlarda Serum Tiroid Hormonları veElektrolitlerinin Belirlenmesi-Lahor, Pakistan'da

Bir Vaka Kontrol Çalışması

University Institute of Medical Laboratory Technology, The University of Lahore, Lahore, Pakistan

Original ResearchTurk J Endocrinol Metab 2019;23:19-24

IntroductionThyroid hormones are essential for bodytemperature regulation, hemodynamics,

metabolic functions, protein synthesis, andmaintenance of electrolyte balance (1,2).About 3-10% of the population, globally, are

DO

I:10

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79/t

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Objective: This study aimed to determine the correlationbetween serum electrolytes and TSH in patients with hy-pothyroidism and hyperthyroidism.Material and Methods: A total of 160 (80 hypothyroid and80 hyperthyroid) patients and 80 age and gender matchedcontrols were enrolled in this study, which was performedbetween September 2017-February 2018. Of the venousblood, 3 mL was collected from each study participant, formeasurement of thyroid hormones (T3, T4, and TSH) andelectrolytes (Na, K and Ca).Results: Serum calcium was observed to be significantlyhigh in hyperthyroid patients as compared to their controls.Serum sodium and potassium levels were not found to dif-fer significantly among hyperthyroid and hypothyroid pa-tients compared to that in their controls. Patients withhyperthyroidism showed significant negative correlation ofTSH with calcium and a non-significant positive correlationwith sodium and potassium. The correlation of TSH with cal-cium was positive while that with potassium and sodiumwas negative in hypothyroid patients, though this co-rela-tion was statistically non-significant.Conclusion: This study found high serum calcium levels inhyperthyroid patients. A significantly negative correlationwas found between TSH and calcium level in hyperthy-roidism.

Keywords: Hyperthyroidism; hypothyroidism; thyroxine;calcium; potassium

Amaç: Bu çalışmada, hipotiroidi ve hipertiroidi hastalarındaserum elektrolitleri ve TSH arasındaki korelasyonun belir-lenmesi amaçlanmıştır.Gereç ve Yöntemler: Eylül 2017-Şubat 2018 tarihleri ara-sında yapılan bu çalışmaya, toplam 160 (80 hipotiroidi ve80 hipertiroidi) hasta ile yaş ve cinsiyeti eşleştirilmiş 80kontrol dâhil edildi. Tiroid hormonlarının (T3, T4 ve TSH) veelektrolitlerinin (Na, K ve Ca) ölçümü için her bir katılımcı-dan 3 mL venöz kan alındı.Bulgular: Hipertiroidili hastalarda serum kalsiyumun kont-rollerine göre anlamlı derecede yüksek olduğu gözlendi.Serum sodyum ve potasyum düzeylerinin, hipertiroidi vehipotiroidi hastaları arasında kontrollerine göre anlamlı de-recede farklı olmadığı bulundu. Hipertiroidi hastalarındaTSH ile kalsiyum arasında anlamlı negatif korelasyon, sod-yum ve potasyum ile anlamlı olmayan pozitif korelasyonsaptandı. Hipotiroidi hastalarında TSH’nin kalsiyum ile ko-relasyonu pozitif, potasyum ve sodyum ile korelasyonu ne-gatif idi ama bu korelasyonlar istatistiksel olarak anlamlıdeğildi.Sonuç: Bu çalışmada, hipertiroidili hastalarda serum kalsi-yum seviyelerinin yüksek olduğu bulundu. HipertiroidizmdeTSH ile kalsiyum düzeyi arasında anlamlı bir negatif kore-lasyon olduğu görüldü.

Anahtar kelimeler: Hipertiroidi; hipotiroidi; tiroksin;kalsiyum; potasyum

19

affected by hypothyroidism; the rate ofprevalence is higher in females (3,4,13). InPakistan, the frequency of hypothyroidism is2% higher than that of hypothyroidism (5).Thyroid diseases are among the most com-mon health problems in northern Pakistan,with the frequency being higher in the fe-males (5.1%) than in males (6).Electrolytes play an essential role in manyfunctions of the body like control of fluidlevel, pH balance, and blood coagulation.Electrolyte balance is very important fornormal functioning of cells and organs in thehuman body (7). Sodium (Na), calcium(Ca), and potassium (K) are the commonelectrolytes analyzed in blood (8,9).Thyroid hormones affect the structure, de-velopment, and hemodynamics of kidney,along with the GFR, the transport along thenephron, as well as Na and water homeosta-sis, though renal failure may lead to thyroiddisorders (10). Hypothyroidism decreasesthe renal size and weight, tubule length, anddiameter and to some level, glomerular vol-ume (11). Conversely, in patients with hy-perthyroidism, renal to body weight ratiosraise to as high as 30% (12). Although theexact mechanism of changes in the kidney isunknown, there is evidence of direct activa-tion of the renin-angiotensin-aldosteronesystem by thyroid hormones (2). Thyroidhormones directly elevate serum Ca andphosphorus (P) levels by stimulating boneresorption. Low levels of thyroid hormone inhypothyroidism lead to hypocalcemia (13).Increased renal water retention, mediatedby vasopressin, is an adverse effect of hy-pothyroidism (14). The activity of Na-Kpump is also regulated by thyroid hormonesin most of the tissues (2). Renal dysfunctionand electrolyte imbalance may be associatedwith thyroid disorders (15,16).Begic-Karup et al.(17) observed an increasein serum Ca in subjects with hyperthy-roidism. Thyroid dysfunction results in in-creased levels of phosphate and calcium(18). Hypothyroidism forms one of the rea-sons for decreased Na levels. Assessment ofpatients with hyponatremia requires themeasurement of Thyroid Stimulating Hor-mone (TSH) (19). On the other side, hy-pokalemia is observed in patients withthyrotoxicosis (20). Although the associationbetween thyroid hormones and kidney func-

tions is well established, but the relationshipbetween thyroid hormones and electrolyteshas not been widely studied in the Pakistanipopulation. Therefore, this study was de-signed to determine the serum Ca, Na, andK levels and to correlate the levels of theseelectrolytes with TSH in patients with hy-pothyroidism and hyperthyroidism.

Material and MethodsThis is a case-control study conducted in theDepartment of Chemical Pathology in JinnahHospital, Lahore between September 2017and February 2018. One hundred and sixtyfemale patients (80 hypothyroid and 80 hy-perthyroid) attending the outpatient depart-ment of Jinnah Hospital and 80 apparentlyhealthy females from same population act-ing as controls, were enrolled in this study.The clinical history of participants wasrecorded on a structured questionnaire. Thestudy was done in accordance with the“Principles of the Helsinki Declaration”. Eth-ical approval from the Institutional ReviewBoard (IRB Faculty of Allied Health Sciences,University of Lahore) was taken on 16th Au-gust, 2017 (Approval number: IRB-UOL-FAHS/266-IA).

Selection CriteriaSubjects between 18-60 years of age, re-cently diagnosed with hypothyroidism (TSH>5.6 mIU/mL, T3 <2.5 pg/mL and T4 <0.61ng/dL) and hyperthyroidism (TSH <0.3mIU/mL, T3 >3.9 pg/mL and T4 >1.12ng/dL) were included in this study as patients.Patients with subclinical thyroid disorder;kidney, liver and bone diseases; diabetesmellitus; children; and subjects who wereon medication or mineral supplements thatmight change the levels of serum elec-trolyte, were excluded from the study.

Sample CollectionAfter obtaining written informed consent, 3mL of blood samples was collected from thecubital vein and stored in a gel vacutainer.After clotting, the vial was centrifuged at3000 revolutions per min (rpm) for 10-15min at 25 °C. Serum T3, T4, and TSH levelswere analyzed by enzyme-linked im-munosorbent assay (ELISA) technique.Serum levels of Na, K, and Ca were meas-ured by RANDOX manufacturer kit (Antrim,

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Northern Ireland) using chemistry analyzerstrip reader (huma Reader H) from Ger-many.

Data AnalysisResults were presented as mean±SD forquantitative variables. One way ANOVA wasapplied to find the difference of mean inquantitative variables between cases (hy-pothyroid and hyperthyroid) and controls.Tukey’s post-hoc test was used to confirmwhere the difference existed betweengroups. All correlation data were analyzedby spearman correlation test using statisti-cal software SPSS Version 25. A p-value ofless than 0.05 was considered statisticallysignificant.

ResultsThe mean age of the studied subjects was40.02±11.3 years. The mean age of hy-pothyroid, hyperthyroid cases, and controlswere 38.13±10.6, 40.53±12.1 and41.37±10.9 years, respectively. There wasno statistically significant age difference be-tween the cases and controls (p>0.05).

Thyroid and electrolyte profile in cases andhealthy controlsThe mean level of TSH in healthy controls,hyperthyroid, and hypothyroid patients was2.54±1.6, 0.32±0.6, and 6.67±0.9 mIU/l,respectively. Serum T3 levels were found tobe 3.05±0.4, 5.11±1.1, and 1.85±0.5pg/mL in the controls, hyperthyroid, and hy-pothyroid patients, respectively. Mean T4levels were 0.90±0.1, 2.08±0.7 and0.49±0.1 ng/dL in controls, hyperthyroid,and hypothyroid patients, respectively.Among the measured electrolytes, the Naand K levels in serum were observed to benon-significantly different among hypothy-roid, hyperthyroid, and control subjects(p>0.05) (Figure 1). There was a statisti-

cally significant difference between themean Ca levels among the groups(p=0.004). Tukey‘s post-hoc test revealedthat the mean Ca was statistically signifi-cantly higher in hyperthyroid (8.90±1.4mg/dL) patients as compared to that in thehypothyroid patients (8.22±1.6 mg/dLp=0.015) and healthy controls (8.18±1.6mg/dL p=0.009). There was no statisticallysignificant difference between the hypothy-roid and control groups (p=0.983). The re-sults are summarized in Table 1 and Figure2.

Correlation of TSH with electrolyte profilein hypothyroid and hyperthyroid patientsTSH levels in patients were studied in rela-tion to serum Ca, Na, and K levels. A statis-tically significant negative relationship wasfound between serum Ca and TSH levels(r=-0.185, p<0.05) although a non-signifi-cant positive correlation was seen betweenTSH and the levels of Na (r=0.017) and K(r=0.143, p>0.05) in hyperthyroid patients.Serum TSH and Ca levels showed a non-sig-nificant positive correlation in hypothyroidpatients (r=0.047, p>0.05). A negative butnon-significant correlation was found be-tween serum TSH and Na (r=-0.143), and Klevels (r=-0.119, p>0.05).

Turk J Endocrinol Metab Mubarak et al.2019;23:19-24 Thyroid Hormones and Electrolytes During Thyroid Dysfunction

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Parameters Hypothyroid (n=80) Controls (n=80) Hyperthyroid (n=80) p-value

Age (years) 38.13±10.6 41.37±10.9 40.54±12.1 0.17

Calcium (Ca) mg/dL 8.22±1.6 8.18±1.6 8.90±1.4 0.004

Sodium (Na) mmol/l 143.32±8.9 143.11±9.0 142.38±8.8 0.78

Potassium (K) mmol/l 4.15±0.8 4.19±0.8 4.21±0.7 0.87

Table 1. Comparison of age and electrolyte profile between the cases and controls (n=240).

Figure 1: Comparison of electrolyte profile in hyperthy-roid, hypothyroid patients and controls.

DiscussionThis case control study was designed to in-vestigate the association between thyroidand serum electrolyte levels in patients withhypothyroidism and hyperthyroid and theircontrols. Thyroid diseases are one of themost common health problems in Pakistan,with higher frequency in females as com-pared to that in males (19). The correlationbetween thyroid disorder and electrolyte im-balance has been revealed in different stud-ies. In the present study, serum Ca wasfound to be high in hypothyroid patients, ascompared to the control group, although thedifference was not significant. Serum Na andK levels were not statistically different be-tween hypothyroid patients and control sub-jects. These findings were similar to thoseof Abebe et al. (21) (2016) wherein the Caand K levels were not different between thehypothyroid patients and control.This study was, however, in contrast to thestudies carried out by Amrut (22) in 2016and Arvind et al. (7) in 2015, where de-creased levels of Na, K, and Ca were re-ported in hypothyroid cases as compared tothat in the controls. Jaskiran et al. (23) 2014and Murgod et al. (8) 2012 reported signifi-cantly decreased Ca and Na levels in hy-pothyroid patients which were in contrast tothe present study; however, K levels werenot statistically different between hypothy-roid patients and controls in Jaskiran studywhich was in accordance with findings of thecurrent study.The authors of the present study also corre-lated serum levels of Ca, Na, and K withTSH. In the case of hypothyroidism, serumNa and K levels were found to be negatively

correlated while Ca level was observed to bepositively linked with TSH, though the cor-relation was not statistically significant.These results are supported by those ofArvind et al. (7) (2015) who reported thatTSH and serum electrolytes are not statisti-cally correlated. Similarly, Alaeldin et al.(24) documented a significant positive cor-relation between TSH and Ca in hypothyroidpatients. Murgod et al. (8) showed a signif-icant negative correlation between TSH,serum Na, K and Ca in hypothyroid patients.The present study is also in concordancewith research done by Amrut (22) and Ku-mara et al. (25) who demonstrated a non-significant correlation between electrolytelevels and TSH.This research revealed a significant highserum Ca level in hyperthyroid patients,though there were non-significant differ-ences in Na and K levels between the hy-perthyroid patients and controls. Theresults of the present study are differentfrom the findings of Abebe (21) (2016) andArvind el al. (7) (2015) where Ca level wasnon-significantly different and Na level wassignificantly different between the patientand controls. The results of studies byAbebe et al. (21) and Arvind et al. (7) arealso in accordance with that of the presentstudy in terms of K that was not statisti-cally significantly different between hyper-thyroid and control groups. Kumara et al.(25) reported that there was no associa-tion between Na with hyperthyroidism.Schwarz et al. (20) documented similarfinding for Ca but contrasting results for Naand K.A significant negative correlation was foundbetween serum levels of TSH and Ca in hy-perthyroid patients in this study. This findingis in agreement with that of Jasim et al. (26)in 2015. Kumara et al. (25) documented anon-significant correlation of TSH with K inhyperthyroidism, which is in agreement withthe present study.

ConclusionThis study demonstrated the significant ef-fect of thyroid hormones on the levels ofserum Ca in hyperthyroid patients. Thepresent study indicated increased levels ofserum Ca and Na, but low levels of serum Kin patients with hypothyroidism as com-

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Figure 2: Mean calcium level in cases (hypothyroid andhyperthyroid) and controls.

pared to that in the controls, although thedifference was not statistically significant.The present study also demonstrates a sig-nificant increase in Ca and a non-significantdecrease in Na level in hyperthyroid pa-tients. A significant negative correlation hasbeen observed between TSH and Ca in hy-perthyroid patients.

Study limitationsDue to financial and time constraint, thepower of the study is weak. Owing to thesmall sample size of this study, it may notbe suitable to mention that the variations inCa levels are appropriate to influence pa-tient condition.

RecommendationsFurther studies with a sample size largerthan this study are required to concludewhether regular measurement of serumelectrolytes can improve the symptoms ofpatients with thyroid disorders.

Data AvailabilityThe data used to support the findingsof this study can be sent by the correspon-ding author (Ms. Bushra Mubarak:Bushra.mubarik@yahoo.com) on request tothe reviewers and researchers who wish toreproduce the results.

Ethical ConsiderationsEthical clearance from the Institutional Ethicalreview committee was obtained. The studyobjectives are explained to all study subjects.Informed consent was received from all studyparticipants before venipuncture.

AcknowledgementWe are thankful to the University Instituteof Medical Laboratory Department, the Uni-versity of Lahore for being helpful and sup-portive and express our deepest gratitude toProf. Dr. Nazar Ullah Raja (Head of Depart-ment of University Institute of Medical LabTechnology) and Dr. Kashaf Junaid.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor from

a company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the au-thors and / or family members of the sci-entific and medical committee members ormembers of the potential conflicts of inter-est, counseling, expertise, working condi-tions, share holding and similar situationsin any firm.

Authorship ContributionsIdea/Concept: Sohail Ashraf, BushraMubarak; Design: Bushra Mubarak; Con-trol/Supervision: Bushra Mubarak; Data Col-lection and/or Processing: Sohail Ashraf,Raheela Aslam; Analysis and/or Interpreta-tion: Bushra Mubarak; Literature Review:Raheela Aslam; Writing the Article: RaheelaAslam; Critical Review: Bushra Mubarak;References and Fundings: Bushra Mubarak,Sohail Ashraf; Materials: Sohail Ashraf.

References1. Mohamedali M, Maddika SR, Vyas A, Iyer V, Cheriyath

P. Thyroid disorders and chronic kidney disease. Int JNephrol. 2014; 2014:1-6. [Crossref] [PubMed] [PMC]

2. Mariani LH, Berns JS. The renal manifestations ofthyroid disease. J Am Soc Nephrol. 2012;23:22-26. [Crossref] [PubMed]

3. Hall JE, Guyton AC. Guyton and Hall textbook ofmedical physiology. 12th ed. Philadelphia, PA: Saun-ders Elsevier; 2011. p.917.

4. Fatourechi V. Subclinical hypothyroidism: an updatefor primary care physicians. Mayo Clin Proc.2009;84:65-71. [Crossref] [PubMed] [PMC]

5. Attaullah S, Haq BS, Muska M. Thyroid dysfunctionin Khyber Pakhtunkhwa, Pakistan. Pak J Med Sci.2016;32:111-115. [PubMed] [PMC]

6. Yousaf M, Shah J, Jan MR. Frequency of thyroid dys-functions in general population of Ppeshawar cityand its association with serum alanine transaminaselevel. Isra Med J. 2017;9:84-87.

7. Arvind B, Shrestha S, Rai R, Kumar MS. Assessmentof serum minerals and electrolytes in thyroid pa-tients. IJASR. 2015;1:259-263.

8. Murgod R, Soans G. Changes in electrolyte and lipidprofile in hypothyroidism. Int J Life Sci Pharma Res.2012;2:185-194.

9. Filippatos TD, Liamis G, Christopoulou F, Elisaf MS.Ten common pitfalls in the evaluation of patientswith hyponatremia. Eur J Intern Med. 2016;29:22-25. [Crossref] [PubMed]

10. Basu G, Mohapatra A. Interaction between thyroid dis-order and kidney disease. Indian J Endocrinol Metab.2012;16:204-213. [Crossref] [PubMed] [PMC]

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Turk J Endocrinol Metab Mubarak et al.2019;23:19-24 Thyroid Hormones and Electrolytes During Thyroid Dysfunction

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11.Bradley SE, Coelho JB, Sealey JE, Edwards KD,Stéphan F. Changes in glomerulotubular dimen-sions, single nephron glomerular filtration rates andthe renin-angiotensin system in hypothyroid rats.Life Sci. 1982;30:633-639. [Crossref]

12.Wang W, Li C, Summer SN, Falk S, Schrier RW.Polyuria of thyrotoxicosis: downregulation of aqua-porin water channels and increased solute excre-tion. Kidney Int. 2007;72:1088-1094. [Crossref][PubMed]

13.Auwerx J, Bouillon R. Mineral and bone metabolismin thyroid disease. Q J Med. 1986;60:737-752.[PubMed]

14.Iwasaki Y, Oiso Y, Yamauchi K, Takatsuki K, KondoK, Hasegawa H, Tomita A. Osmoregulation ofplasma vasopressin in myxedema. J Clin EndocrinolMetab. 1990;70:534-539. [Crossref] [PubMed]

15.Iglesias P, Díez JJ. Thyroid dysfunction and kidneydisease. Eur Soc Endocrinol. 2009;160:503-515. [Crossref] [PubMed]

16.Hajji R, Derbali F, Mnafgui K, Zaribi S, Elleuch M,Kammoun N, Jallali Z. A transient protein urea-anunusual complication of hypothyroidism. Am J Med.2014;2:237-239.

17.Begic-Karup S, Wagner B, Raber W, Schneider B,Hamwi A, Waldhäusl W, Vierhapper H. Serum cal-cium in thyroid disease. Wien Klin Wochenschr.2012;113:65-68.

18.Vanderpump MP. The epidemiology of thyroiddisease. Br Med Bull. 2011;99:39-51. [Crossref][PubMed]

19.Al-Tonsi AA, Abdel-Gayoum AA, Saad M. The sec-ondary dyslipedemia and deranged serum phos-

phate concentration in thyroid disorders. Exp MolPathol. 2004;76:182-187. [Crossref] [PubMed]

20.Schwarz C, Leichtle AB, Arampatzis S, Fiedler GM,Zimmermann H, Exadaktlyos AK, Lindner G. Thy-roid function and serum electrolytes: does an asso-ciation really exist? Swiss Med Wkly. 2012;142:36-69. [Crossref]

21.Abebe N, Kebede T, Wolde M. Assessment of renalfunction and electrolytes in patients with thyroiddysfunction in Addis Ababa, Ethiopia: a crosssectional study. Pan Afr Med J. 2016;24:338.[Crossref] [PubMed] [PMC]

22.Dambal AA, Sidrah SD, Challa AS, Padaki SK.Serum calcium and electrolytes in hypothyroidism-a case control study. IJCMR. 2016;3:704-706.

23.Jaskiran K, Ahmad N, Gupta A. Changes in the elec-trolyte profile of patients having hypothyroidism.JMSCR. 2014;2:633-637.

24.AlaEldin SA, Haala MG, Amna OM, Elzein NM, AShrifE, Hassan, E. Assessment of serum levels of calciumand phosphorous in Sudanese patients with hy-pothyroidism. Asian J Biomed Pharm Sci. 2013;3:21-26.

25.Kumara H, Krishna M, Vishwanath HI. The elec-trolytes imbalance between hypothyroidism and hy-perthyroidism. Inter Jour of Cur Res. 2016;8:31031-31033.

26.Jasim AA, Abdulkalek H, Haider S, Aamer A. Studyof the relationship between calcium ion and thyroidhormones, liver enzymes in some patients ofhypocalcaemia and hypercalcaemia. J Contemp MedSci. 2015;1:27-30.

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Address for Correspondence: Bilal Natiq Nuaman, Al-Iraqia University-Medical College, IraqiaPhone: 009647702594485 E-mail: bilalnatiq@gmail.com

Received: 15/10/2018 Received in revised form: 26/11/2018 Accepted: 27/11/2018 Available online: 20/03/2019

®Copyright 2018 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Migraine is Strongly Associated withCentral Obesity Than with General Obesity:

A Case-Control StudyMigren Genel Obeziteden Daha Fazla ve Güçlü Şekilde

Santral Obezite ile İlişkilidir: Bir Vaka-Kontrol Çalışması

Al-Iraqia University-Medical College, Iraqia*Al-Nuaman Teaching Hospital,Iraqia

Original ArticleTurk J Endocrinol Metab 2019;23:25-32

IntroductionA migraine is a common disorder that man-ifests as recurrent episodes of a headacheaccompanied by features of sensitivity tolight, sound, and/or nausea, and has a life-time prevalence of 13-33% (1). Although amigraine is the second common cause of aheadache after a tension headache, it is the

most common form of a headache that pres-ents to physicians as it is more severe thana tension headache (2). About 67% of pa-tients with a migraine consult primary carephysicians, and only 16% of them consult aneurologist (3). Although presentations of atension headache and migraine are compa-rable, clinical features specific to a migraine

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Objective: Obesity and migraine are common diseasesworldwide, but their association is not confirmed. If an as-sociation is proved, weight loss can be made a managementobjective of a migraine. To assess the risk of migraines inIraqi patients with general obesity and central obesity.Material and Methods: A case-control, hospital-basedstudy was conducted at Al-Nuaman Teaching Hospital,Baghdad, Iraq from February 2017-September 2017. Onehundred-forty Iraqi patients were enrolled, including 50 pa-tients with migraines and 90 controls without any migraine.General obesity and central obesity were assessed by exa-mining the body mass index and waist-to-height ratio, res-pectively.Results: There is a significant association between migrainesand general obesity and between migraines and central obesity(p<0.001, Odds ratio: general obesity 6.8, central obesity12.2).Conclusion: The risk of migraines in patients with centralobesity is double the risk in patients with general obesity.

Keywords: Central obesity; general obesity; migraine;case-control study; logistic regression

Amaç: Obezite ve migren dünya çapında yaygın hastalık-lardır, ancak birliktelikleri doğrulanmamıştır. Eğer birlikte-likleri kanıtlanırsa, kilo kaybı migren yönetiminde hedefhâline gelebilmektedir. Bu çalışmada, genel ve santralobezitesi olan Irak’lı hastalarda migren riskinin değerlen-dirilmesi amaçlanmıştır.Gereç ve Yöntemler: Şubat 2017-Eylül 2017 arasında,Al-Nuaman Eğitim Hastanesinde (Bağdat, Irak) vaka-kont-rolü, hastane-tabanlı bir çalışma yürütülmüştür. Çalış-maya, 50’si migrenli, 90’ı migrensiz olan (kontrol) 140Irak’lı hasta dahil edilmiştir. Genel ve santral obezite sıra-sıyla beden kitle indeksi ve bel-boy oranı incelenerek de-ğerlendirilmiştir.Bulgular: Migren ile genel ve santral obezite arasında an-lamlı bir ilişki bulunmaktadır (p<0,001, Odds oranı: genelobezite 6,8, santral obezite 12,2).Sonuç: Santral obezitesi olan hastalarda migren riskiningenel obezitesi olan hastalardan iki kat fazla olduğu bu-lunmuştur.

Anahtar kelimeler: Santral obezite; genel obezite; migren;vaka-kontrol çalışması; lojistik regresyon

25

than to a tension headache include photo-phobia, phonophobia, nausea, food triggers,and lack of physical activity (4-6).Many explanations have been proposed inthe pathophysiology of a migraine, includingdietary disorder, low physical activity, inflam-mation, and hypothalamic disorder (7-9).These possible mechanisms also contributeto the pathogenesis of obesity. Some evi-dence shows that obesity may promotecharacteristics of migraine episodes (10-12), but not a tension headache (13, 14).Obesity can be classified as general obesity,measured by body mass index (BMI), andcentral obesity, measured by many parame-ters, and the best of these is termed as awaist-to-height ratio (WtHR) (15).Many studies have evaluated the associationbetween obesity and migraine; most ofthem were cross-sectional studies that couldnot document cause and effect. To the bestof our knowledge, there are limited case-control studies investigating such an associ-ation, at least in Iraq. Therefore, thiscase-control study aimed to assess the as-sociation between parameters of obesity andthe risk of a migraine, and to evaluatewhether a migraine is strongly associatedwith central obesity or general obesity.

Material and MethodsThe study was done in accordance with the“Principles of the Helsinki Declaration” andthe ethics committee's approval is taken forthe study.

Study DesignA case-control study was conducted and ap-proved by the Internal Medicine and Neurol-ogy Departments of Iraqia Medical Collegeand AL-Nuaman Teaching Hospital.

CasesAll patients complaining from (undiagnosed)a headache or a migraine who visited med-ical and neurological outpatient departmentsof AL-Nuaman Teaching Hospital from Feb-ruary 2017 to September 2017 were eligiblefor enrollment. Magnetic Resonance Imag-ing of the brain was performed for selectedcases to exclude secondary causes. Overall,50 patients with a migraine were included.Informed consent has been obtained fromthe patients.

Inclusion CriteriaSimplified diagnostic criteria for a migrainewere adapted from the InternationalHeadache Society Classification. These cri-teria include repeated episodes of aheadache persisting for 4-72 hs in otherwisenormal patients, plus two or more of thefollowing features: moderate-severe inten-sity, pulsating pain, one-sided pain, and ex-acerbation by motion, plus one of thefollowing features: photophobia, phonopho-bia, and nausea (16).

Exclusion CriteriaAny features indicating a life-threatening ill-ness, including:1-Onset after age 55 years; 2-Considerablefever, vomiting, or weight loss; 3-Importantpast medical history (malignancy or tuber-culosis); and 4-Abnormal neurologic exami-nation (including fundoscopic examination)(17). Additionally, pregnant women were ex-cluded.

ControlsOutpatients in addition to the medical andnon-medical staff of AL-Nuaman TeachingHospital with no history of a migraine orchronic diseases were randomly chosen ascontrols, and the same patient exclusion cri-teria were applied. Overall, 90 controls wereincluded.Patients and controls were categorized ac-cording to age as follows: <25, 25-35, 35-45, and 45-55 years.All patients and controls supplied informedpermission for participation in the study.

Anthropometric MeasurementsWeight (in kg), height (in m or cm), andwaist circumference (WC, in cm) weremeasured for patients and controls. Generalobesity assessed by calculating BMI throughdividing weight by height (in m2). A cutoffpoint of 30 was used to determine generalobesity, which was defined as having BMI≥30 kg/m2. Central obesity determined bycalculating WtHR by dividing WC by height.A WHtR cutoff point of 0.5 was used for as-sessing central obesity, which was definedas having WHtR >0.5.

Statistical AnalysisData were analyzed using SPSS version

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* significant association.

(patients) Migraine (% of total) (control) No migraine (% of total) P Value

Gender .128

Male 15.7% 35.7%

Female 20% 28.6%

Age .715

<25 4.3% 5.7%

25 - 35 11.4% 25.7%

35 - 45 12.1% 22.1%

45 - 55 7.9% 10.7%

BMI categories .000*

<30 20.9% 58.6%

>30 15% 5.7%

WHtR categories .000*

<0.5 10% 53.6%

>0.5 25.7% 10.7%

Table 1. Basic characteristics of patients and controls.

20.0. Cross-tabulation analysis (Pearson‘sand Chi square) was performed to evaluatethe association between obesity (generaland central) and migraine. A logistic regres-sion was accomplished to establish the ef-fects of general obesity and central obesityon the possibility to have a migraine. Exp(B) and 95 % confidence intervals (95%CIs) were calculated to establish whethermigraine is strongly associated with generalobesity or central obesity. A P value of <0.05was indicated as the level of significance.

Results

Study PopulationAfter the exclusion criteria were applied, 40patients were excluded (75% of them werewomen) and a total of 50 patients (with amigraine) were enrolled along with 90 per-sons (without a migraine).The mean (±standard deviation) age of participants was35.8±8.8 years, and 51.4% of participantswere men. Of the 50 patients, 28 werewomen (56%) and 22 were men (44%), andthe male-to-female ratio was 1:1.3. About75% of women with a migraine were be-tween 25 and 45 years of age, while 63% ofmen with migraine were between 35 and 55years of age. No significant gender-specificand age-specific differences were observedbetween patients and controls (P=0.128 and

P=0.715, respectively). Characteristics ofpatients and controls are shown in Table 1.Characteristics of patients with a migraineare shown in Table 2. About two-thirds ofpersons with central obesity had a non-obese pattern of BMI, and less than one-sixth of patients with general obesity had aWtHR <0.5 (Figure 1).

Association Between Obesity and MigraineThe frequency of general obesity in patientswith a migraine was 42%, which was aboutfour times more than that in controls, thus,there is a strong association between amigraine and general obesity (P<0.001)(Figure 2). The frequency of general obesity(BMI>30 kg/m2) in male and female mi-graineurs was 45.4% and 39.3%, respec-tively (P<0.0001)The frequency of central obesity in patientswith migraines was 72%, which was aboutfour times more than that in controls, thus,there is a strong association between amigraine and central obesity (P<0.001)(Figure 2). The frequency of central obesity(WHtR >0.5) in male and female mi-graineurs was 81.8% and 64.3%, respec-tively (P=0.00001).

Odds Ratio for a Migraine in Patients withGeneral Obesity Versus Central Obesity

Patients with general obesity (BMI>30

Turk J Endocrinol Metab Nuaman et al.2019;23:25-32 Obesity is a Risk Factor for Migraine

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kg/m2) were six times more likely to have amigraine than those with BMI <30 (oddsratio [OR] 6.8, 95% CI=2.3, 20) (Table 3).Patients with central obesity (WHtR >0.5)were 12 times more likely to have a mi-

graine than those with WHtR <0.5 (OR12.2, 95% CI=5, 29.8) (Table 3). Therefore,the likelihood of having a migraine was twicemore in patients with central obesity than inpatients with general obesity.

DiscussionA migraine and obesity are chronic prevalentdiseases in the world with undeterminedpathogenesis and associations. This studyrevealed that the frequency of general obe-sity and central obesity in patients with amigraine (42% vs. 72%, respectively) wasmuch higher than the frequency in controls(9% vs. 17%, respectively). Furthermore,the risk of a migraine in patients with gen-eral obesity was six times more than con-trols (OR 6.8, 95% CI 2.3, to 20), while therisk in those with central obesity was 12times more than that in controls (OR 12.2,95% CI=5, 29.8). These data suggest thatobesity is a risk factor for a migraine and itis strongly associated with central obesitythan general obesity. This is the first case-control study at least in Iraq that examinedthe association and risk of a migraine ingeneral obesity versus central obesity usingcategorical variables.The large difference in the frequency of cen-tral obesity between male (82%) and female(64%) migraineurs may be explained bythe fact that central obesity in women, incontrast to adult men, is most pronouncedafter menopause, and most postmenopausalwomen were excluded from the study as weexcluded any patient ≥55 years (18-20).Obesity is associated with many pain-relatedmedical conditions including fibromyalgia(21,22), osteoarthritis (23,24), abdominalpain (25,26), and back pain (27). Severalstudies have proven the association be-tween obesity and headache, including mi-graine. Most of these studies examined theeffects of general obesity on migraine andconfirmed such significant association (28-34) and some of them found that a migraineis only associated with morbid obesity (35-37). However, some studies have revealedno association between a migraine and gen-eral obesity (10,12,38-40), or even showedan association between migraine and beingunderweight (12,41).Limited studies have considered the effectsof central obesity on migraines, except for

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Variable Percentage

General obesity (BMI>30) 42%

Central obesity (WHtR>0.5) 72%

Hypertension 32%

Diabetes mellitus 14%

Smoking 23%

Table 2. Characteristics of patients with migraine.

Figure 1: Distrubition of central obesity among patientswith general obesity.

Figure 2: Frequency of general obesity and central obe-sity among patients and control.

a single category in a study by Lee Peterlinet al. (42), all of these studies confirmed astrong positive association (43-45). Lee Pe-terlin et al. (42), demonstrated a positiveassociation between migraine prevalencewith both general obesity and central obe-sity in men and women ≤55 years, however,in men >55 years there was no significantassociation between a migraine and generalobesity or central obesity, while in women>55 years, migraine was not associated withgeneral obesity but was inversely associatedwith central obesity. Most of these studieswere cross-sectional, which unlike case-con-trol studies, cannot accord a connection be-tween a cause and an effect.Several studies have shown that WHtR is su-perior to other indices of central obesity(28,46,47), as it considers the stature of anindividual. Although Omid Sadeghi (44) wasthe first to use WHtR as an indicator of cen-tral obesity, he did not use it to define cen-tral obesity. In our study, we defined centralobesity as WHtR of ≥0.5.Although Miri et al. (OR 3.06, 95% CI 1.11-8.43) (48), Scher et al. (OR 5.28, 95% CI1.3-21.1) (48), and Peres et al. (P< 0.0001)(30) established a strong positive associa-tion between general obesity and migrainein case-control studies, our study comparedboth general and central types of obesityand demonstrated a significant associationof migraine with both types, but mainly withcentral obesity. Many studies have provedthat central obesity is commonly an impor-tant risk factor of a migraine than generalobesity (31,49,50).The association between obesity and mi-graine can be elucidated by many factors:inflammatory, hypothalamic, life-style-related like lack of exercise, and psycholog-ical comorbidities (51). Adipose tissue,especially visceral adipose tissue, secretemany inflammatory mediators likeadipokines (52), tumor necrosis factor α(53), and calcitonin-related peptide (54,55),which can trigger a migraine, and this may

explain the strong association between cen-tral obesity and migraine than general obe-sity.The hypothalamus is integral in the patho-physiology of obesity and migraine, as hy-pothalamic peptides and neurotransmitters,like serotonin (56), and orixen A (57), playa role in over eating in obese patients, andcan trigger a migraine attack.Furthermore, some evidence suggests thatweight loss can improve symptoms of a mi-graine in obese patients whether behavioralsymptoms or after bariatric surgery (58,59),but the strongest evidence was a Women‘sHealth and Migraine randomized controlledtrial (60).This study had many limitations including asmall sample size, inequality between casesand controls, overweight persons were cat-egorized within the non obese category, andcharacteristics of a migraine were not as-sessed. Further studies are required toprove such an association, which is impor-tant in the management of a migraine.In conclusion, there is a strong associationbetween obesity and migraine and centralobesity is an important risk factor for a mi-graine.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand/or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

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95%C.I.for EXP(B)

B S.E. Wald df Sig. Exp(B) Lower Upper

General obesity 1.9 .55 12.2 1 .000 6.8 2.3 20.0

Central obesity 2.5 .45 30.4 1 .000 12.2 5.0 29.8

Table 3. Odds ratio for migraines in patients with general obesity versus central obesity.

30

Authorship ContributionsIdea/Concept: Bilal Natiq Nuaman, Asaad M.Sadik; Design: Bilal Natiq Nuaman, AsaadM. Sadik; Control/Supervision: Bilal NatiqNuaman, Asaad M.Sadik; Data Collectionand/or Processing: Bilal Natiq Nuaman,Asaad M. Sadik; Analysis and/or Interpreta-tion: Bilal Natiq Nuaman, Asaad M.Sadik;Literature Review: Bilal Natiq Nuaman,Asaad M.Sadik; Writing the Article: BilalNatiq Nuaman, Asaad M.Sadik; Critical Re-view: Bilal Natiq Nuaman; References andFundings: Bilal Natiq Nuaman; Materials:Bilal Natiq Nuaman, Asaad M.Sadik.

References1. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current

understanding and treatment. N Engl J Med.2002;346:257-270. [Crossref] [PubMed]

2. Goadsby PJ. Headache. In: Hankey GJ, Wardlaw JM,Gorelick PB, Testai FD, eds. Hankey’s Clinical Neu-rology (2nd ed). Boca Raton; CRC Press; 2014;139.[Crossref]

3. Lipton RB, Stewart WF, Simon D. Medical consulta-tion for migraine: results from the American Mi-graine Study. Headache. 1998;38:87-96. [Crossref][PubMed]

4. Smetana GW. The diagnostic value of historical fea-tures in primary headache syndromes: a compre-hensive review. Arch Intern Med. 2000;160:2729-2737. [Crossref] [PubMed]

5. Wöber C, Brannath W, Schmidt K, Kapitan M, Rudel E,Wessely P, Wöber-Bingöl C. Prospective analysis of fac-tors related to migraine attacks: The PAMINA study.Cephalalgia. 2007;27:304-314. [Crossref] [PubMed]

6. Spierings EL, Ranke AH, Honkoop PC. Precipitatingand aggravating factors of migraine versus tension-type headache. Headache. 2001;41:554-558.[Crossref] [PubMed]

7. Kelman L. The triggers or precipitants of the acutemigraine attack. Cephalalgia. 2007;27:394-402.[Crossref] [PubMed]

8. Bigal ME, Lipton RB, Holland PR, Goadsby PJ. Obe-sity, migraine, and chronic migraine: possible mech-anisms of interaction. Neurology. 2007;68:1851-1861. [Crossref] [PubMed]

9. Overeem S, van Vliet JA, Lammers GJ, Zitman FG,Swaab DF, Ferrari MD. The hypothalamus in episodicbrain disorders. Lancet Neurol. 2002;1:437-444.[Crossref]

10.Keith SW, Wang C, Fontaine KR, Cowan CD, AllisonDB. BMI and headache among women: results from11 epidemiologic datasets. Obesity (Silver Spring).2008;16:377-383. [Crossref] [PubMed]

11.Vo M, Ainalem A, Qiu C, Peterlin BL, Aurora SK,Williams MA. Body mass index and adult weightgain among reproductive age women with migraine.Headache. 2011;51:559-560. [Crossref] [PubMed]

12.Bigal ME, Liberman JN, Lipton RB. Obesity and mi-graine: a population study. Neurology.2006;66:545-550. [Crossref] [PubMed]

13.Bigal ME, Lipton RB. Obesity is a risk factor fortransformed migraine but not chronic tension-typeheadache. Neurology. 2006;67:252-257. [Crossref][PubMed]

14.Bigal ME, Tsang A, Loder E, Serrano D, Reed ML,Lipton RB. Body mass index and episodicheadaches: a population-based study. Arch InternMed. 2007;167:1964-1970. [Crossref] [PubMed]

15.Ashwell M, Cole TJ, Dixon AK. Ratio of waist cir-cumference to height is strong predictor of intra-ab-dominal fat. BMJ. 1996;313:559-560. [Crossref][PubMed] [PMC]

16.Goadsby PJ. Heasdache. In: Long DL, Kasper DL,Hauser SL, et al, eds. Harrison’s Neurology in Clin-ical Medicine (3rd ed). New York: McGraw-Hill Pub-lishing; 2013;56.

17.Goadsby PJ. Heasdache. In: Long DL, Kasper DL,Hauser SL, et al, eds. Harrison’s Neurology in Clin-ical Medicine (3rd ed): New York: McGraw-Hill Pub-lishing; 2013;52.

18.Kissebah AH, Krakower GR. Regional adiposity andmorbidity. Physiol Rev. 1994;74:761-811. [Cros-sref] [PubMed]

19.Wajchenberg BL, Giannella-Neto D, da Silva ME,Santos RF. Depot-specific hormonal characteristicsof subcutaneous and visceral adipose tissueand their relation to the metabolic syndrome.Horm Metab Res. 2002;34:616-621. [Crossref][PubMed]

20.Dieudonné MN, Leneveu MC, Giudicelli Y, PecqueryR. Evidence for functional estrogen receptors alphaand beta in human adipose cells: regional speci-ficities and regulation by estrogens. Am J PhysiolCell Physiol. 2004;286:C655-C661. [Crossref][PubMed]

21.Elert J, Kendall SA, Larsson B, Månsson B, GerdleB. Chronic pain and difficulty in relaxing posturalmuscles in patients with fibromyalgia and chronicwhiplash associated disorders. J Rheumatol.2001;28:1361-1368. [PubMed]

22.Okifuji A, Bradshaw DH, Olson C. Evaluating obe-sity in fibromyalgia: neuroendocrine biomarkers,symptoms, and functions. Clin Rheumatol.2009;28:475-478. [Crossref] [PubMed] [PMC]

23.Lee S, Kim TN, Kim SH. Sarcopenic obesity is moreclosely associated with knee osteoarthritis than isnonsarcopenic obesity: a cross-sectional study.Arthritis Rheum. 2012;64:3947-3954. [Crossref][PubMed]

24.Lee R, Kean WF. Obesity and knee osteoarthritis. In-flammopharmacology. 2012;20:53-58. [Crossref][PubMed]

25.Eslick GD. Gastrointestinal symptoms and obesity:a meta-analysis. Obes Rev. 2012;13:469-479.[Crossref] [PubMed]

26.Bilal Natiq Nuaman. The association between cen-tral obesity and the risk of irritable bowel syn-drome: a case-control study. American Journal ofMedical Sciences and Medicine. 2017;5:23-26.http://pubs.sciepub.com/ajmsm/5/2/1. [Crossref]

27.Fransen M, Woodward M, Norton R, Coggan C,Dawe M, Sheridan N. Risk factors associated withthe transition from acute to chronic occupationalback pain. Spine (Phila Pa 1976). 2002;27:92-98.[Crossref]

Nuaman et al. Turk J Endocrinol MetabObesity is a Risk Factor for Migraine 2019;23:25-32

30

31

28.Chen BD, Yang YN, Ma YT, Pan S, He CH, Liu F, MaX, Fu ZY, Li XM, Xie X, Zheng YY. Waist-to-heightratio and triglycerides/high-density lipoprotein cho-lesterol were the optimal predictors of metabolicsyndrome in Uighur men and women in Xinjiang,China. Metab Syndr Relat Disord. 2015;13:214-220. [Crossref] [PubMed]

29.Scher AI, Stewart WF, Ricci JA, Lipton RB. Factorsassociated with the onset and remission of chronicdaily headache in a population-based study. Pain.2003;106:81-89. [Crossref]

30.Peres MF, Lerário DD, Garrido AB, Zukerman E.Primary headaches in obese patients. ArqNeuropsiquiatr. 2005;63:931-933. [Crossref][PubMed]

31.Gelber RP, Gaziano JM, Orav EJ, Manson JE, Bur-ing JE, Kurth T. Measures of obesity and cardio-vascular risk among men and women. J Am CollCardiol. 2008;52:605-615. [Crossref] [PubMed][PMC]

32.Hershey AD, Powers SW, Nelson TD, Kabbouche MA,Winner P, Yonker M, Linder SL, Bicknese A, SowelMK, McClintock W. Obesity in the pediatric headachepopulation: a multicenter study. Headache.2009;49:170-177. [Crossref] [PubMed]

33.Kinik ST, Alehan F, Erol I, Kanra AR. Obesity andpaediatric migraine. Cephalalgia. 2010;30:105-109.[Crossref] [PubMed]

34.Pinhas-Hamiel O, Frumin K, Gabis L, Mazor-Aronovich K, Modan-Moses D, Reichman B, Lerner-Geva L. Headaches in overweight childrenand adolescents referred to a tertiary-care center inIsrael. Obesity (Silver Spring). 2008;16:659-663.[Crossref] [PubMed]

35.Horev A, Wirguin I, Lantsberg L, Ifergane G. Ahigh incidence of migraine with aura among mor-bidly obese women. Headache. 2005;45:936-938.[Crossref] [PubMed]

36.Yu S, Liu R, Yang X, Zhao G, Qiao X, Feng J, Fang Y,Cao X, He M, Steiner TJ. Body mass index and mi-graine: a survey of the Chinese adult population. JHeadache Pain. 2012;13:531-536. [Crossref] [Pub-Med] [PMC]

37.Vo M, Ainalem A, Qiu C, Peterlin BL, Aurora SK,Williams MA. Body mass index and adult weightgain among reproductive age women with migraine.Headache. 2011;51:559-569. [Crossref] [PubMed][PMC]

38.Winter AC, Berger K, Buring JE, Kurth T. Body massindex, migraine, migraine frequency and migrainefeatures in women. Cephalalgia. 2009;29:269-278.[Crossref] [PubMed] [PMC]

39.Mattsson P. Migraine headache and obesity inwomen aged 40-74 years: a population-basedstudy. Cephalalgia. 2007;27:877-880. [Crossref][PubMed]

40.Queiroz LP, Peres MF, Piovesan EJ, Kowacs F, CiciarelliMC, Souza JA, Zukerman E. A nationwide population-based study of migraine in Brazil. Cephalalgia.2009;29:642-649. [Crossref] [PubMed]

41.Ford ES, Li C, Pearson WS, Zhao G, Strine TW, Mok-dad AH. Body mass index and headaches: findingsfrom a national sample of US adults. Cephalalgia.2008;28: 1270-1276. [Crossref] [PubMed]

42.Peterlin BL, Rosso AL, Rapoport AM, Scher AI. Obe-sity and migraine: the effect of age, gender and adi-pose tissue distribution. Headache. 2010;50:52-62.[Crossref] [PubMed] [PMC]

43.Rossoni de Oliveira V, Camboim Rockett F, Castro K,da Silveira Perla A, Chaves ML, Schweigert Perry ID.Body mass index, abdominal obesity, body fat andmigraine features in women. Nutr Hosp. 2013;28:1115-1120. [PubMed]

44.Sadeghi O, Askari G, Maghsoudi Z, Ghiasvand R,Khorvash F. The association between abdominalobesity and characteristics of migraine attacks inIranian adults. Iran J Nurs Midwifery Res. 2016;21:271-277. [Crossref] [PubMed] [PMC]

45.Verrotti A, Agostinelli S, D’Egidio C, Di Fonzo A,Carotenuto M, Parisi P, Esposito M, Tozzi E, Belcas-tro V, Mohn A, Battistella PA. Impact of a weight lossprogram on migraine in obese adolescents. Eur JNeurol. 2013;20:394-397. [Crossref] [PubMed]

46.Zhang ZQ, Deng J, He LP, Ling WH, Su YX, Chen YM.Comparison of various anthropometric and body fatindices in identifying cardiometabolic disturbancesin Chinese men and women. PLoS One. 2013;8:e70893. [Crossref] [PubMed] [PMC]

47.Jayawardana R, Ranasinghe P, Sheriff MH, MatthewsDR, Katulanda P. Waist to height ratio: a better an-thropometric marker of diabetes and cardio meta-bolic risks in South Asian adults. Diabetes Res ClinPract. 2013;99:292-299. [Crossref] [PubMed]

48.Miri A, Nasiri M, Zonoori S, Yarahmad F, Dab-bagh-Moghadam A, Askari G, Sadeghi O, Asadi M.The association between obesity and migrainein a population of Iranian adults: a case-controlstudy. Diabetes Metab Syndr. 2018;12:733-736.[Crossref] [PubMed]

49 Yusuf S, Hawken S, Ounpuu S, Bautista L, FranzosiMG, Commerford P, Lang CC, Rumboldt Z, Onen CL,Lisheng L, Tanomsup S, Wangai P Jr, Razak F,Sharma AM, Anand SS. Obesity and the risk of my-ocardial infarction in 27,000 participants from 52countries: a case-control study. Lancet. 2005;366:1640-1649. [Crossref]

50.Wang Y, Rimm EB, Stampfer MJ, Willet WC, Hu FB.Comparison of abdominal adiposity and overall obe-sity in predicting risk of type 2 diabetes amongmen. Am J Clin Nutr. 2005;81:555-563. [Crossref][PubMed]

51.Tietjen GE, Peterlin BL, Brandes JL, Hafeez F,Hutchinson S, Martin VT, Dafer RM, Aurora SK, SteinMR, Herial NA, Utley C, White L, Khuder SA. De-pression and anxiety: effect on the migraine-obe-sity relationship. Headache. 2007;47:866-875.[Crossref] [PubMed]

52.Duarte H, Teixeira AL, Rocha NP, Domingues RB.Increased serum levels of adiponectin in migraine.J Neurol Sci. 2014;342:186-188. [Crossref][PubMed]

53.Rozen T, Swidan SZ. Elevation of CSF tumor necro-sis factor alpha levels in new daily persistentheadache and treatment refractory chronic mi-graine. Headache. 2007;47:1050-1055. [Crossref][PubMed]

54.Edvinsson L, Goadsby PJ. Neuropeptides in migraineand cluster headache. Cephalalgia. 1994;14:320-327. [Crossref] [PubMed]

Turk J Endocrinol Metab Nuaman et al.2019;23:25-32 Obesity is a Risk Factor for Migraine

31

55.Goadsby PJ, Edvinsson L. The trigeminovascularsystem and migraine: studies characterizing cere-brovascular and neuropeptide changes seen in hu-mans and cats. Ann Neurol. 1993;33:48-56.[Crossref] [PubMed]

56. Blundel JE, Halford JCG. Serotonin and appetite regu-lation: implications for the pharmacological treatmentof obesity. CNS Drugs. 1998;9:473-495. [Crossref]

57.Sarchielli P, Rainero I, Coppola F, Rossi C, Mancini M,Pinessi L, Calabresi P. Involvement of corti-cotrophin-releasing factor and orexin-A in chronicmigraine and medication-overuse headache: find-ings from cerebrospinal fluid. Cephalalgia.2008;28:714-722. [Crossref] [PubMed]

58.Bond DS, Vithiananthan S, Nash JM, Thomas JG,Wing RR. Improvement of migraine headaches in

severely obese patients after bariatric surgery. Neu-rology. 2011;76:1135-1138. [Crossref] [PubMed][PMC]

59.Novack V, Fuchs L, Lantsberg L, Kama S, Lahoud U,Horev A, Loewenthal N, Ifergane G. Changes inheadache frequency in premenopausal obesewomen with migraine after bariatric surgery: a caseseries. Cephalalgia. 2011;31:1336-1342. [Crossref][PubMed]

60.Bond DS, O’Leary KC, Thomas JG, Lipton RB, Pa-pandonatos GD, Roth J, Rathier L, Daniello R, WingRR. Can weight loss improve migraine headaches inobese women? Rationale and design of the Women’sHealth and Mingraine (WHAM) randomized con-trolled trial. Contemp Clin Trials. 2013;35:133-144.[Crossref] [PubMed] [PMC]

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Address for Correspondence: Ceyla Konca Değertekin, Ufuk University Faculty of Medicine,Department of Endocrinology and Metabolism, Ankara, TurkeyPhone: +90 312 2044000 E-mail: ceylakonca@yahoo.com

Received: 25/09/2018 Received in revised form: 29/11/2018 Accepted: 12/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

A Bibliometric Analysis of Turkey’s Contribution toBone Health Literature from

an Endocrinologist PerspectiveTürkiye’nin Kemik Hastalıkları Literatürüne Katkısını

Endokrinolojik Çerçeveden Değerlendiren Bibliyometrik Bir Analiz

Department of Endocrinology and Metabolism, Ufuk University Facuty of Medicine, Ankara, Turkey*Department of Endocrinology and Metabolism, Başkent University Facuty of Medicine, Ankara, Turkey

**Department of Endocrinology and Metabolism, Marmara University Facuty of Medicine, İstanbul, Turkey

Original ArticleTurk J Endocrinol Metab 2019;23:33-37

DO

I:10

.251

79/t

jem

.201

8-62

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Objective: To analyze the trend of Turkish publications re-lated to bone health with respect to global publications and todetermine the relative contribution of endocrinologists tometabolic bone disease literature.Material and Methods: Publications related to bone healthup to and including the year 2017 were retrieved from the“Web of Science” (WoS) and “Türkiye Atıf Dizini” (TAD) data-base using metabolic bone disease related MeSH terms. Excel(v15.30) and Endnote X8 were used to summarize the bib-liometric features, including the number of publications, au-thors, their affiliations, and contributing countries. Keywordswere divided, for a detailed analysis, into three clusters: os-teoporosis, parathyroid, and vitamin D-related.Results: A total of 1.880.666 papers were retrieved fromWoS globally and, of those, 21.165 (1.13%) were publishedfrom Turkey. Of the papers published from Turkey, 3.0% wereprimarily contributed by endocrinologists. The relative con-tribution of endocrinology to osteoporosis-related (4.6% vs.1.5%), parathyroid-related (23.7% vs. 5.3%), and vitaminD-related (23.7% vs. 5.3%) publications was higher for arti-cles originating from Turkey compared to the global data. En-docrinology was among the top five specialties contributing toTurkish metabolic bone disease literature indexed in WoS andTAD.Conclusion: Turkey has a less than expected rate of researchoutput in terms of metabolic bone disease. The relatively highercontribution of endocrinology to that effort is promising. Sup-porting bone research might accelerate the efforts of Turkishresearchers in the field of metabolic bone health.

Keywords: Metabolic bone disease; bibliometric analysis;Turkey; endocrinology; osteoporosis

Amaç: Bu çalışmada, metabolik kemik hastalıkları konusundaTürkiye’den yapılmış olan araştırmaların dünya literatürü ilekıyaslandığındaki durumunun ve bu bilimsel üretimde endok-rinologların yerinin değerlendirilmesi amaçlanmıştır.Gereç ve Yöntemler: 2018 yılına kadar “Web of Science” (WoS)ve “Türkiye Atıf Dizini” (TAD) veri tabanlarında indekslenmişyayınlar, metabolik kemik hastalıkları ile ilgili olan MeSH anahtarkelimeleri kullanılarak tarandı. Elde edilen bibliyometrik verilerianaliz etmek için Excel (v15.30) and Endnote X8 programları kul-lanıldı ve yayın sayısı, yazar bilgisi, yazarların branş ve kurumları,yayının yapıldığı ülke verileri değerlendirmeye alındı. Anahtar ke-limeler alt gruplara ayrılarak; osteoporoz, paratiroid ve vitamin Dile ilişkili yayınlar olarak da ayrıca incelendi.Bulgular: WoS veri tabanında tüm dünyadan 1.880.666 yayınbulunduğu ve bunların 21,165 (%1,13)’inin Türkiye’den yapıldığıve Türkiye’den yapılan yayınların %3,0’ının da endokrinologlartarafından yönetildiği bulundu. Osteoporoz (%4,6’ta karşı %1,5),paratiroid (%23,7’ye karşı %5,3) ve vitamin D ilişki (%23.7 vs.%5.3) olarak tanımlanan yayınlarda endokrinologların katkısınınTürkiye için tüm dünya rakamlarının üzerinde olduğu görüldü.Hem WoS hem de TAD veri tabanlarında endokrinolojinin, me-tabolik kemik hastalıkları literatürüne en çok katkı yapan ilk beşbranş içerisinde olduğu saptandı.Sonuç: Türkiye’den metabolik kemik hastalıkları konusundayapılan toplam yayın sayısının beklenenin altında olduğudüşünülmektedir. Bu bilimsel üretimde endokrinologlarınhatırı sayılır bir katkısı var gibi durmakla birlikte, metabolikkemik hastalıkları araştırmalarına endokrinoloji camiası baştaolmak üzere ilgili tüm branşların vereceği bilimsel desteğinartırılmasının yayın sayısı ve kalitesinin yükseltilmesindeönemli rol oynayacağı görüşündeyiz.

Anahtar kelimeler:Metabolik kemik hastalıkları;bibliyometrik analiz; Türkiye; endokrinoloji; osteoporoz

33

The content of this manuscript had been presented as an oral presentation at the40th Turkish Congress of Endocrinology and Metabolism (09-13.05.2018)

IntroductionMetabolic bone health is an important butoften neglected area in daily medical prac-tice. The growing burden of osteoporosisdue to the aging of the population and veryhigh prevalence of hypovitaminosis-D alarmthat proper steps should be taken for thebenefit of public health. The data for this ac-tion plan are derived from the research lit-erature. Thus, the structured knowledge ofthe current literature on bone health is cru-cial for planning future scientific efforts.Bibliometric analysis is a helpful tool for ob-taining information regarding the currentstate of research in different areas of medi-cine. It could reveal the research trend in acertain field and evaluate academic produc-tion of a country or certain specialty or evenindividual researchers (1).Owing to the multifunctional dynamics ofthe bone tissue, the term “metabolic bonedisease” covers a broad spectrum of dis-eases that are related to many different spe-cialties in medicine. We, as endocrinologists,are one of the core specialists working in thefield of metabolic bone health.Therefore, in this study, we aimed to analyzethe scientific output on metabolic bone dis-eases in our country (Turkey), along with thesubspecialty, endocrinology, in comparison toglobal trends through a bibliometric approach.

Material and MethodsA bibliometric analysis was performed usingthe ISI Web of Science (WoS) and “Türkiye AtıfDizini” (TAD). Endnote X8 was used for WoSdatabase analysis. The time period for dataanalysis was considered up to and including2017. The publications from 2018 were not in-cluded due to incomplete availability at thetime of analysis. The search terms were basedon Medical Subject Headings (MeSH) terms onWoS and the corresponding Turkish transla-tions for TAD. The MeSH terms were insertedinto the search field to perform a ‘‘topic’’search. The search terms were as follows:theme=(“Bisphosphonate” [MeSH] OR“Bone” [MeSH] OR “Bone fracture” [MeSH]OR ”Bone mineral density” [MeSH] OR “Cal-cium” [MeSH] OR “Denosumab” [MeSH] OR“Hyperparathyroidism” [MeSH] OR “Hy-poparathyroidism” [MeSH] OR “Hypophos-phatemia” [MeSH] OR “Osteoblast” [MeSH]OR “Osteocalcin” [MeSH] OR “Osteoclast”

[MeSH] OR “Osteogenesis imperfecta”[MeSH] OR “Osteomalacia” [MeSH] OR “Os-teoporosis” [MeSH] OR “Osteoprotegerin”[MeSH] OR “Paget disease of bone” [MeSH]OR “Parathyroid” [MeSH] OR “RANK”[MeSH] OR “Rickets” [MeSH] OR “Teri-paratide” [MeSH] OR “Vitamin D” [MeSH])The topic search was then subdivided intothree clusters for theme MeSH terms for adetailed analysis for “osteoporosis-related”,“parathyroid-related” and “vitamin D-re-lated” papers as follows:Osteoporosis-related: theme= (”Osteo-porosis” [MeSH] OR “Bone mineral density”[MeSH] OR “Calcium” [MeSH] OR “Teri-paratide” [MeSH] OR “Bisphosphonate”[MeSH] OR “Denosumab” [MeSH] OR “Bonefracture” [MeSH])Parathyroid-related: theme= (”Hyper-parathyroidism” [MeSH] OR “Hypoparathy-roidism” [MeSH] OR “Hypophosphatemia”[MeSH] OR “Parathyroid” [MeSH])Vitamin D-related: theme= (”Vitamin D”[MeSH] OR “Osteomalacia” [MeSH] OR“Rickets” [MeSH])We refined the search for Turkey by using“Turkey” in the country keyword followed bythe aforementioned MeSH terms as a searchtopic.All types of publications were included in theanalysis. For simplification of categorization,publications were classified into four groups:original articles, reviews, case reports andshort reports (including editorials, letter tothe editors, others…). No language restric-tions were employed. The outcome variablesincluded document type, country of origin,publication date, source title, authors andauthors’ specialty, and institutions. The datawere retrieved from WoS and TAD databaseswere imported into Microsoft Excel for analy-sis. The researchers manually cleaned andanalyzed the data in Excel and compiled thefollowing information: (a) total number ofpapers published globally and from Turkey;(b) relative contribution of endocrinologiststo research productivity globally and fromTurkey; (c) detailed analysis of specialties’contributions to papers indexed in WoS andfrom Turkey between years 2011–2017. Aflowchart summarizing the production stepsis given in Figure 1. The study was carriedout in accordance with the principles of theDeclaration of Helsinki.

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Figure 1: The stepwise approach applied in this study.

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ResultsThe total number of documents retrievedfrom WoS in the field of metabolic bone dis-ease up to and including the year 2017 was1,880,666, without specifying the name ofany country. When “Turkey” was used as acounty code, the number of articles re-trieved at the same time period was 21,165,which was 1.13% of the global research pro-ductivity related to metabolic bone disease.The first article published globally on meta-bolic bone disease was in 1784 at LondonMedical Journal and the oldest Turkish arti-cle dated back to 1987 and was published inArchives of Otorhinolaryngology.Among the documents published globally,20,699 (1.1%) were leaded by specialists inendocrinology, while 644 (3.0%) of the pa-pers published from Turkey were leaded byendocrinologist. Clustering of the keywordsretrieved that, of the 817,007 “osteoporo-sis-related” publications worldwide, 12,376(1.5%) were primarily led by endocrinolo-gists while the relative contribution ofendocrinology was higher for parathyroid-related [2,532 (5.3%) out of 47,892) andvitamin D-related [4,405 (5.3%) out of83,514] publications. When the same analy-sis was applied to papers from Turkey, therelative contribution of endocrinologists was4.6% (330 out of 7,146) for osteoporosis-

related, 23.7% (129 out of 545) for parathy-roid-related, and 18.4% (207 out of 1,127)for vitamin D-related publications.When the research output from Turkey in-dexed in WoS between years 2011–2017was examined in more detail, we had a clearpicture on the distribution of specialties andtypes of articles. The top five research spe-cialties in the 1334 documents on metabolicbone diseases published from Turkey wereInternal Medicine (n=241, 18.0%; includingInternal Medicine subspecialties such as en-docrinology), Dentistry (n=217, 16.3%),Pediatrics (n=214, 16.0%), Orthopedics(n=112, 8.4%), and Physical Therapy andRehabilitation (n=98, 7.4%) while thestand-alone contribution of Endocrinologywas 6.8% (n=90). The majority of the arti-cles published from Turkey during that timeperiod were original articles (n=1,058,78.8%), followed by case reports (n=192,14.3%), short reports (n=64, 4.8%), andreviews (n=28, 2.1%).We performed a similar kind of analysis forTAD for publications originating from Turkeybetween years 2011-2017 and retrieved 628publications. The top five research special-ties were Physical Therapy and Rehabilita-tion (n=151, 24.0%), Pediatrics (n=89,14.2%), Endocrinology (n=79, 12.6%), Bio-chemistry (n=31, 4.9%), and Orthopedics

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(n=30, 4.8%). The type of article distribu-tion was as follows: original articles (n=319,50.8%), reviews (n=201, 32.0%), and casereports (n=108, 17.2%).

DiscussionIn this study, we investigated the global andlocal trends in metabolic bone disease liter-ature with respect to the role of endocrinol-ogy. We preferred WoS database owing toits high volume and coverage for miningworldwide data and TAD for analyzing localpublication trends. Although the quality andquantity of research indexed might differfrom one database to another, WoS remainsone of the best available tools for analyzingglobal data.Bibliometric analysis is one of the ways toevaluate the research performance on aspecific area of medicine or to analyze therate and quality of scientific output of a cer-tain group of researchers. We believe that itis vital for the medical authorities of acountry to know where they stand in thearea of scientific production in order to re-fine where they should head to in the fu-ture. That information gained from thebibliometric analysis may even be used toformulate policy regarding research fund-ing (1).Our analysis showed that Turkey has a sta-ble but low level of contribution to meta-bolic bone disease literature. To the best ofour knowledge, this is the first bibliometricstudy from Turkey on metabolic bonehealth. A comprehensive bibliographicanalysis by Sweileh et al. analyzed the re-search trends in the field of osteoporosis in21 Arab countries and 3 Middle Easternnon-Arab countries, including Israel,Turkey, and Iran (2). They found that theleading country in osteoporosis researchwas the United States of America, whichcontributed to 33.82% of all publications.They also found that Turkey ranked 16th

while Israel and Iran ranked 24th and 31st,respectively, in terms of rate of total publi-cation in osteoporosis research. It is wellknown that the rate and quality of scientificresearch is a direct reflection of gross do-mestic product (GDP) per capita of a coun-try and the share of GDP spent on researchand development (3). Thus, funding issues,scarcity of translational laboratory setups,

and lack of scientific collaborations mightbe the underlying issues responsible for theless-than-expected publication productionrate in our country.We also investigated to what extend theTurkish endocrinologists have contributed tothe analyzed field of research. The rate ofTurkish endocrinologist leading the publica-tions was similar to the global rates. How-ever, when the publications weresub-classified, the contribution of endocri-nologist was higher for osteoporosis-relatedarticles and even higher for parathyroid-re-lated and vitamin D-related articles.A more detailed analysis showed that themost frequent article type submitted fromTurkey was original articles and specialtiesas dentistry and physical therapy and reha-bilitation made significant contributions.

Study LimitationsSince the detection of publications wasMeSH term based, inappropriate choices ofkeywords might misclassify the papers.Most of the publications involved a collabo-ration of researchers from different special-ties. To enable a specialty classification forpublications, only the first author’s specialtywas considered in the analysis. Incompletedescription of the affiliation might have ledto errors of specialty classification.Articles published in non-WoS and non-TADjournals were not included.

ConclusionTurkey has a low rate of research output interms of metabolic bone disease. The rela-tively higher contribution of endocrinologyto that effort is promising. We would like tosuggest that supporting research with inter-national and national collaborations andyielding higher impact articles might accel-erate the efforts of Turkish researchers inthe field of metabolic bone health.

Source of FinanceDuring this study, no financial or spiritualsupport was received either from any phar-maceutical company that has a direct con-nection with the research subject or from acompany that provides or produces medicalinstruments and materials which may nega-tively affect the evaluation process of thisstudy.

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Conflict of InterestThere is no conflict of interest to disclose be-tween the authors and/or family membersof the scientific and medical committeemembers or members of the potential con-flicts of interest, counseling, expertise,working conditions, shareholding and similarsituations in any firm.

Authorship ContributionsIdea/Concept: Ceyla Konca Değertekin,Özlem Turhan İyidir, Dilek Gogas Yavuz; De-sign: Ceyla Konca Değertekin, Özlem Turhanİyidir, Dilek Gogas Yavuz; Control/Supervi-sion: Ceyla Konca Değertekin, Özlem Turhanİyidir, Dilek Gogas Yavuz; Data Collectionand/or Processing: Ceyla Konca Değertekin,Özlem Turhan İyidir, Dilek Gogas Yavuz;Analysis and/or Interpretation: Ceyla KoncaDeğertekin, Özlem Turhan İyidir, Dilek GogasYavuz; Literature Review: Ceyla KoncaDeğertekin, Özlem Turhan İyidir, Dilek Gogas

Yavuz; Writing the Article: Ceyla KoncaDeğertekin, Özlem Turhan İyidir, Dilek GogasYavuz; Critical Review: Ceyla KoncaDeğertekin, Özlem Turhan İyidir, Dilek GogasYavuz; References and Funding: Ceyla KoncaDeğertekin, Özlem Turhan İyidir, Dilek GogasYavuz; Materials: Ceyla Konca Değertekin,Özlem Turhan İyidir, Dilek Gogas Yavuz.

References1. Brüggmann D, Mäule LS, Klingelhöfer D, Schöffel N,

Gerber A, Jaque JM, Groneberg DA. Groneberg.World-wide architecture of osteoporosis research:density-equalizing mapping studies and genderanalysis. Climacteric. 2016;19:463-470. [Crossref][PubMed]

2. Sweileh WM, Al-Jabi SW, Zyoud SH, Sawalha AF,Ghanim MA. Osteoporosis is a neglected health pri-ority in Arab World: a comparative bibliometricanalysis. Springerplus. 2014;3:427. [Crossref][PubMed]

3. Jamjoom BA, Jamjoom AB. Impact of country-spe-cific characteristics on scientific productivity in clin-ical neurology research. eNeurologicalSci.2016;4:1-3. [Crossref] [PubMed]

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Original ResearchTurk J Endocrinol Metab 2019;23:38-46

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Address for Correspondence: Diğdem Özer Etik, Başkent University Faculty of Medicine,Department of Gastroenterology, Ankara, Turkey

Phone: +90 5332402368 E-mail: digdemozer@hotmail.comReceived: 09/07/2018 Received in revised form: 04/12/2018 Accepted: 22/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

The Effect of Treatment of Iron Deficiency Anemiaon Thyroid Volume

Demir Eksikliği Tedavisinin Tiroid Volümü Üzerine Etkisi

Başkent University Faculty of Medicine, Department of Gastroenterology, Ankara, Turkey*Ankara University Faculty of Medicine. Department of Endocrinology and Metabolism, Ankara, Turkey

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Objective: Iron and iodine, which are the two importantmicronutrients, are still deficient in a large number ofwomen worldwide. This study aimed to examine the thyroidvolumes of iron deficient, anemic women before and aftercorrection of the anemia in a mildly iodine deficient envi-ronment.Material and Methods: Sixty six women aged 18-45 yearswere prospectively enrolled in this study. Inclusion criteriaincluded serum hemoglobin (Hb) level <11.0 g/dL, ferritinlevel <13 ng/mL, thyroid hormones within normal referenceranges and negative thyroid antibodies. Oral iron supple-ment (567 mg ferrous sulfate, twice a day) for six monthswas prescribed and strongly recommended. All patientswere re-evaluated at the end of the iron treatment.Results: Initially, the median (minimum/maximum) Hb andferritin levels of patients were 10.2 g/dL (5.6/11.1) and3.95 ng/mL (0.44/10.7), respectively. Six months later, me-dian Hb and ferritin values increased significantly to 13.15g/dL (9.3/15.6) (p<0.001) and 19.575 ng/mL (3.74/79)(p<0.001) respectively. Median thyroid volume decreasedsignificantly from 15.705 mL (7.15/54.2) to 13.212 mL(6.11/52.8) (p<0.001). The patients were grouped accor-ding to the improvements in Hb and ferritin levels, initialthyroid gland volume, and response to the treatment. Thereduction in thyroid gland size, at the end of the treatment,was more significant in patients with improvement in bothHb and ferritin levels as compared to those with improve-ment only in Hb levels (p<0.05).Conclusion: Iron may be responsible for efficient organifi-cation of iodine, active iodine utilization from thyroglobulin,and control of hyperkinetic blood-flow to the thyroid gland.The findings of this study support that other than iodine, ironsupplementation has a significant effect on the regression ofthyroid volume in women with iron deficiency anemia.

Keywords: Iron; iodine; anemia; goiter;thyroid hormones

Amaç: Demir ve iyot, iki önemli mikro besin olup, dünyagenelinde yaygın olarak kadınlarda hâlen eksiklikleri görül-mektedir. Bu çalışmada, hafif iyot eksikliği bölgesindekidemir eksikliği anemisi bulunan kadınların, aneminin düzel-mesinden önce ve sonra tiroid volümlerinin değerlendiril-mesi amaçlanmıştır.Gereç ve Yöntemler: Çalışmaya; yaş aralığı 18-45 yıl olan,66 kadın hasta katılmıştır. Çalışmaya dâhil edilme kriterleri;serum hemoglobin (Hb) düzeyi <11,0 g/dL, ferritin düzeyi<13 ng/mL, tiroid hormonlarının normal sınırlarda ve tiroidantikorlarının negatif olması olarak belirlenmiştir. Her has-taya ağızdan demir desteği (567 mg ferrous sülfat, günde ikikez) reçete edilmiş ve kuvvetle önerilmiştir. Tüm hastalardemir tedavisi sonrası yeniden değerlendirilmiştir.Bulgular: Başlangıçta hastaların medyan (minimum/mak-simum) Hb ve ferritin düzeyleri sırasıyla, 10,2 g/dL(5,6/11,1) ve 3,95 ng/mL (0,44/10,7) idi. Altı ay sonra, Hbdüzeyleri 13,15 g/dL (9,3/15,6) (p<0,001) ve ferritin dü-zeyleri 19,575 ng/mL (3,74/79) (p<0,001) ile anlamlı artışgösterdi. Medyan (minimum/maksimum) tiroid volümü detedavi öncesi 15,705 mL (7,15/54,2) iken, tedavi sonrası13,212 mL (6,11/52,8) (p<0,001) ile anlamlı azalma gös-terdi. Hastalar ayrıca, Hb ve ferritin değerindeki iyileşmeye,tedavi başlangıcındaki tiroid bezi büyüklüğüne ve tedavi ya-nıtına gore karşılaştırıldılar. Tedavi sonunda tiroid bezi volü-mündeki gerileme, Hb ve ferritin değerinde iyileşme göste-renlerde, yalnız Hb değeri düzelenlere göre daha belirgin idi(p<0,05).Sonuç: Demir; iyotun etkin organifikasyonundan, tiroglo-binde iyotun etkin kullanımından, tiroid bezinin hiperkinetikkan akımının kontrolünden sorumlu olabilmektedir. Çalış-mamız da demir eksikliği anemisi olan kadınlarda, demir te-davisinin, artmış tiroid volümünün düzelmesine belirginkatkısı olduğunu desteklemektedir.

Anahtar kelimeler: Demir; iyot; anemi; guatr;tiroid hormonları

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IntroductionThe present scenario of the extent of iodinedeficiency (ID) holds immense importanceworldwide. Great efforts, especially withsalt iodinization, are being made in order toprevent and eliminate health problems aswell as social and economic consequencesrelated ID (1). According to the WorldHealth Organization (2004) data, 664 mil-lion people on an average are at risk for ill-nesses due to ID, in Europe and EasternMediterranean (2). Turkey is a severe tomild iodine deficient area; improvement iniodized salt consumption in the area hasdecreased the prevalence of ID in nationalsurveys, as compared to that in 1997 and2002 (i.e., 58% and 38.9%, respectively)(3).Iron deficiency (IRD), another major publichealth problem, has several effects on theneural development, immune capacity aswell as intellectual and physical perform-ance in both, adult population and children(4, 5). Globally, the prevalence of IRD ane-mia has fallen from 33% to 29% during1995-2011 in non-pregnant women (6).The Health Statistics 2013 Report by Min-istry of Health indicates that 9.8% of theTurkish women experienced IRD anemiaand the risk for IRD was higher amongwomen between 15-49 years of age (7).These rates were supported with thosefrom another study from Ege University,which showed that the prevalence of IRDwas 15.6% while that of IRD anemia was10.3% (8).Combined iodine and iron deficiency are re-lated to low socioeconomic conditions, inad-equate food intake, poor quality diet, andpoor bioavailability (9, 10). Furthermore,the women of the reproductive age groupare at a greater risk for these micronutrientdeficiencies because of increased physiolog-ical needs (11, 12). IRD also affects iodinemetabolism, and thus thyroid metabolism(13). IRD can cause hyperkinetic flow in thethyroid gland and a decreased enzymaticactivity of the heme-dependent thyroid per-oxidase (TPO) (13). This study was aimed toinvestigate whether iron replacement ther-apy changes thyroid hormone metabolismand thyroid gland volume in females withIRD anemia.

Material and MethodsThis prospective study was conducted for ap-proximately 18 months in the Department ofInternal Medicine, Ankara University, IbniSina Hospital. The female patients matchingthe inclusion criteria were evaluated and theinclusion criteria were Age: 18-45 years, He-moglobin (Hb) <11.5 g/dL and Mean Cor-puscular Volume (MCV) <80 fl, MeanCorpuscular hemoglobin (MCH) <27 pg incomplete blood count, Peripheral BloodSmear: hypochromic and microcytic erythro-cyte morphology, serum iron <35 µg/dL,serum iron binding 245-450 µg/dL or >450µg/dL, saturation of transferrin <13%, fer-ritin < 10 ng/mL, normal thyroid functiontests [sensitive thyroid stimulating hormone(sTSH) 0.35-5.5 mIU/mL, free thyroxine(fT4) 10-23 pmol/L, free triiodothyronine(fT3) 2.8-7 pmoL/L], negative thyroid auto-antibodies [Anti-Thyroglobulin (Anti-Tg) <60U/mL, Anti-Thyroid peroxidase (Anti-TPO)<60 U/mL]. The exclusion criteria were asfollows: Microcytic and hypochromic anemiadue to causes other than iron deficiency; pa-tients who needed to be treated urgently be-cause of cancer, heart failure, acutegastrointestinal bleeding; abnormalities ofthyroid function tests and positive thyroidauto- antibodies; heterogeneous gland struc-ture of thyroid glands in ultrasonographic im-aging and co-existence of any chronic illness.All participants were given detailed informa-tion about the research in advance, and thenmade to sign the informed consent forms.The study protocol was approved by theAnkara University Ethical Committee and thisstudy was carried out according to the prin-ciples of the Conference of Helsinki.The patients diagnosed with IRD anemia,who met the inclusion criteria and voluntar-ily agreed to participate in the study, wereexamined for thyroid hormones (fT4, fT3,sTSH), thyroid auto-antibodies (Anti-Tg,Anti-TPO), urinary iodine concentration(UIC), and measurement of thyroid glandvolume by ultrasonography. All the eligiblepatients were found to be euthyroid andtested negative for thyroid auto-antibodies.These values of basal examination wererecorded and defined as the values beforethe treatment. A ferrous sulfate formulation(567 mg) equivalent to 100 mg elementaliron per capsule was prescribed and recom-

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mended twice a day up to the patient’s tol-erance. The same preparation was takenthroughout the treatment of iron deficiencyby all the patients and no iodine-containingmultivitamin preparation was not used.All the patients were informed about the sideeffects of oral iron therapy. Following com-pletion of the six-month-treatment, Hb level,iron status, thyroid hormones, UIC and ultra-sonographic volume measurement of thyroidgland were repeated. These values were de-fined as the end of treatment values. Thyroidgland measurement was taken by the sameresearcher via ultrasonography using GeneralElectric Logic 200 Pro Ultrasound with high-frequency (7 MHz) linear probe (GE MedicalSystems, Milwukee, WI, USA). As soon as anodule on the thyroid gland was detected,thin needle aspiration was applied; the sizeof the nodule was also followed before andafter the treatment. The volume of the thy-roid lobe was calculated from the measure-ments of the maximal depth, the maximalwidth, and the maximal length of each lobeand multiplied by b/6. Total thyroid volumewas found by the sum of the volumes of rightand left lobe. Thyroid volume >16 mL inwomen was regarded as goiter (3).At the end of the treatment, the patientswere grouped according to the improve-ments in Hb and ferritin values found by theend of the study (sufficient improvement/insufficient improvement) and thyroid glandvolume at the beginning of the study(goitrous/non-goitrous). All parameterswere compared for each group.The samples of blood and urine were obtainedfrom each participant in the morning after anovernight fast. All sera were immediately an-alyzed for TSH, fT4, fT3 and thyroid auto-an-tibodies based on chemiluminescenceimmunoassay (Beckman kits, Beckman Coul-ter, Inc, Miami, FL, USA) (Immulite 2000 Im-munoassay System, Siemens Healthineers,Erlangen, Germany). Urinary iodine excretionwas measured using an ammonium persul-fate method based on the Sandell-Kolthoff re-action. Hb, MCV and MCH were measuredusing Beckman Coulter STKS Hematology An-alyzer. Serum iron status was measured byBeckman Coulter CX7 based on ferrozine col-orimetric reaction. Serum ferritin level wasmeasured using ferritin enzyme immunoas-say test kits.

Statistical EvaluationStatistical evaluation was done by SPSS 25.0(IBM Corporation, Armonk, New York, UnitedStates) and PAST 3 (Hammer Q, Harper.D.A.T, Ryan P.D, Paleontological statistics).Mardia (Dornik and Hansen omnibus) test wasused for the analysis of multivariate normallydistributed data while variance homogeneitywas evaluated by Boxnm test. The independ-ent samples t-test with the Bootstrap resultsand the Mann-Whitney U test with the MonteCarlo simulation technique were used for thecomparison of the two independent groupsaccording to the quantitative data. The pairedsamples t-test with the Bootstrap results andWilcoxon Signed Ranks test with Monte Carlosimulation technique were used to comparethe two repetitive measurements of depend-ent quantitative variables. General LinearModel-Repeated ANOVA was used to investi-gate the interaction of repeated quantitativemeasurements of the variables. Quantitativevariables have been expressed as mean±SD(Standard Deviation) and median (minimum/maximum) in the text and tables. The vari-ables were examined at 95% confidence leveland the p-value was considered significantwhen less than 0.05.

ResultsThe study participants included femalesaged 35.6±8.4 years. As shown in Table 1,all patients had iron deficiency anemia atthe beginning of the treatment; improve-ments in all hematological parameters wereobserved at a significant level, after thetreatment (p<0.001). Ferritin values in the17 patients were observed to be below thenormal level at the end of the treatment.Before the treatment, thyroid function testswere at a normal level and thyroid auto-an-tibodies were negative in all patients. Theirmedian UIC was 82.5 µg/L (1/450). Thetotal thyroid volume of the patients wasmeasured to be 16.705 mL (7.15/54.2) be-fore the treatment. The total thyroid volumeof 30 patients was measured above 16 mL,and therefore they were said to be goitrous.A nodule was found on the right lobe ofeight patients and on the left lobe of ninepatients. Thyroid cancer was not detected inany patient during the thin needle aspira-tions. After continuing iron therapy for sixmonths, no significant change was observed

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in fT3, sTSH, and UIC values. However, thefT4 value was 15.55 pmol/L (11.4/22.5) be-fore the treatment, which increased to16.4pmol/L (5.97/22.8) after the treatment. Thetotal thyroid volume decreased to 13.212mL (6.11/52.8). These results were statisti-cally significant (p<0.05) (Table 1).The patients were grouped according to theimprovements in Hb and ferritin values.Forty-nine patients showed sufficiently im-proved values in both, Hb and ferritin levels(improved IRD group), while 17 patients onlyhad improved values of Hb levels (unim-proved IRD group), even beyond ferritin lev-els, at the end of the treatment (Table 2).They were compared on the basis of the thy-roid volume change. While the median thy-roid volume was 16.24 mL (7.15/54.2) in theimproved IRD group before the treatment, itdecreased to 13.65 mL (6.11/58.8) after thetreatment. The median thyroid volume was14.4 mL (8.297/29.17) in unimproved IRDgroup before the treatment, it decreased to12.9 mL (7/31.857) after the treatment.There was a significant difference among thegroups with regard to the thyroid volumechange in favor of improved IRD group(p=0.048) (Table 3, Figure 1).The patients were grouped according to thevolume of the thyroid gland at the beginningof the study. Goitrous patients and non-goitrous patients were compared with theirresponse to oral iron therapy. The medianthyroid volume of 30 patients in the goitrous

group was 19.65 mL (16/54.2) before treat-ment, which decreased to 16.525 mL(7.76/58.8) after the treatment. The medianthyroid volume of 36 patients in the non-goitrous group was 13.045 mL(7.15/15.934) before the treatment, whichdecreased to 10.84 mL (6.11/16.73) afterthe treatment. There was no difference interms of reduction of thyroid gland volumebetween the groups (p=0.117). The analysisof values of their thyroid and iron deficiencyvariables before and after the treatment,between these two groups, showed no sig-nificant difference (Table 2, Table 3).

DiscussionThis study was carried out to point out thechanges in thyroid gland volume and thyroidhormone metabolism after oral iron therapyin women with IRD anemia. The study re-vealed that the thyroid gland volumes ofwomen with IRD anemia regressed signifi-cantly after the oral iron replacement ther-apy. fT4 level also increased after thetreatment, without any changes in sTSH andfT3 levels. Interestingly, the reduction in thethyroid gland size was more significant inpatients showing improvement in both, Hb,and ferritin levels than those showing im-provement only in Hb levels.Of the school age children, 20-30% haveboth, iron deficiency and goiter, in northwestAfrica (14). In India, it was found that 15%of the teenage pregnant women have goiter

a Wilcoxon sing Test (Monte Carlo). b Paired T Test (Bootstrap). Min.: Minimum; Max.: Maximum; SD.: Standard deviation.

Variable Median (Min./Max.) Before Treatment (N=66) After Treatment (N=66) P

Iron deficiency variables

Hb (mg/dL) 10.2 (5.6/11.1) 13.15 (9.3/15.6) <0.001a

Iron (mcg/dL) 19 (2/93) 71 (14/238) <0.001a

Iron binding capacity (mcg/dL) 429 (280/524) 312 (237/435) <0.001a

Saturation of transferrine (%) 5 (0.6/21) 22.65 (4.2/63.6) <0.001a

Ferritin (ng/mL) 3.95 (0.44/10.7) 19.575 (3.74/79) <0.001a

Thyroid variables

fT3 (pmol/L) (Mean±SD.) 4.91±0.98 5.17±0.91 0.066b

fT4 (pmol/L) 15.55 (11.4/22.5) 16.4 (5.97/22.8) 0.019a

sTSH (mIu/mL) 1.6 (0.5/4.08) 1.475 (0.509/6.55) 0.467a

UIC (Mg/L) 82.5 (1/450) 118 (12/450) 0.119a

Thyroid gland volume (mL) 16.705 (7.15/54.2) 13.212 (6.11/52.8) <0.001a

Table 1. The patients’ iron deficiency parameters and thyroid parameters, and comparison between baseline andafter treatment values.

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and iron deficiency (15). In Iran, among2917 school age children, 80% childrenwere having ferritin concentrations <10mg/dL and also goiter; however, only 20%children with ferritin concentrations >10mg/dL had goiter (16). Two studies fromTurkey reported that neither multinodulargoiter nor iodine deficiency showed any cor-relation with iron status (17, 18). Erdoganet al. detected median UIC to be 26 µg/L in1997-1999, 90 µg/L in 2002 and 135 µg/L in2009 during the follow-up monitoring sur-veys in school age children in Ankara (19).In the present study, the UIC levels of pa-tients were found to be similar at the begin-ning and end of the treatment, being 82.5µg/L (1/450) and 118 µg/L (12/450), re-spectively. Goiter was observed in 45.4%patients out of all the subjects with IRD ane-mia in this study. In the subgroup analysis,median UIC levels of individuals with goiterwere found to be lower than those of non-goitrous patients. All patients benefited from

oral iron replacement therapy, especially interms of regression in thyroid gland size, al-though median UIC levels did not changesignificantly either in the goitrous or non-goitrous group. It is striking that iron, apartfrom iodine, has an effect on thyroid vol-ume. Zimmermann performed a study onchildren between 6-12 years of age in Coted’Ivore of North Africa where iron and iodinedeficiency were seen together, which was insupport of the present study (20). In thestudy, 51 patients having only goiter and 53patients having both, goiter and iron defi-ciency anemia, were followed for 30 weeksunder only iodine replacement therapy. Inpatients having only goiter, thyroid volumedecreased by 22% till the 10th week and fur-ther by 45% till the 30th week (20). How-ever, in the patients with both goiter andiron deficiency together, thyroid volume de-creased by 20% till the 10th week and didnot decrease any further between weeks 10-30 (20). After the 30th week, iron replace-

Mann Whitney U Test (Monte Carlo); Min.: Minimum; Max.: Maximum; SD.: Standard deviation; IRD: Iron deficiency.

Thyroid gland volume status IRD

Non-goitrous Goitrous Unimproved IRD Improved IRD

Variable Median (Min./Max.) (n=36) (n=30) P Goitrous (n=17) (n=49) P IRD

Hb (mg/dL)

Before 10.25 (6.1/11.1) 10.11 (5.6/11) 0.741 10.2 (6.5/10.9) 10.2 (5.6/11.1) 0.510

After 12.95 (9.3/15.4) 13.5 (10.4/15.6) 0.348 12.4 (10.4/15.1) 13.5 (9.3/15.6) 0.001

Alteration (After-Before) 3.05 (1.2/8.4) 3.6 (1/8.8) 0.275 2.9 (1/5.1) 3.4 (1.2/8.8) 0.047

Iron(mcg/dL)

Before 19 (3/93) 18.5 (2/52) 0.193 17 (7/93) 19 (2/65) 0.441

After 71 (14/219) 71 (14/238) 0.599 41 (14/106) 72 (17/238) 0.002

Alteration (After-Before) 49 (-21/215) 57 (6/217) 0.215 24 (-21/89) 56 (-3/217) 0.002

Iron binding capacity (mcg/dL)

Before 397.5 (294/522) 437.5 (280/524) 0.319 439 (317/522) 412 (280/524) 0.407

After 317.5 (237/398) 306 (273/435) 0.340 336 (289/398) 309 (237/435) 0.013

Alteration (After-Before) -84 (-257/61) -126.5 (-220/14) 0.238 -97 (-183/-17) -105 (-257/61) 0.788

Saturation of transferrine (%)

Before 5.4 (0.6/21) 4.35 (0.9/13) 0.106 4.4 (1.2/21) 5.2 (0.6/13) 0.271

After 21.95 (4.2/61.7) 23.5 (4.6/63.6) 0.726 13.9 (4.2/26.6) 26 (5.8/63.6) <0.001

Alteration (After-Before) 14.25 (-0.2/58.3) 19.8 (1.6/56.7) 0.439 7.3 (-0.2/22.7) 21 (1.6/58.3) <0.001

Ferritin(ng/mL)

Before 4 (0.44/10.7) 3.7 (1.3/10) 0.524 3.2 (0.44/10.7) 4.11 (1/10) 0.100

After 16.9 (4/77) 20.5 (3.74/79) 0.185 8 (3.74/11.02) 24 (14/79) <0.001

Alteration (After-Before) 13.47 (-0.02/70.79) 16.875 (1.05/72.72) 0.107 4.1 (-0.02/8.83) 21 (13/72.72) <0.001

Table 2. The comparisons of non-goitrous group and goitrous group, and unimproved IRD group and improvedIRD group according to iron deficiency parameters.

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43

ment therapy was supplemented to thisgroup and thyroid volume was observed todecrease to 38% that of the initial volume(20). This finding suggested that iron playsa role in thyroid metabolism (21-24). Zim-mermann performed another study in 166school aged children with goiter and iron de-ficiency and followed them for 20 weeks(23). One group of children was adminis-tered iron while the rest received placebo.In the group that received iron treatment,the reduction of thyroid volume was twice asmuch as it was in the placebo group (23). Itsupported the fact that thyroid volume isunquestionably influenced by iron status(25). The thyroid gland is a highly vascular-ized gland and blood flow influences an im-portant part of the thyroid gland volume.IRD anemia exerts a hyperkinetic flow in thethyroid gland. It is proposed that the appar-ent elevation of blood volume on the thyroidvessel bed causes an increase in thyroid vol-ume. This mechanism may be responsiblefor the decrease in volume after oral irontherapy (16, 20). On the other hand, pa-

tients in whom both Hb and ferritin valuesimproved sufficiently, showed a more signif-icant reduction in thyroid volume than in thepatients having still low ferritin value at theend of the treatment. It was thus empha-sized that iron may be an independent ben-eficial factor for thyroid gland volume.

a Mann Whitney U Test(Monte Carlo), b General Linear Model Repeated Anova (Wilks' Lambda), c Independent Samples T Test(Bootstrap). Min.: Minimum; Max.: Maxi-mum; SD.: Standard deviation; IRD: Iron deficiency.

Thyroid gland volume status IRD

Non-goitrous Goitrous Unimproved IRD Improved IRD

Variable Median (Min./Max.) (n=36) (n=30) P Goitrous (n=17) (n=49) P IRD

fT3 (pmol/L) Mean±SD.

Before 5.01±0.96 4.79±1.01 0.264c 4.54±0.99 5.04±0.95 0.074c

After 5.07±1.04 5.30±0.73 0.426c 4.83±1.02 5.29±0.85 0.114c

Alteration (After-Before) 0.06±1.19 0.40±1.01 0.059b 0.29±1.19 0.25±1.11 <0.001b

fT4 (pmol/L)

Before 15.95 (12.7/22.5) 15.25 (11.4/19.7) 0.075a 15.5 (12.7/22.5) 15.6 (11.4/19.7) 0.971a

After 17.2 (11.2/20.4) 16.05 (5.97/22.8) 0.266a 16.4 (5.97/19) 16.4 (10.2/22.8) 0.290a

Alteration (After-Before) 0.3 (-5/4.9) 1.1 (-7.63/7.5) 0.579a 0 (-7.63/3.1) 1.1 (-5/7.5) 0.117a

sTSH(mIu/mL)

Before 1.785 (0.8/4.08) 1.185 (0.5/2.35) <0.001a 1.6 (0.5/3.1) 1.6 (0.57/4.08) 0.986a

After 1.74 (0.689/6.55) 1.235 (0.509/2.77) 0.001a 1.57 (0.668/4.49) 1.47 (0.509/6.55) 0.730a

Alteration (After-Before) -0.03 (-1.45/2.89) 0.13 (-1.62/0.94) 0.619a 0.14 (-1.45/2.33) 0.06 (-1.62/2.89) 0.804a

UIC (Mg/L)

Before 98 (1/420) 58.5 (1/450) 0.024a 80 (10/180) 84 (1/450) 0.798a

After 138 (12/450) 88 (14/450) 0.024a 87 (34/450) 127 (12/450) 0.265a

Alteration (After-Before) 2.5 (-293/270) 12 (-141/351) 0.829a -5 (-129/270) 13 (-293/351) 0.808a

Thyroid gland volume (mL)

Before 13.045 (7.15/15.934) 19.65 (16/54.2) <0.001a 14.4 (8.297/29.17) 16.24 (7.15/54.2) 0.129a

After 10.84 (6.11/16.73) 16.525 (7.76/58.8) <0.001a 12.9 (7/31.857) 13.65 (6.11/58.8) 0.488a

Alteration (After-Before) -1.485 (-5.09/4.61) -2.685 (-11.79/5.52) 0.117a -1.3 (-9.74/4.61) -1.98 (-11.79/5.52) 0.048a

Table 3. The comparisons of non-goitrous group and goitrous group, and unimproved IRD group and improvedIRD group according to thyroid parameters.

Figure 1: Comparison of the alteration in total thyroidgland volume between unimproved IRD and improvedIRD groups.IRD: Iron deficiency.

It is obvious that TSH is a trophic factor forthe thyroid gland. When the whole group wasconsidered, an increase in fT4 level was seenwith oral iron therapy; however, fT3 and sTSHlevels did not change even at the end of thetreatment. The correction in the iron statusmay have been related to the better organifi-cation of iodine, better utilization of tyrosineresidues in thyroglobulin and thus formationof more efficient T4. The TPO is a heme pro-tein with a prosthetic group of ferriprotopor-phyrin IX comprising iron in its structure. Theiodine reacts with tyrosine residues in thy-roglobulin through the activity of TPO; thisstep is essential for thyroid hormone synthe-sis. IRD may decrease TPO enzyme activityand result in hypothyroxinemia (26). Hess etal. found that the TPO activity, in the thyroidgland, determined by the guaiacol assay inrats, which were fed on an iron deficient dietcontaining 3, 7 and 11 mcg iron/g, was de-creased by 33, 45, and 56%, respectively(23). However, no further information onwhich serum iron level and which hemoglobinlevel may change this enzyme activity isavailable. Hu et al. found that total serum T4levels were positively related to liver iron,serum ferritin, serum iron and Hb concentra-tion in rats with IRD (27). Khatiwada et al.studied 227 school children aged 6-12 yearsin Nepal and found that the risk of having hy-pothyroidism (overt and subclinical) in ane-mic and iron deficient children was 5.513 and1.939, respectively, as compared to the chil-dren who were non-anemic and had iron insufficient amounts (28). Yu et al. reportedthat fT4 levels were significantly lower inboth, 3340 pregnant and 1052 non-pregnantwomen with IRD (29). The study fromEftekhari in Iranian adolescents with IRDshowed that despite an increase in fT3 andfT4 concentrations, the TSH concentration re-mained unaffected by iron supplementation(30). Recently, Maldonado-Araque et al. con-firmed the association between IRD, hy-pothyroxinemia, and hypotriiodothyroninemiain Spanish general adult population (31). Theresults suggested that several mechanismsare involved in IRD and thyroid hormone me-tabolism. Iron deficiency may alter the controlof hypothalamus-hypophysis-thyroid axis,modify nuclear thyroid hormone binding andhepatic thyroid hormone turnover and impairoxygen transport to the thyroid gland. These

mechanisms jointly contribute to change inthyroid hormone metabolism and thyroidgland volume in patients with IRD (27-31).The studies on micronutrient deficiencies arefrequently performed on pregnant women,infants or school age children. The strengthof this study was that healthy women par-ticipated and it comprised a homogenousgroup with iodine and iron deficiency. How-ever, the study should also have includedpatients with sufficient UIC. Further molec-ular research is necessary to determine theeffects of iron on enzymes related to thyroidhormone metabolism.To conclude, the study found a significantreduction in thyroid gland volume in womenwith IRD anemia consistently when the ironwas replaced. Thus, iron supplementation isnot only beneficial for IRD anemia but alsoameliorates increased thyroid gland volume.In societies where iron and iodine deficiencyare seen together especially in youngwomen, iron therapy and iodine supplemen-tation are inevitable. It is suggested thatthyroid gland volume and functions must beevaluated once again after iron therapy.

Source of FinanceDuring this study, no financial or spiritual sup-port was received neither from any pharma-ceutical company that has a direct connectionwith the research subject, nor from a companythat provides or produces medical instrumentsand materials which may negatively affect theevaluation process of this study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Murat Faik Erdoğan; Design:Diğdem Özer Etlik, Murat Faik Erdoğan; Con-trol/Supervision: Diğdem Özer Etlik; DataCollection and/or Processing: Diğdem ÖzerEtlik; Diğdem Özer Etlik; Analysis and/or In-terpretation: Diğdem Özer Etlik; LiteratureReview: Diğdem Özer Etlik; Writing the Arti-cle: Diğdem Özer Etlik; Critical Review: MuratFaik Erdoğan; Materials: Diğdem Özer Etlik.

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References1. Pearce EN, Andersson M, Zimmermann MB. Global

iodine nutrition: where do we stand in 2013? Thy-roid. 2013;23:523-528. [Crossref] [PubMed]

2. Benoist B, Andersson M, Egli I, Takkouche B, AllenH. Iodine status worldwide World Health Organisa-tion Global Database on Iodine Deficiency. Geneva:WHO Library Cataloguing-in-Publication Data;2004:58.

3. Erdoğan G, Erdogan MF, Emral R, Baştemir M, SavH, Haznedaroğlu D, Ustündağ M, Köse R, Kamel N,Genç Y. Iodine status and goiter prevalence inTurkey before mandatory iodization. J EndocrinolInvest. 2002;25:224-228. [Crossref] [PubMed]

4. Allali S, Brousse V, Sacri AS, Chalumeau M, de Mon-talembert M. Anemia in children: prevalence,causes, diagnostic work-up, and long–term conse-quences. Expert Rev Hematol. 2017;10:1023-1028. [Crossref] [PubMed]

5. Watson J, Lee M, Garcia-Casal MN. Consequencesof inadequate intakes of vitamin A, vitamin B12, vi-tamin D, calcium, iron, and folate in older persons.Curr Geriatr Rep. 2018;7:103-113. [Crossref][PubMed] [PMC]

6. World Health Organization. The Global Prevalenceof Anaemia in 2011; World Health Organization:Geneva, Switzerland, 2015. [Link]

7. Republic of Turkey Ministry of Health Statistics An-nuals 2013, Ankara 2014. [Link]

8. Saydam BK, Genc RE, Sarac F, Turfan EC. Preva-lence of anemia and related factors among womenin Turkey. Pak J Med Sci. 2017;33:433-438. [Pub-Med] [PMC]

9. Harika R, Faber M, Samuel F, Kimiywe J, MulugetaA, Eilander A. Micronutrient status and dietary in-take of ıron, vitamin A, iodine, folate and zinc inwomen of reproductive age and pregnant women inEthiopia, Kenya, Nigeria and South Africa: a sys-tematic review of data from 2005 to 2015. Nutri-ents. 2017;9. [Crossref]

10.Nair MK, Augustine LF, Konapur A. Food-based in-terventions to modify diet quality and diversity toaddress multiple micronutrient deficiency. FrontPublic Health. 2016;3:277. [Crossref] [PubMed][PMC]

11.Gernand AD, Schulze KJ, Stewart CP, West KP Jr,Christian P. Micronutrient deficiencies in pregnancyworldwide: health effects and prevention. Nat RevEndocrinol. 2016;12:274-289. [Crossref] [PubMed][PMC]

12.Darnton-Hill I, Webb P, Harvey PW, Hunt JM,Dalmiya N, Chopra M, Ball MJ, Bloem MW, deBenoist B. Micronutrient deficiencies and gender:social and economic costs. Am J Clin Nutr.2005;81:1198S-1205S. [Crossref] [PubMed]

13.Zimmermann MB, Köhrle J. The impact of iron andselenium deficiencies on iodine and thyroid metab-olism: biochemistry and relevance to public health.Thyroid. 2002;12:867-878. [Crossref] [PubMed]

14.Wolde-Gebriel Z, West CE, Gebru H, TadesseAS, Fisseha T, Gabre P, Aboye C, Ayana G, HautvastJG. Interelationship between vitamin A, iodine andiron status in schoolchildren in Shoa Region, central

Ethiopia. Br J Nutr. 1993;70:593-560. [Crossref][PubMed]

15.Pathak P, Singh P, Kapil U, Raghuvanshi RS. Preva-lence of iron, vitamin A and iodine deficienciesamongst adolescent pregnant mothers. Indian J Pe-diatr. 2003;70:299-301. [Crossref] [PubMed]

16.Azizi F, Mirmiran P, Sheikholeslam R, Hedeyati M,Rastmanesh R. The relation between serum ferritinand goiter, urinary iodine and thyroid hormone con-centration. Int J Vitam Nutr Res. 2002;72:296-299. [Crossref] [PubMed]

17.Yavuz O, Yavuz T, Kahraman C, Yeşildal N, BundakR. The relationship between iron status and thyroidhormones in adolescents living in an iodine deficientarea. J Pediatr Endocrinol Metab. 2004;17:1443-1449. [Crossref] [PubMed]

18.Giray B, Arnaud J, Sayek I, Favier A, Hincal F. Traceelements status in multinodular goiter. J Trace ElemMed Biol. 2010;24:106-110. [Crossref] [PubMed]

19.Erdoğan MF, Ağbaht K, Altunsu T, Ozbaş S, YücesanF, Tezel B, Sargin C, Ilbeğ I, Artik N, Köse R, Er-doğan G. Current iodine status in Turkey. J En-docrinol Invest. 2009;32:617-622. [Crossref][PubMed]

20.Zimmermann M, Adou P, Torresani T, Zeder C, Hur-rell R. Persistence of goiter despite oral iodine sup-plementation in goitrous children with irondeficiency anemia in Cote d’Ivoire. Am J Clin Nutr.2000;71:88-93. [Crossref] [PubMed]

21.Sivakumar B, Brahmam GN, Madhavan Nair M, Ran-ganathan S, Vishnuvardhan Rao M, VijayaraghavanK, Krishnaswamy K. Prospects of fortification of saltwith iron and iodine. Br J Nutr. 2001;85:S167-173. [Crossref] [PubMed]

22.Zimmermann MB, Zeder C, Chaouki N, Torresani T,Saad A, Hurrell RF. Addition of microencapsulatediron to iodized salt improves the efficacy of iodine ingoitrous, iron-deficient children: a randomized,double-blind, controlled trial. Eur J Endocrinol.2002;147:747-753. [Crossref] [PubMed]

23.Hess SY, Zimmermann MB, Adou P, TorresaniT, Hurrell RF. Treatment of iron deficiency in goitrouschildren improves the efficacy of iodized salt in Coted’Ivoire. Am J Clin Nutr. 2002;75:743-748. [Cros-sref] [PubMed]

24.Beard JL, Brigham DE, Kelley SK, Green MH. Plasmathyroid hormone kinetics are altered in iron-defi-cient rats. J Nutr. 1998;128:1401-1408. [Crossref][PubMed]

25.Andersson M, Karumbunathan V, Zimmermann MB.Global iodine status in 2011 and trends over thepast decade. J Nutr. 2012;142:744-750. [Crossref][PubMed]

26.Le SN, Porebski BT, McCoey J, Fodor J, Riley B,Godlewska M, Góra M, Czarnocka B, Banga JP,Hoke DE, Kass I, Buckle AM. Modelling of thyroidperoxidase reveals insights into its enzyme functionand autoantigenicity. PLoS One. 2015;10:e0142615. [Crossref] [PubMed] [PMC]

27.Hu X, Teng X, Zheng H, Shan Z, Li J, Jin T, Xiong C,Zhang H, Fan C, Teng W. Iron deficiency withoutanemia causes maternal hypothyroxinemia in preg-nant rats. Nutr Res. 2014;34:604-612. [Crossref][PubMed]

45

Turk J Endocrinol Metab Özer Etik et al.2019;23:38-46 Iron Deficiency and Thyroid Volume

45

46

Özer Etik et al. Turk J Endocrinol MetabIron Deficiency and Thyroid Volume 2019;23:38-46

46

28.Khatiwada S, Gelal B, Baral N, Lamsal M. Associa-tion between iron status and thyroid function inNepalese children. Thyroid Res. 2016;29:2. [Cros-sref] [PubMed] [PMC]

29.Yu X, Shan Z, Li C, Mao J, Wang W, Xie X,Liu A, Teng X, Zhou W, Li C, Xu B, Bi L, Meng T,Du J, Zhang S, Gao Z, Zhang X, Yang L, Fan C, TengW. Iron deficiency, an independent risk factor forisolated hypothyroxinemia in pregnant and non-pregnant women of childbearing age in China. J ClinEndocrinol Metab. 2015;100:1594-1601. [Crossref][PubMed]

30.Eftekhari MH, Keshavarz SA, Jalali M, ElgueroE, Eshraghian MR, Simondon KB. The relationship

between iron status and thyroid hormone concen-tration in iron-deficient adolescent Iranian girls. AsiaPac J Clin Nutr. 2006;15:50-55. [PubMed]

31.Maldonado-Araque C, Valdes S, Lago-Sampedro A,Lillo-Muñoz JA, Garcia-Fuentes E, Perez-Valero V,Gutierrez-Repiso C, Goday A, Urrutia I, Peláez L,Calle-Pascual A, Castaño L, Castell C, Delgado E,Menendez E, Franch-Nadal J, Gaztambide S4, Gir-bés J, Ortega E, Vendrell J, Chacón MR, Chaves FJ,Soriguer F, Rojo-Martínez G. Iron deficiency is as-sociated with hypothyroxinemia and hypotri-iodothyroninemia in the Spanish general adultpopulation: Di@bet.es study. Sci Rep. 2018;8:6571.[Crossref] [PubMed] [PMC]

Relationship Between Sarcopenia andType 2 Diabetes Mellitus in Elderly Patients

Yaşlı Hastalarda Sarkopeni veTip 2 Diabetes Mellitus Arasındaki İlişki

Division of Endocrinology and Metabolism, Gaziantep University School of Medicine, Gaziantep*Division of Geriatric Medicine, Gaziantep University School of Medicine, Gaziantep

Address for Correspondence: Zeynel Abidin Sayiner, Gaziantep University, School of Medicine,Division of Endocrinology & Metabolism, Gaziantep, Turkey

Phone: 0342 360 60 60 E-mail: zeynelasayiner@hotmail.comReceived: 30/08/2018 Received in revised form: 15/10/2018 Accepted: 12/11/2018 Available online: 20/03/2019

®Copyright 2018 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

ReviewTurk J Endocrinol Metab 2019;23:47-52

IntroductionType 2 diabetes mellitus (T2DM) is a globalhealth concern. Its prevalence has continuedto increase even during 2018, and it has beenpredicted that it would affect 592 million in-dividuals by 2035 (1). The occurrence ofT2DM is at its peak during the age of 65 yearsin males and 75 years (2,3) in females.Among the elderly population, T2DM hasbeen associated with decreased physical ac-tivity and low muscle strength. Although

chronic conditions like hypertension, visualimpairment, coronary heart disease, periph-eral artery diseases, obesity, arthritis, anddepression are major risk factors for T2DM,yet the reason for physical disability is still notcompletely understood (4). Approximatelyhalf the causes of physical disability amongelderly T2DM patients remain unexplained(5). Studies on the musculoskeletal systemsof elderly T2DM patients have presented con-flicting results due to the pathogenetic com-

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Sarcopenia has been defined as a condition of decreasedmuscle strength, as measured by gait speed and gripstrength, in the presence of low muscle mass. It is alsoknown that the total muscle mass generally decreases by1% after the age of 40 years. Type 2 diabetes mellitus(T2DM) is a global health concern that has continued to af-fect people even during 2018; its prevalence increases withage. Among the several factors that lead to sarcopenia inelderly patients, insulin resistance is one. However, it is stillnot clear whether this resistance is a coincidence or a con-sequence of diabetes. Common pathophysiological mecha-nisms between sarcopenia and diabetes make it difficult todistinguish the order of development of sarcopenia andT2DM. Prospective studies have demonstrated that lowmuscle mass and muscle strength may be associated withthe development of T2DM. It has also been shown thatT2DM exacerbates sarcopenia in elderly T2DM patients. Ne-vertheless, further research is needed to ascertain the exactnature of the relationship between sarcopenia and T2DM,so that their underlying causes may be minimized.

Keywords: Sarcopenia; type 2 diabetes mellitus;ageing; insulin resistance

Sarkopeni, düşük kas kütlesinin varlığında yürüyüş hızı vekavrama gücü ile ölçülen azalmış kas gücü durumu olaraktanımlanmıştır. Ayrıca, toplam kas kütlesinin 40 yaşındansonra genellikle %1 azaldığı da bilinmektedir. Tip 2 dia-betes mellitus (Tip 2 DM), 2018 yılında hala insanları et-kilemeye devam eden küresel bir sağlık sorunudur veprevalansı yaşla birlikte artmaktadır. Yaşlı hastalarda sar-kopeniye yol açan çeşitli faktörler arasında insülin direncide bulunmaktadır. Bununla birlikte, bu direncin bir rast-lantı mı yoksa diyabetin bir sonucu mu olduğu hâlâ netdeğildir. Sarkopeni ve diyabet arasındaki yaygın ortak pa-tofizyolojik mekanizmalar sarkopeni ve Tip 2 DM gelişimsırasını ayırt etmeyi zorlaştırmaktadır. Prospektif çalışma-lar, düşük kas kütlesinin ve kas gücünün Tip 2 DM'nin ge-lişimi ile ilişkili olabileceğini göstermiştir. Tip 2 DMvarlığının yaşlı Tip 2 DM hastalarında sarkopeniyi artırdığıda gösterilmiştir. Bununla birlikte, sarkopeni ve Tip 2 DMarasındaki ilişkinin kesin doğasını saptamak için dahafazla detaylı araştırmaya ihtiyaç olduğu aşikârdır.

Anahtar kelimeler: Sarkopeni; tip 2 diabetes mellitus;yaşlanma; insulin rezistansı

47

plexity of the condition. Alterations in themuscular function of these patients may actas a pathophysiological pathway for the phys-ical disability. Nevertheless, this possibilityhas not yet been thoroughly explored. TheHealth, Aging, and Body Composition (ABC)study investigated the body compositionamong adults aged 70 to 79 years and re-ported that older adults with T2DM havelower skeletal muscle strength and quality(6). In a study performed on diabetic patientswith dementia, it was found that musclestrength and muscle quality decreased, al-though the muscle mass did not change (7).Furthermore, while it is known that skeletalmuscle tissue is the largest insulin-dependentorgan in the body, whether the loss of mus-cle mass and function leads to increased in-sulin resistance and, consequently, diabetesor vice versa still remain unclear. Thereforethe present study attempts to understand thenature of this relationship.

How can insulin resistance anddiabetes lead to sarcopenia?Several factors may cause sarcopenia in eld-erly patients, insulin resistance being one ofthem. Additionally, the presence of T2DMaccelerates muscle loss and involves thepresence of factors such as glucose toxicity,insulin resistance, reduced bone metabo-lism, increased inflammatory processes, andgenetics. These factors cause wide varia-tions in muscle mass and the degree ofstrength among individuals; therefore, theresults of different studies related to thistopic are inconsistent.Previous studies have observed a decreasein the genetic expression of insulin-likegrowth factor-1 (IGF1), ciliary neurotrophicfactor (CNF), and insulin-like growth factorbinding protein-5 (IGFB5) gene expressionalong with an increase in the expression ofthe MSTN gene. The MSTN gene gives in-structions for controlling myostatin activity.A mutation in this gene results in decreasedmuscle function (8).Another study demonstrated that other con-ditions including the increased expression ofinflammation and apoptosis mediationgenes such as the complement componentfork-head box O3A (FOXO3A), galectin-1,CCAAT/enhancer binding-b (C/EBP-b) and1q subcomponent peptide (C1Q-a) may also

exist (9). Yet, the number of genes sus-pected for sarcopenia possesses too manypolymorphisms, with only a few of thembeing specific for sarcopenia. Therefore,careful isolation of significant genes is es-sential for pharmacogenetic intervention ofsarcopenia in elderly T2DM patients.Diabetic rat models have demonstrated al-tered metabolism and function of skeletalmuscles; the main mechanism involved in thisprocess is the reduced glucose uptake in type-1 fiber-rich muscles. Furthermore, fiber atro-phy has been observed to occur in the fastand slow muscles among diabetic rats (10).Several other studies have proved the exis-tence of a common pathway between sar-copenia and an insulin-resistant state(11,12). These studies have revealed thedominance of myofiber lipid accumulation inboth the conditions. Furthermore, the im-paired synthesis of a myosin heavy chainhas been observed to be connected withboth, ageing and post-prandial insulin se-cretion. It has therefore been concluded thatmuscle protein synthesis is resistant to in-sulin action in the non-diabetic elderly pa-tients. On the other hand, additive insulinresistance may play a role in sarcopenia inelderly diabetic patients (13).Contrarily, some studies did not report anychange in muscle protein synthesis andamino acid usage of muscles (14,15). More-over, the cellular mechanism responsible forreduced protein synthesis, due to insulin re-sistance, in elderly diabetic patients has stillnot been established. However, it is possiblethat the regulation of gene translation signal-ing pathways may play a major role in this re-duction. Insulin resistance is also associatedwith an impaired mitochondrial function inmuscle tissue, and most diabetic patients ex-perience a reduction in mitochondrial size.It is a well-known fact that insulin resistanceincreases the cytoplasmic fatty acids in eld-erly patients, and this accumulation, in turn,increases the stress on cellular mitochon-dria. Such mitochondrial stress may be acommon pathophysiological pathway in bothinsulin resistance and ageing. In addition,myosteatosis may also play a role.Myosteatosis is a condition characterized bylipid or adipose cell infiltration in musclecells due to aging. It implicates increasedstress on cellular mitochondria which in turn

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results in increased oxidative stress and thephosphorylation of insulin receptors thatmay cause impaired insulin binding to cells.Overall, these changes lead to impairedmuscle function and may cause sarcopeniain diabetic patients (16,17).Diabetes also leads to decreased motor-endplate innervation due to peripheral neuropa-thy, which may consequently result in a de-crease in coordinated muscle contraction.Ageing may also contribute to a decrease inmotor-end plates. The reductive impact ofboth, ageing and T2DM on IGF-1 levels andprotein synthesis is a well-known fact amongresearchers. Moreover, the decline in IGF-1level induces atherogenic activation and in-creased proteolysis. Low levels of bioavail-able testosterone may play a crucial role inboth ageing and T2DM patients in consider-ation of the fact that testosterone stimulatesthe inhibition of adipocyte production. Inboth these types of patients, exercise capac-ity is decreased and weight loss may causemuscle wasting. Anorexia is also commonlyobserved among elderly patients and maysometimes be considered as a physiologicalfactor of ageing. However, if anorexia super-imposes a disease, it may induce muscle at-rophy and severe weight loss.Atherosclerosis, a common health problemamong elderly patients, decreases blood flowto the muscles and leads to muscle hypoxia,which in turn causes tissues to become in-tolerant to exercise and, therefore, gatherpro-inflammatory cytokines (18).A general loss of self-management abilityamong T2DM patients may also play a rolein the development of sarcopenia. It is well-known that T2DM may be associated with animpaired executive function (IEF) amongpatients with normal cognition, yet themechanism of IEF in T2DM is not fully un-derstood. Cerebral microvascular diseaseand chronic hyperglycemia are also possibleconfounding factors for functional neuronaldysfunction, which lead to IEF. Hence, a lossof self-management ability may be a re-sponsible mechanism for the developmentof sarcopenia in patients with T2DM (19).Ageing is associated with a decrease in in-sulin secretion by 0.7% per year. In a patientwith T2DM, this reduction can even reach upto 50%. Persistent hyperglycemia leads tothe increased production of advanced glyca-

tion end products (AGEs) which accumulatein the muscle, resulting in muscular stiffnessand reduced muscle function. These AGEsmay play a role in sarcopenia through theup-regulation of inflammation as well as en-dothelial dysfunction in the microcirculationof skeletal muscles (20). In light of theabove information, it can be said that the va-riety of pathophysiological mechanisms in-volved in both these processes causedifficulty in distinguishing the precise orderof development of sarcopenia and T2DM.

Does sarcopenia cause insulin resistance?Prospective studies have demonstrated thatlow muscle mass and strength may be asso-ciated with the development of T2DM (21). Ithas been determined that an assessment ofthe presence of sarcopenia can be used asboth, primary and secondary forms of pre-vention of T2DM in elderly patients (22).Moreover, it is advantageous to study olderadults with T2DM to assess the presence ofsarcopenia in these patients when they showa poor metabolic response to exercises. Asmentioned previously, the skeletal muscle isthe largest insulin-dependent tissue of thebody. Furthermore, sarcopenia promotes in-sulin resistance regardless of obesity. Thepresence of both, sarcopenia and obesity, to-gether causes more severe insulin resistance;(23) again making it difficult to distinguish therelationship between sarcopenia and insulinresistance. Further, regarding the action of in-sulin on mitochondrial proteins, it has beenobserved that insulin is a major regulatingfactor for mitochondrial oxidative phosphory-lation in skeletal muscles. Thus, insulin resist-ance is involved in muscle protein loss relatedto ageing and may lead to sarcopenia (24).

Therapeutic approaches for elderlydiabetic sarcopenic patientsExercise may play an important role in re-versing sarcopenia and improving glucoseregulation among elderly patients. An exer-cise regimen including strength and powertraining as well as balance exercises mayimprove functional capacities and metabolicprofiles in patients. However, the role oftight glycemic control still remains unclear.Uncontrolled diabetes (HbA1c ≥8.0% or≥8.5%) has been associated with low walk-ing speed while good glycemic control

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(HbA1c <7%) has been associated with bet-ter performance (25). Ozturk et al. (26)have demonstrated that lowering HbA1c lev-els may positively affect the muscle mass ofelderly diabetic patients. However, otherstudies have not observed any positive im-pact of tight glycemic control on physicalfunction; although tight glycemic controlmay be associated with an increased risk ofhypoglycemia, falls, and fractures (27,28).Sarcopenia, which develops in geriatric pa-tients, is often associated with changes inthe endocrine and nervous system. Klinefel-ter syndrome or motor neuron disease (e.g.,amyotrophic lateral sclerosis) is known to beassociated with impaired muscle structureand decreased physical performance. There-fore, these diseases are used as prototypicdisease models to study the isolated en-docrinological and neurodegenerativecauses of sarcopenia (29).Sarcopenia and Physical fRailty in the olderpeople: Multi-component T TreatmentStrategies (SPRINT) study emphasizes theimportance of prevention of immobility inelderly individuals with physical fragility andsarcopenia (30).Pharmacological interventions have notbeen proven to be superior to exercise train-ing regimens, and their benefits for improv-ing appetite are limited. For example,hormone replacement therapy involving an-drogens and growth hormones has failed tohave a positive impact on the frailty of eld-erly patients. On the other hand, several an-tidiabetic drugs have shown positive effectson sarcopenia (31). For example, it hasbeen speculated that metformin may causemuscle strength improvement among T2DMpatients (32). Furthermore, glitazones anddipeptidyl peptidase-4 inhibitors may im-prove the blood supply of muscles (33,34).On the other hand, it has been shown thatsulfonylureas, especially glibenclamide, andglinides may have an atrophic effect onmuscles (35). Lastly, although insulin in-creases protein synthesis in young adults,this effect has not been observed amongelderly individuals (36). In addition, newtherapies such as testosterone, selective an-drogen receptor modulators, myostatin in-hibitors, ghrelin analogs, vitamin K andmesenchymal stem cell therapy have beenobserved to be promising treatments (37).

ConclusionThe prevalence of sarcopenia and T2DMamong contemporary elderly population con-tinues to increase. Oxidative injury, mitochon-drial dysfunction, lipid and AGE accumulation,the dysregulation of several genetic pathways,a loss of self-management, hormonal changesparticularly testosterone deficiency, and de-creased motor-end plates are all major factorsin the development of both, sarcopenia and di-abetes. These common pathophysiologicalmechanisms between sarcopenia and diabetesmake it difficult to determine the exact natureof the relationship between sarcopenia andT2DM. Thus, this distinction must remain anactive area of research. Future studies shouldattempt to distinguish more clearly, the orderof development of sarcopenia and diabetes inorder to minimize the common underlyingcauses of both these disorders.

AcknowledgementsWe thank Morgan Blair for language im-provement and proofreading this article.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Zeynel Abidin Sayiner, ZeynelAbidin Öztürk; Design: Zeynel Abidin Sayiner,Zeynel Abidin Öztürk; Control/Supervision:Zeynel Abidin Sayiner, Zeynel Abidin Öztürk;Data Collection and/or Processing: ZeynelAbidin Sayiner, Zeynel Abidin Öztürk; Analysisand/or Interpretation: Zeynel Abidin Sayiner,Zeynel Abidin Öztürk; Literature Review:Zeynel Abidin Sayiner, Zeynel Abidin Öztürk;Writing The Article: Zeynel Abidin Sayiner,

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Zeynel Abidin Öztürk; Critical Review: ZeynelAbidin Sayiner, Zeynel Abidin Öztürk; Refer-ences And Fundings: Zeynel Abidin Sayiner,Zeynel Abidin Öztürk; Materials: ZeynelAbidin Sayiner, Zeynel Abidin Öztürk.

References1. Diabetes UK. Diabetes: Facts and stats. Diabetes

UK Care Connect Campaign; 2014:17. [Link]2. Kautzky-Willer A, Harreiter J, Pacini G. Sex and gen-

der differences in risk, pathophysiology and compli-cations of type 2 diabetes mellitus. Endocr Rev.2016;37:278-316. [Crossref] [PubMed] [PMC]

3. King H, Aubert RE, Herman WH. Global burden ofdiabetes, 1995-2025: prevalence, numerical esti-mates, and projections. Diabetes Care.1998;21:1414-1431. [Crossref] [PubMed]

4. Manco M, Nolfe G, Calvani M, Natali A, Nolan J, Fer-rannini E, Mingrone G; European Group for the Studyof Insulin Resistance. Menopause, insulin resistance,and risk factors for cardiovascular disease.Menopause. 2006;13:809-817. [Crossref] [PubMed]

5. Von Korff M, Katon W, Lin EH, Simon G,Ciechanowski P, Ludman E, Oliver M, Rutter C,Young B. Work disability among individualswith diabetes. Diabetes Care. 2005;28:1326-1332.[Crossref] [PubMed]

6. Park SW, Goodpaster BH, Strotmeyer ES, deRekeneire N, Harris TB, Schwartz AV, Tylavsky FA,Newman AB. Decreased muscle strength and qual-ity in older adults with type 2 diabetes: the health,aging, and body composition study. Diabetes.2006;55:1813-1818. [Crossref] [PubMed]

7. Tsugawa A, Ogawa Y, Takenoshita N, Kaneko Y,Hatanaka H, Jaime E, Fukasawa R, Hanyu H. De-creased muscle strength and quality in diabetes-re-lated dementia. Dement Geriatr Cogn Dis Extra.2017;7:454-462. [Crossref] [PubMed] [PMC]

8. Dennis RA, Przybyla B, Gurley C, Kortebein PM,Simpson P, Sullivan DH, Peterson CA. Aging altersgene expression of growth and remodeling factorsin human skeletal muscle both at rest and in re-sponse to acute resistance exercise. Physiol Ge-nomics. 2008;32:393-400. [Crossref] [PubMed]

9. Zahn JM, Sonu R, Vogel H, Crane E, Mazan-Mam-czarz K, Rabkin R, Davis RW, Becker KG, Owen AB,Kim SK. Transcriptional profiling of aging in humanmuscle reveals a common aging signature. PLoSGenet. 2006;2:e115. [Crossref] [PubMed] [PMC]

10.Punkt K, Psinia I, Welt K, Barth W, Asmussen G. Ef-fects on skeletal muscle fibres of diabetes andGinkgo biloba extract treatment. Acta Histochem.1999;101:53-69. [Crossref]

11.Janssen I, Ross R. Linking age-related changes inskeletal muscle mass and composition with metab-olism and disease. J Nutr Health Aging.2005;9:408-419. [PubMed]

12.Furler SM, Poynten AM, Kriketos AD, Lowy AJ, EllisBA, Maclean EL, Courtenay BG, Kraegen EW, Camp-bell LV, Chisholm DJ. Independent influences of cen-tral fat and skeletal muscle lipids on insulinsensitivity. Obes Res. 2001;9:535-543. [Crossref][PubMed]

13.Rasmussen BB, Fujita S, Wolfe RR, Mittendorfer B,Roy M, Rowe VL, Volpi E. Insulin resistance of mus-cle protein metabolism in aging. FASEB J.2006;20:768-769. [Crossref] [PubMed] [PMC]

14.Möller-Loswick AC, Zachrisson H, Hyltander A,Körner U, Matthews DE, Lundholm K. Insulin selec-tively attenuates breakdown of nonmyofibrillar pro-teins in peripheral tissues of normal men. Am JPhysiol. 1994;266:E645-E652. [PubMed]

15.Nygren J, Nair KS. Differential regulation of proteindynamics in splanchnic and skeletal muscle beds byinsulin and amino acids in healthy human subjects.Diabetes. 2003;52:1377-1385. [Crossref] [PubMed]

16.Boushel R, Gnaiger E, Schjerling P, Skovbro M,Kraunsøe R, Dela F. Patients with type 2 diabeteshave normal mitochondrial function in skeletal mus-cle. Diabetologia. 2007;50:790-796. [Crossref][PubMed] [PMC]

17.Turner N, Heilbronn LK. Is mitochondrial dysfunc-tion a cause of insulin resistance? Trends EndocrinolMetab. 2008;19:324-330. [Crossref] [PubMed]

18.Morley JE, Malmstrom TK, Rodriguez-Mañas L, Sin-clair AJ. Frailty, sarcopenia and diabetes. J Am MedDir Assoc. 2014;15:853-859. [Crossref] [PubMed]

19.Thabit H, Kyaw Tun T, McDermott J, Sreenan S. Ex-ecutive function and diabetes mellitus--a stone leftunturned? Curr Diabetes Rev. 2012;8:109-115.[Crossref] [PubMed]

20.Semba RD, Bandinelli S, Sun K, Guralnik JM, Fer-rucci L. Relationship of an advanced glycation endproduct, plasma carboxymethyl-lysine, with slowwalking speed in older adults: the InCHIANTI study.Eur J Appl Physiol. 2010;108:191-195. [Crossref][PubMed] [PMC]

21.Bianchi L, Volpato S. Muscle dysfunction in type 2diabetes: a major threat to patient’s mobility andindependence. Acta Diabetol. 2016;53:879-889.[Crossref] [PubMed]

22.Park SW, Goodpaster BH, Strotmeyer ES, Kuller LH,Broudeau R, Kammerer C, de Rekeneire N, HarrisTB, Schwartz AV, Tylavsky FA, Cho YW, Newman AB;Health, Aging, and Body Composition Study. Accel-erated loss of skeletal muscle strength in olderadults with type 2 diabetes: the health, aging, andbody composition study. Diabetes Care. 2007;30:1507-1512. [Crossref] [PubMed]

23.Mitranun W, Deerochanawong C, Tanaka H, SuksomD. Continuous vs interval training on glycemic con-trol and macro- and microvascular reactivity in type2 diabetic patients. Scand J Med Sci Sports.2014;24:e69-76. [Crossref] [PubMed]

24.Bhanji RA, Narayanan P, Allen AM, Malhi H, Watt KD.Sarcopenia in hiding: the risk and consequence ofunderestimating muscle dysfunction in nonalcoholicsteatohepatitis. Hepatology. 2017;66:2055-2065.[Crossref] [PubMed]

25.Guillet C, Boirie Y. Insulin resistance: a contributingfactor to age-related muscle mass loss? DiabetesMetab. 2005;31:5S20-5S26.

26.Ozturk ZA, Türkbeyler HA, Demir Z, Bilici M, KepekçiY. The effect of blood glucose regulation on sar-copenia parameters in obese and diabetic patients.Turk J Phys Med Rehab. 2018;64:72-79. [Crossref]

51

Turk J Endocrinol Metab Sayiner et al.2019;23:47-52 Sarcopenia and T2DM Interaction in Elderly Patients

51

27.Yau CK, Eng C, Cenzer IS, Boscardin WJ, Rice-Trum-ble K, Lee SJ. Glycosylated hemoglobin and func-tional decline in community-dwelling nursinghome-eligible elderly adults with diabetes mellitus.J Am Geriatr Soc. 2012;60:1215-1221. [Crossref][PubMed] [PMC]

28.Kalyani RR, Tian J, Xue QL, Walston J, Cappola AR,Fried LP, Brancati FL, Blaum CS. Hyperglycemia andincidence of frailty and lower extremity mobility lim-itations in older women. J Am Geriatr Soc.2012;60:1701-1707. [Crossref] [PubMed] [PMC]

29.Stangl MK, Bo cker W, Chubanov V, Ferrari U, Fis-chereder M, Gudermann T, Hesse E, Meinke P,Reincke M, Reisch N, Saller MM, Seissler J1,Schmidmaier R, Schoser B, Then C, Thorand B,Drey M. Alzheimer disease; dementia; diabetesmellitus; dynapenia; muscle; sarcopenia. Exp ClinEndocrinol Diabetes. 2018 Sep 10. [Epub ahead ofprint]. [Crossref]

30.Marzetti E, Cesari M, Calvani R, Msihid J, Tosato M,Rodriguez-Manas L, Lattanzio F, Cherubini A, BejuitR, Di Bari M, Maggio M, Vellas B, Dantoine T, Cruz-Jentoft AJ, Sieber CC, Freiberger E, Skalska A,Grodzicki T, Sinclair AJ, Topinkova E, Ryznarova I,Strandberg T, Schols AMWJ, Schols JMGA, Roller-Wirnsberger R, Jonsson PV, Ramel A, Del Signore S,Pahor M, Roubenoff R, Bernabei R, Landi F;SPRINTT Consortium. The “Sarcopenia and PhysicalfRailty IN older people: multi-componenT Treatmentstrategies” (SPRINTT) randomized controlled trial:case finding, screening and characteristics of eligi-ble participants. Exp Gerontol. 2018;113:48-57.[Crossref] [PubMed]

31.Morley JE, Kim MJ, Haren MT. Frailty and hor-mones. Rev Endocr Metab Disord. 2005;6:101-108. [Crossref] [PubMed]

32.Wang CP, Lorenzo C, Espinoza SE. Frailty attenuatesthe impact of metformin on reducing mortality inolder adults with type 2 diabetes. J Endocrinol Dia-betes Obes. 2014;2.

33.Lee CG, Boyko EJ, Barrett-Connor E, Miljkovic I,Hoffman AR, Everson-Rose SA, Lewis CE, CawthonPM, Strotmeyer ES, Orwoll ES; Osteoporotic Frac-tures in Men (MrOS) Study Research Group. Insulinsensitizers may attenuate lean mass loss in oldermen with diabetes. Diabetes Care. 2011;34:2381-2386. [Crossref] [PubMed] [PMC]

34.Abdulla H, Phillips B, Smith K, Wilkinson D, AthertonPJ, Idris I. Physiological mechanisms of action of in-cretin and insulin in regulating skeletal muscle me-tabolism. Curr Diabetes Rev. 2014;10:327-335.[Crossref] [PubMed]

35.Mele A, Calzolaro S, Cannone G, Cetrone M, ConteD, Tricarico D. Database search of spontaneous re-ports and pharmacological investigations on the sul-fonylureas and glinides-induced atrophy in skeletalmuscle. Pharmacol Res Perspect. 2014;2:e00028.[Crossref] [PubMed] [PMC]

36.Sinclair A, Vellas B. Editorial: frailty-an emerginghigh impact complication of diabetes requiring spe-cific management approaches. J Nutr Health Aging.2017;21:193-194. [Crossref] [PubMed]

37.Batsis JA, Villareal DT. Sarcopenic obesity in olderadults: aetiology, epidemiology and treatmentstrategies. Nat Rev Endocrinol. 2018;14:513-537.[Crossref] [PubMed] [PMC]

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Address for Correspondence: Sepideh Tahsini Tekantapeh, Tabriz University of Medical Science,Endocrine Research Center, Tabriz, Iran

Phone: 09143826012 E-mail: tahsinis@tbzmed.ac.irReceived: 30/01/2016 Received in revised form: 06/02/2017 Accepted: 23/05/2017 Available online: 20/03/2019

®Copyright 2018 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Overlapping Between Thymus NeuroendocrineCarcinoma as an Ectopic Cushing Syndrome andExogenous Cushing’s Syndrome: A Case Report

Ektopik Cushing Sendromu Olan Timus Nöroendokrin Karsinomuile Ekzojen Cushing Sendromu Örtüşmesi: Bir Olgu Sunumu

Tabriz University of Medical Science, Endocrine Research Center, Tabriz, Iran

Case ReportTurk J Endocrinol Metab 2019;23:53-57

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Cushing’s syndrome results from an excess production of the hormonecortisol by the adrenal gland. It can be distinguished into ectopic andexogenous, also known as iatrogenic, depending on whether the causeexists inside or outside the body, respectively. The exogenous diseasecan occur due to the intake of corticosteroids medication. Thymicneuroendocrine carcinoma is one of the most common etiologies ofectopic Cushing’s syndrome. We report a case of overlapping conditionbetween ectopic and exogenous Cushing’s syndromes and discussedthe invasive characteristics of thymic low-grade neuroendocrine carci-noma and its capability to transform to a high-grade carcinoma. A 29-year-old male patient was presented with Cushing’s symptoms andhypokalemia. He had a history of repeated weekly dexamethasone in-jections during last year to treat generalized weakness, without physi-cian's prescription. He reported relative improvement in his generalcondition with the use of corticosteroids. The case was managed asan iatrogenic Cushing’s syndrome because of excessive use of corti-costeroids and low cortisol levels despite suppressed ACTH. He pre-sented with weakness and hypercortisolism eight months after thediscontinuation of dexamethasone with an ACTH >1.500 pg/mL; thesefeatures were in favor of ectopic Cushing's syndrome. Also, a thymusmass was detected on imaging. We performed thymus resection dueto the early stage of the syndrome and there was no sign of metasta-sis to other organs. Pathology reported a thymic carcinoid tumor. Nor-mal calcium, PTH, prolactin, and gastrin levels ruled out theinvolvement of MEN I. Tumor cells were immunoreactive for ACTH, anda whole body scan was performed. An 18-month delay in visiting thedoctor and not undergoing whole body scan led to a severe relapsewith full-blown Cushing’s syndrome, generalized bone pain, pulmo-nary metastatic nodules, hyperplasic adrenals, and widespread bonemetastases as demonstrated by the whole body bone scan. Bilateraladrenalectomy was performed. Metastatic neuroendocrine carcinomagrade III was reported in the pathology. After consultation with an on-cologist, palliative chemotherapy with octreotide was started. He diedbecause of pulmonary metastases, severe opportunistic organism in-fections, and septic shock. This case represented one of endogenoushypercortisolism (ectopic Cushing’s syndrome) masked by the excessexogenous use of glucocorticoids, with unexpected relapse of localizedand lowstage thymus neuroendocrine carcinoid tumor. Its conversionto invasive type within less than two years after thymus resection ledto adrenals, lungs, and all bones metastases.

Keywords: Bilateral adrenal hyperplasia; ectopic Cushing’s syndrome;exogenous Cushing’s syndrome; octreotide;thymus neuroendocrine carcinoma

Cushing sendromu, adrenal bez tarafından kortizol hormonunun fazlaüretimi sonucu gelişmektedir. Buna yol açan sebebin vücudun içindeveya dışında oluşuna göre ektopik ve ekzojen -iyatrojenik olarak da bi-linir- şeklinde ayırt edilebilmektedir. Ekzojen hastalık, kortikosteroid ilaçalımına bağlı olarak ortaya çıkabilmektedir. Timik nöroendokrin karsi-nom, ektopik Cushing sendromunun en sık görülen etiyolojilerinden bi-ridir. Bu çalışmada, ektopik ve ekzojen Cushing sendromlarınınörtüştüğü bir vaka sunulmuş ve timik düşük dereceli nöroendokrin kar-sinomun invaziv özelliklerinin ve yüksek dereceli bir karsinoma dö-nüşme yeteneğinin tartışılması amaçlamıştır. Yirmi dokuz yaşındakierkek hasta, Cushing semptomları ve hipokalemi ile başvurdu. Doktorreçetesi olmaksızın, genel halsizliği tedavi etmek için son bir yıl bo-yunca tekrarlanan haftalık deksametazon enjeksiyonu öyküsü vardı.Hasta, genel kondisyonunda kortikosteroid kullanımı ile rölatif bir dü-zelme olduğunu bildirdi. Süprese ACTH'ye rağmen düşük kortizol dü-zeyleri ve aşırı kortikosteroid kullanımı nedeniyle olgu, iyatrojenikCushing sendromu olarak ele alındı. Deksametazonun kesilmesindensekiz ay sonra ACTH düzeyi >1,500 pg/mL olan hasta, hiperkortizolizmve hâlsizlik ile başvurdu; bu özellikler ektopik Cushing sendromu le-hine idi. Ayrıca, görüntülemede timus kitlesi saptandı. Sendromunerken evrede olması nedeniyle timus rezeksiyonu yapıldı ve diğer or-ganlara metastaz belirtisi görülmedi. Patoloji tarafından timik karsinoidtümör rapor edildi. Normal kalsiyum, PTH, prolaktin ve gastrin düzey-leri ile MEN I dışlandı. Tümör hücreleri ACTH için immünreaktif idi vetüm vücut taraması yapıldı. Doktor kontrolüne 18 aylık bir gecikme ilegelinmesi ve tam vücut taraması yapılmaması; tam teşekküllü Cushingsendromu, yaygın kemik ağrısı, pulmoner metastatik nodüller, hiperp-lazik adrenaller ve tam vücut kemik taramasında gösterildiği gibi yay-gın kemik metastazları olan ciddi bir nükse neden oldu. Bilateraladrenalektomi yapıldı. Patoloji tarafından metastatik nöroendokrin kar-sinom grade III olarak rapor edildi. Bir onkologla istişarede bulunul-duktan sonra, oktreotid ile palyatif kemoterapiye başlandı. Hastapulmoner metastazlar, ciddi fırsatçı organizma enfeksiyonları ve septikşok nedeni ile kaybedildi. Bu hastada, aşırı ekzojen glukokortikoid kul-lanımıyla maskelenmiş endojen hiperkortizolizm (ektopik Cushing sen-dromu) ile lokalize ve düşük evre timus nöroendokrin karsinoidtümörün beklenmedik şekilde nüksü ve timus rezeksiyonundan sonraiki yıldan kısa bir süre içinde invaziv tipe dönüşerek adrenalde, akci-ğerde ve tüm kemiklerde metastazlara yol açması sunulmuştur.

Anahtarkelimeler:Bilateral adrenal hiperplazi; ektopik Cushing sendromu;ekzojen Cushing sendromu; oktreotid;timus nöroendokrin karsinomu

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IntroductionEctopic Cushing’s syndrome constitutes one-fifth of all adrenocorticotropic hormone(ACTH)-dependent Cushing’s syndromecauses and one-tenth of all Cushing’s syn-drome etiologies. The most common etiol-ogy of ectopic Cushing’s syndrome is theformation of bronchial carcinoids (1).Thymic carcinoid tumor also has a relativelyhigh prevalence ectopic Cushing’s syndromecauses with a progressive pattern (2). Thepresentation of carcinoid and neuroen-docrine carcinoma of the thymus, as an ec-topic ACTH-induced Cushing’s syndrome, isvery rare (3). Neuroendocrine carcinoid ischaracterized by multiple neurosecretorygranules that release ACTH or rarely CRHleading to Cushing’s symptoms (4, 5). Clin-ical presentations along with imaging andhormonal laboratory data assist in specifyingthe primary site of ectopic secretion of ACTH(1). The aim of this case presentation is toreport the masking effect of ectopic Cush-ing’s syndrome by an excess exogenous useof corticosteroids. Despite being pathologi-cally low grade, it can progress invasivelywithin months even after complete resectionof the thymus.

Case ReportA 29-year-old male patient, without any pre-vious medical problem, reported to the clinicwith swelling of legs and weight gain of 35kg during 1 year. The patient stated self-pre-scribed multiple dexamethasone injectionsweekly during last year to counter general-ized weakness and reported relative im-provement in his general condition by theuse of the corticosteroid. On physical exam-ination, obvious purple striates at the lowerpart of abdomen with at least 2 cm trans-verse diameter, non-pitting lower extremityedema, truncal obesity, moon face appear-ance, and some degree of proximal myopa-thy were observed. Blood pressure wasmeasured to be 138/94 mmHg. On initialassessment, hypokalemia (K: 2.9 mEq/L),normal range of aldosterone (88 pg /mL),low cortisol (8:00 a.m.) level (2 µg/dL), lowlevel of 24-h-urine free cortisol excretion(3.6 µg/24 h), and suppressed ACTH (6рg/mL) were reported. With low cortisol andsuppressed ACTH along with a history of ex-cessive exogenous corticosteroids injection,

iatrogenic Cushing’s syndrome was sug-gested as the most probable diagnosis. Thepatient was discharged with glucocorticoidtapering and discontinuation. Despite rec-ommendations for followup visits, he did nothave any medical visit during eight monthsafter discharge. Aftereight months, he re-ported to the clinic with lower extremityswelling and hypertension with blood pres-sure (BP) of 147/98. He denied any corti-costeroid injection after discharge. Onre-evaluation, high cortisol 8A.M. (122 µg/dL), high 24-h-urine free cortisol excretion(221 µg/24 h), positive low-dose dexam-ethasone test (plasma cortisol, 87 µg/dLafter 0.5 mg dexamethasone q6h for twodays) with very high ACTH (>1500 pg /mL)were reported. Because of the likely in-volvement of the most probable ACTH-de-pendent Cushing’s syndrome, we conductedtests for the analysis of primary site of ACTHsecretion. The chest X-ray (CXR) demon-strated wide mediastinum and obtuse anglecarina. Thoracic computed tomography (CT)scan without contrast showed anterior me-diastinal mass with a size of 66 × 47 mmand some calcified foci. Based on the imag-ing findings, thymoma was the most likelydiagnosis. Abdominal and pelvic CT-scanshowed no evidence of other organ involve-ment. Thymectomy was performed at thesame admission. During surgery, a com-pletely encapsulated mass was seen. Thymiccarcinoid tumor (typical type) without cap-sular invasion was reported in mediastinalmass pathology. There was no involvementof lymph nodes. Immunohistochemistry(IHC) showed positive epithelial membraneantigen (EMA), neuron-specific enolase(NSE), and chromogranin. A staining andnegative carcinoembryonic antigen (CEA),SD45, and CD117 staining. Further, tumorcells were immunoreactive for ACTH. Nor-mal serum calcium, parathyroid hormone(PTH), prolactin, and gastrin levels ruled outprobable MEN I. Chromogranin A level aftersurgery was 34.1 ng/mL (normal range<36.4 ng /mL). We considered the case tobe an early stage of thymic carcinoid tumor(stage I), and therefore, in addition tothymectomy, no further chemotherapy orradiotherapy was performed. Whole bodyscan was requested to detect the possiblehidden metastases. In the first month after

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thymectomy, normal ACTH and cortisol lev-els were obtained. The patient did not un-dergo a whole body scan despite ouremphasis and did not visit the clinic for fol-low-up. After 18 months, he presented withlower extremity swelling, obesity, and gen-eralized body bone pain with high alkalinephosphate (ALP) of 1,414 IU/L. As sus-pected, a whole body scan showed wide-spread multiple bone metastases (Figure 1).The chest-CT-scan, without contrast, re-ported right paratracheal, subcarinal, andbilateral pulmonary hilum lymphadenopa-thy, 8-mm pulmonary nodules, and bilateralpleural effusion in the presence of bilateraladrenal hyperplasia. Bilateral adrenalectomywas performed. The pathology report men-tioned neuroendocrine type carcinoma gradeIII. The IHC showed positive CK, NSE, chro-mogranin, and Ki67 staining and negativeTTF1 and CD45 staining. He was dischargedwith prednisolone 10 mg daily and fludro-cortisone 0.1 mg daily and was referred toan oncologist who started palliativechemotherapy with octreotide. After twomonths, he was admitted to the hospitalwith fever, dyspnea, and respiratory dis-tress. Multiple mixed lytic and blastic bonelesions in all spinal bones and ribs andscapula were seen. The mosaic pattern inlung parenchyma, patchy alveolar consoli-dations, and multiple pulmonary noduleswere observed in the chest CTscan (Figure2). He was admitted to intensive care unit(ICU) with respiratory distress and wasintubated. With high suspicion to oppor-tunistic organism-induced pneumonia, bron-choscopy and pleurocentesis were done. Thepleural culture showed the presence ofPneumocystis carinii. Meropenem,ciprofloxacin and cotrimoxazole werestarted. Unfortunately, he died of severesepsis and multiple pulmonary metastasesin the ICU.

DiscussionCarcinoid tumors are characterized by theexpression of somatostatin receptors.Positron emission tomography (PET)/CT,based on isotope labeling, should assist inthe diagnosis of neuroendocrine tumors inearlier stages (6, 7). Aktas et al. suggestedthe use of 18F-FDG PET/CT scan to detectthe ectopic site of ACTH-secreting tumors

when ectopic Cushing’s syndrome is themost probable diagnosis. In our case, 18F-FDG PET/CT scan showed diffused and in-creased uptake in bilateral adrenalhyperplasia with low FDG affinity in neu-roendocrine mass indicating the tumor to be

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Figure 1: Widespread bone metastases in whole bodyscan 18 months after the thymic neuroendocrine carci-noma resection that is indicative of its invasive hemato-genous spread.

Figure 2: Patchy alveolar consolidations because of op-portunistic organism induced pneumonia and metastaticpulmonary nodules in both lungs with the origin of thymicneuroendocrine carcinoma after bilateral adrenalectomy.

of low grade (8). According to Matejka et al.,somatostatin receptor scintigraphy, using111Indium–octreotide and 99mTechnetium-albumin macroaggregates, can detect unde-tectable ACTH-secreting neuroendocrinecarcinoid tumors (9). Andrés et al. reporteda 50-year-old male patient with thymic car-cinoid, which unlike the usual course, led toectopic Cushing’s syndrome without anymetastases. The patient received multi-modal treatment and showed complete clin-ical and biochemical response (2).Schalin-Jäntti et al. reported a 41-year-oldmale patient with well-differentiated thymicneuroendocrine carcinoma after resectionthat was detected with CT-scan. It was in re-mission for six years. After relapse, fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) PET/CT detected an uptake of theisotope at mediastinum that was resected(10). About 95% of thymic neuroendocrinetumors have metachronous metastasis andtherefore should be followed-up (11). Nodalmetastasis is common in thymic neuroen-docrine tumors and serves as an importantprognostic factor in the surveillance of thesetumors (12). Initially, this patient presentedwith ectopic Cushing’s syndrome masked byexogenous Cushing’s syndrome and ACTHlevel. After eight months, a discontinuationof exogenous corticosteroid userevealed hishidden ectopic Cushing’s syndrome. Thymusmass was detected on medical investiga-tions. After clearly distinguishing ectopicCushing’s syndrome and thymus mass, wedecided to perform a resection of thymuscarcinoid owing to an early stage (stage I)and involvement of no other organ. In thiscase, despite the early stage of thymus car-cinoid tumor, we incredibly faced thymuscarcinoid relapse with adrenal metastases,pulmonary and bone metastases after 18months, and high-grade differentiation oftumor to grade III neuroendocrine carci-noma. The invasive character and poorprognosis, even after complete resection ofcarcinoma, led to its spread via thehematogenous path, and unfortunately, thepatient died from opportunistic organism-in-duced severe sepsis and multi-organ metas-tases. This case presents an example ofmasking ectopic Cushing’s syndrome by ex-ogenous Cushing’s syndrome. The maskingfeature, owing to its aggressive pattern, in

turn, converts the low-grade thymic neu-roendocrine carcinoma to an invasive typewithin a period of less than two years. Thus,frequent follow-ups are essential to detectany relapse.

AcknowledgementsThe authors would like to acknowledge thepatient’s sister for her cooperation and giv-ing consent. I would like to thank Dr. Es-maiel Faraji for his help concerningradiological explorations and giving a basicidea of reporting this case and help in col-lecting data.

Conflict of InterestNo conflict of interest was declared by theauthors.

Financial DisclosureThe authors declared that this study re-ceived no financial support.

Author ContributionsConcept: Esmail Faraji; Design: EsmailFaraji; Data Collection or Processing: Sepi-deh Tahsini Tekantapeh; Analysis or Inter-pretation: Sepideh Tahsini Tekantapeh;Literature Search: Esmail Faraji; Writing:Sepideh Tahsini Tekantapeh.

References1. Alexandraki KI, Grossman AB. The ectopic ACTH

syndrome. Rev Endocr Metab Disord. 2010;11:117-126. [Crossref] [PubMed]

2. Andrés R, Mayordomo JI, Ramón y Cajal S, Tres A.Paraneoplastic Cushing’s syndrome associated to lo-cally advanced thymic carcinoid tumor. Tumori.2002;88:65-67. [PubMed]

3. Arora R, Gupta R, Sharma A, Dinda AK. Primaryneuroendocrine carcinoma of thymus: a rare causeof Cushing’s syndrome. Indian J Pathol Microbiol.2010;53:148-151. [Crossref] [PubMed]

4. Carrillo-Muñoz A, Onofre-Borja M, Borrego-BorregoR, Chávez-Mercado L, Navarro-Reynoso FP, Ibarra-Pérez C. Atypical intermediate-grade mediastinalcarcinoid. Case presentation. Cir Cir. 2011;79:191-195.

5. Dutta D, Mukhopadhyay S, Maisnam I, Ghosh S,Mukhopadhyay P, Chowdhury S. Neuroendocrinecarcinoma of the thyroid causing adrenocorti-cotrophic hormone-dependent Cushing’s syndrome.Thyroid. 2013;23:120-123. [Crossref] [PubMed]

6. Asha HS, Sudeep K, Alexander M, Korula A, Gnana-muthu BR, Thomas N. Cushing’s syndrome in a caseof thymic carcinoma. Indian J Endocrinol Metab.2011;15:346-348. [Crossref] [PubMed] [PMC]

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7. de Perrot M, Spiliopoulos A, Fischer S, Totsch M,Keshavjee S. Neuroendocrine carcinoma (carci-noid) of the thymus associated with Cushing’s syn-drome. Ann Thorac Surg. 2002;73:675-681.[Crossref]

8. Aktas GE, Soyluoglu Demir S, Sarikaya A. Bilateralsymmetrical adrenal hypermetabolism on FDGPET/CT due to Cushing syndrome in well differen-tiated neuroendocrine carcinoma. Rev Esp MedNucl Imagen Mol. 2015;35:118-120. [Crossref][PubMed]

9. Matejka G, Toubeau M, Bernard A, Belleville Y, Vail-lant G, Brun JM. [Thymic carcinoid tumor causingparaneoplastic Cushing syndrome. Diagnostic valueof double-labelled tomoscintigraphy]. Presse Med.1996;25:1201-1202. [PubMed]

10.Schalin-Jäntti C, Asa SL, Arola J, Sane T. Recurrentacute-onset Cushing’s syndrome 6 years after re-moval of a thymic neuroendocrine carcinoma: fromectopic ACTH to CRH. Endocr Pathol. 2013;24:25-29. [Crossref] [PubMed]

11.Christakis I, Qiu W, Silva Figueroa AM, Hyde S, CoteGJ, Busaidy NL, Williams M, Grubbs E, Lee JE, Per-rier ND. Clinical features, treatments, and outcomesof patients with thymic carcinoids and multiple en-docrine neoplasia type 1 syndrome at MD Andersoncancer center. Horm Cancer. 2016;7:279-287.[Crossref] [PubMed]

12.Weksler B, Holden A, Sullivan JL. Impact of positivenodal metastases in patients with thymic carcinomaand thymic neuroendocrine tumors. J Thorac Oncol.2015;10:1642-1647. [Crossref] [PubMed]

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Case ReportTurk J Endocrinol Metab 2019;23:58-63

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Address for Correspondence: Murat Tuncel, Hacettepe University Faculty of Medicine,Department of Nuclear Medicine, Ankara, Turkey

Phone: +90 312 3051336 E-mail: muratmtx@yahoo.comReceived: 28/09/2018 Received in revised form: 02/12/2018 Accepted: 12/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Critical Role of Ga-68 DOTATATE PET-CTin a Patient with Neuroendocrine Tumor and

Second Primary CancerNöroendokrin Tümörlü ve İkincil Primer Tümörü Olan Hastada

Ga-68 DOTATATE PET-BT’nin Kritik Rolü

Department of Nuclear Medicine, Hacettepe University Faculty of Medicine,*Department of Medical Oncology,Hacettepe University Faculty of Medicine, Ankara, Turkey

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A 70-year-old female with the diagnosis of the metastaticneuroendocrine tumor was referred to our clinic with newabdominal lymph nodes in computed tomography (CT). Thisfinding was considered as the disease progression, andcapecitabine along with temozolomide was added to her cur-rent lanreotide therapy. The origin of the new lymph nodeswas uncertain due to no response to chemotherapy and thestability of the lymph nodes. 68Ga-DOTATATE PET-CT wasperformed to resolve the inconsistency in clinical and imag-ing findings. PET-CT images showed high 68Ga-DOTATATEuptake in abdominal, cervical, left supraclavicular lymphnodes, and few metastatic foci in the liver, which were com-patible with a neuroendocrine tumor. Additionally, therewere bilaterally enlarged lymph nodes in the neck, axillary,intra-abdominal and inguinal area with no tracer uptake. Theincongruent findings of PET-CT suggested a biopsy of non-radio-avid lymph nodes for the possible exclusion of otheretiologies. Biopsy revealed that the enlargement of thelymph nodes was caused by small lymphocytic lymphoma(SLL) rather than neuroendocrine metastases. 68Ga-DOTATATE PET-CT led to a critical change in the diseasemanagement and confirmed the diagnosis of the secondarytumor with the aid of biopsy. A high radiotracer uptake ofneuroendocrine metastases on Ga-68 DOTATATE PET-CTsuggested to change the chemotherapy (capecitabine+temozolomide) to Y-90/Lu-177 DOTATATE therapy, which ledto disease stabilization and minor regression. Her newly di-agnosed stable SLL was followed accordingly. It can be con-cluded that 68Ga-DOTATATE PET-CT plays a critical role in themanagement of patients with neuroendocrine tumors andshould be used as a problem solving tool in patients with thediscrepancy between clinical and imaging findings.

Keywords: Neuroendocrine tumor; lymphoma; PET-CT;peptide receptor radionuclide therapy;Ga–68 DOTATATE

Metastatik nöroendokrin tümörü nedeni ile takipte olan 70 ya-şındaki hasta, bilgisayarlı tomografi (BT) sinde yeni gelişen ab-dominal lenf nodları nedeni ile kliniğimize refere edildi. Yapılandeğerlendirme sonrası, yeni gelişen lenf nodları hastalık prog-resyonu olarak kabul edildi ve hastanın tedavisine, kullanmaktaolduğu lanreotide ek olarak kapesitabin ve temozolomid ek-lendi. Ancak, hastanın kemoterapi yanıtı olmadı ve takip gö-rüntülemelerde lenf nodları stabil olarak seyretti. Bu uyumsuzyanıt nedeni ile hastalık varlığını doğrulama ve ileri araştırmayapmak için hastamıza 68Ga-DOTATATE PET-CT yapıldı. PET-BTgörüntülerinde abdominal, servikal, sol supraklaviküler lenfnodlarında ve karaciğerde birkaç odakta nöroendokrin tümörmetastazı ile uyumlu yüksek 68Ga DOTATATE tutulumu sap-tandı. Ek olarak; bilateral servikal, aksiller, intraabdominal veinguinal bölgelerde radyoaktif madde tutulumu göstermeyenbüyümüş lenf nodları dikkati çekti. PET-BT’deki uyumsuz bul-gular nedeni ile, olası diğer hastalıkların dışlanması amacıylaradyoaktif madde tutmayan lenf nodlarının biyopsisine kararverildi. Yapılan biyopside bu lenf nodlarının nöroendokrin tü-mörü metastazı olmayıp, küçük lenfositik lenfoma (KLL) yabağlı olduğu saptandı. 68Ga DOTATATE PET-BT hastamızdadoğru yerden biyopsi yapılmasına vesile olarak ikinci tümör sap-tanmasını sağlamış ve hasta yönetiminde kritik bir değişikliğeyol açmıştır. Ayrıca, PET-BT’de hastamızda nöroendokrin tümörmetastazlarında yüksek radyoaktif madde tutulumu görülmesietkin olmayan kemoterapiden (kapesitabin+temozolomid) vaz-geçilip, Y-90-Lu-177 DOTATATE tedavisine geçilmesini sağlamışve verilen bu yeni tedavi hastalıkta stabilazyon ve minör geri-lemeye yol açmıştır. Hasta, yeni tanısı konulan ve stabil seyre-den KLL nedeni ile ek takibe alındı. Sonuç olarak, 68GaDOTATATE PET-BT, hastamızda olduğu gibi nöröendokrin tü-mörlü hastaların tedavi yönetiminde kritik rol oynamakta olup,klinik ve görüntüleme yöntemlerinin uyumsuzluğunda problemçözücü bir teknik olarak kullanılmalıdır.

Anahtar kelimeler: Nöroendokrin tümör; lenfoma; PET-CT;peptid reseptör radyonüklid tedavi;Ga-68 DOTATATE

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Figure 1: Contrast enhanced CT images showed mesenteric, peri-pancreatic, paraaortic and paracaval lymph nodes(white arrows).

IntroductionNeuroendocrine tumors (NETs) are a hetero-geneous group of neoplasms that arise fromthe cells of the neuroendocrine system. Thegastrointestinal tract is the most common sitethat accounts for 67% of NETs (1). These tu-mors are commonly diagnosed by endoscopy,computed tomography (CT), or magnetic res-onance imaging. Besides, molecular imagingtechniques are used to identify unique meta-bolic and structural differences. Well differen-tiated NETs tend to grow slowly and havelower metabolic rates. The lower glucose uti-lization results in lower sensitivity for the de-tection with fluorodeoxyglucose (FDG)positron emission tomography (PET) (2).NETs are usually well differentiated anddemonstrate overexpression of cell surfacereceptors of somatostatin (mainly SSR2 andSSR5) that enables molecular imaging ofNETs with radiolabeled somatostatin analogs(SSR imaging) (3). The superiority of SSR im-aging over conventional imaging in NETs hasbeen proved in many clinical situations (4).The major superiority of the SSR imaging isthe specificity of the radiotracer to the NETsthat enables accurate staging of the disease.Most of the guidelines recommend routineuse of abdominal/pelvic multiphasic CT orMRI in staging, though 68Ga-DOTATATE PET-CT (SSR imaging) has been found to be most

appropriate. On the other hand, in the followup only abdominal/pelvic multiphasic CT orMRI is recommended (5). Anatomical imag-ing modalities have limitations: they are notspecific and new structural changes can beevaluated as progression even if they are notassociated with the primary disease. In thiscase report, we emphasize the specificity of68Ga DOTATATE PET-CT and its value in follow-up in a patient with a previous diagnosis ofNET and a new secondary tumor.

Clinical CaseA 70-year-old female with the diagnosis ofmetastatic NET was referred to our clinic.She had a medical history of previous ilealresection with mesenteric lymph node dis-section for ileal NET carried out four yearsago. Her NET had a Ki-67 index of 10% withrare mitotic activity (WHO Grade 2). Herpost-operative In-111 Octreotide scanshowed residual disease foci in the right cer-vical region, left supraclavicular fossa, andin the para-aortic region, and she was beingfollowed up with Lanreotide therapy forthree years.After three years of the stable disease, CTimages showed the development of newabdominal mesenteric, peri-pancreatic,para-aortic, and para-caval lymph nodes(Figure 1: white arrows) in addition to her

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Figure 2: Ga-68 DOTATATE PET-CT images revealed high Ga-68 DOTATATE uptake in mesenteric, paraaortic, rightupper cervical, left supraclavicular, lymph nodes (SUV max:21) and few foci in liver (a: black arrows in maximumintensity projection images, b-c: white arrows in low dose CT and fusion PET-CT). Additionally there were lymphnodes in neck, axillar spaces, intra-abdominal and inguinal bilaterally which show no tracer uptake (b-c red arrowsin low dose CT part of PET-CT).

residual disease in the abdomen. This find-ing was considered as the disease progres-sion, and Capecitabine plus Temozolomidetherapy was added to Lanreotide. Despitechemotherapeutic intensification, the sizeof the lymph nodes showed neither in-crease nor decrease after six months. 68Ga-DOTATATE PET-CT was performed tounravel the inconsistency in the clinical andimaging findings. PET-CT images showedhigh Ga-68 DOTATATE uptake in mesen-teric, paraaortic, right upper cervical, leftsupraclavicular, and lymph nodes (SUVmax:21) and few foci in liver (Figure 2a:black arrows in maximum intensity projec-tion images, Figure 2b, c: white arrows inlow dose CT and fusion PET-CT). Addition-ally, there were enlarged lymph nodes in bi-laterally neck, axillary, intra-abdominal andinguinal spaces which showed no tracer up-take (Figure 2b, c red arrows in low doseCT part of PET-CT). The incongruent find-

ings of PET-CT suggested to carry out thebiopsy of non-radio-avid lymph nodes forpossible exclusion of other diseases. Thebiopsy revealed that the enlargement of thelymph nodes was caused by small lympho-cytic lymphoma (SLL) rather than neuroen-docrine metastases. The chemotherapeuticagents were then stopped, and the patientwas followed by the observation for SLL.However, for NET, the patient was referredto the Nuclear Medicine department for ra-dionuclide therapy due to slowly progress-ing tumor under Lanreotide therapy. Owingto a high radiotracer uptake (SUV max: 21)of neuroendocrine metastases on Ga-68DOTATATE PET-CT and normal kidney func-tions, the patient was considered suitablefor peptide receptor radionuclide therapy.She received one cycle of 4.4 GBq Y-90DOTATATE and one cycle of 7.4 GBq Lu-177DOTATATE therapy (Figure 3a, b). After twocycles, her Ga-68 DOTATATE PET-CT

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(Figure 4 b,d,f) showed a decrease in thesize and tracer uptake of lymph nodes inthe right neck, left supraclavicular fossa,

abdominal lymph nodes and disappearanceof foci in the liver compared to the pre-therapy scan (Figure 4 a,c,e).

Figure 3: Post therapy bremsstrahlung images after 4.4 GBq Y-90 DOTATATE (a) planar whole body post therapyimages after one cycle of 7.4 GBq Lu-177 DOTATATE therapy (b). Both scans showed increased uptake in residualdisease in neck and abdominal lymph nodes.

Figure 4: Ga-68 DOTATATE PET-CT was performed after 2 cycles (b,d,f) showed decrease in size and tracer up-take of lymph nodes in right neck, left supraclavicular fossa, abdominal lymph nodes and disappearance of foci inliver when compared to pre-therapy scan. (a,c,e). Mesenteric lymph node size decreased from 25x44 mm to 19x34mm and paraaortic lymph node from 18x21 to 11x20 mm.

Discussion68Ga-DOTATATE PET-CT imaging is themethod of choice in the staging of NETs. Ina study that evaluated patients with knownor suspected neuroendocrine tumors, itshowed sensitivity, specificity, accuracy,positive predictive value, and negative pre-dictive value of 97%, 95.1%, 96.6%,98.5%, and 90.4%, respectively (4). Simi-larly, a meta-analysis found 68Ga-DOTATATEto have an estimated sensitivity and a speci-ficity of 91% (6). The high specificity of theradiotracer is useful as a problem solvingtool in situations like diseases that mimicNETs. In our patient, the new lymph nodeswere considered as the disease progressionwith CT. However, no response to therapyand stability of the lymph nodes createdsuspicion about their origin. Although rou-tine use of 68Ga-DOTATATE is not recom-mended in the guidelines, this specific tracercould be a helpful tool in suspicious situa-tions like in our patient. 68Ga-DOTATATEPET-CT, in some situations like our case, canlead to a critical change in the managementof patients and the diagnosis of the second-ary tumor. PET-CT images also offer a pos-sible therapy option by showing a highradiotracer uptake in NET metastases whichis essential for effective Y-90/Lu-177DOTATATE therapy. Clinical impact of Ga-68DOTATATE PET-CT has also been reported byseveral groups. The referring physicians re-ported that Ga-68 DOTATATE led to achange in suspicion of metastatic disease in24% of the patients (increased in 10% anddecreased in 14%) and intended manage-ment changes were reported in 60% of pa-tients (7). A recent systemic review andmeta-analysis also reported a change in themanagement after SSTR PET/CT occurringin 44% (range, 16-71%) of NET patients(6).This case, to the best of our knowledge, isthe first report of a patient with NET andsecondary cancer as small cell lymphoma.Although the diagnosis of SLL was problem-atic, it showed relatively indolent behaviorand could be followed until several signs ofdisease progression were seen (like pro-gressive cytopenia, significant disease re-lated symptoms, etc.). Although 68Ga-68DOTATATE PET-CT has considerable speci-ficity, some benign and malignant entities,

like hemangioma and meningioma, mayshow faint uptakes (8). Though, SLL did notshow uptake in our patient, there are fewreports of uptake of 68Ga–68 DOTATATE inlymphomas. SSR status was differentamong lymphoma cell types and SSR ex-pression was higher in Hodgkin’s lymphomaof nodular sclerosis subtype and in diffuselarge B-cell lymphoma and lowest with SLL(9).As discussed regarding the clinical effectof 68Ga–68 DOTATATE PET-CT, this modal-ity not only solved the diagnostic dilemmabut also offered new therapy options. Pep-tide receptor radionuclide therapy (PPRT)is a novel therapy option for patientsshowing a high degree of SSR expressionas detected by 68Ga-68 DOTATATE PET-CT.Phase 3 randomized controlled NETTER-1trial for midgut NETs provided strong evi-dence for PPRT in patients with midgutNET (10). The patients with a high degreeof uptake in PET scans, when given Lu-177octreotate therapy compared to high doseoctreotide, show a better progression-freeoverall survival rate. Similarly, our patientwith mild progression received Y-90 andLu-177 octreotate sequentially andshowed a minor response. Finally, 68Ga-DOTATATE PET-CT plays a critical role inthe management of patients with neu-roendocrine tumors and should be used asa problem solving tool in patients with thediscrepancy between clinical and imagingfindings.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientificand medical committee members or mem-bers of the potential conflicts of interest,counseling, expertise, working conditions,share holding and similar situations in anyfirm.

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Authorship ContributionsIdea/Concept: Tuğçe Telli, Murat Tuncel,Saadettin Kılıçkap; Design: Murat Tuncel,Saadettin Kılıçkap; Control/Supervision:“Murat Tuncel, Saadettin Kılıçkap; Data Col-lection and/or Processing: Tuğçe Telli, MuratTuncel; Analysis and/or Interpretation:Tuğçe Telli, Murat Tuncel; Literature Review:Tuğçe Telli, Murat Tuncel, Saadettin Kılıçkap;Writing the Article: Tuğçe Telli, Murat Tun-cel, Saadettin Kılıçkap; Critical Review:Murat Tuncel; References and Fundings:Murat Tuncel, Saadettin Kılıçkap; Materials:Murat Tuncel, Saadettin Kılıçkap.

References1. Intenzo CM, Jabbour S, Lin HC, Miller JL, Kim SM,

Capuzzi DM, Mitchell EP. Scintigraphic imaging ofbody neuroendocrine tumors. Radiographics.2007;27:1355-1369. [Crossref] [PubMed]

2. Garin E, Le Jeune F, Devillers A, Cuggia M, de La-jarte-Thirouard AS, Bouriel C, Boucher E, Raoul JL.Predictive value of 18F-FDG PET and somatostatinreceptor scintigraphy in patients with metastatic en-docrine tumors. J Nucl Med. 2008;50:858-864.[Crossref] [PubMed]

3. Reubi JC. Peptide receptors as molecular targets forcancer diagnosis and therapy. Endocr Rev.2003;24:389-427. [Crossref] [PubMed]

4. Skoura E, Michopoulou S, Mohmaduvesh M, Panagi-otidis E, Al Harbi M, Toumpanakis C, Almukhailed O,Kayani I, Syed R, Navalkissoor S, Ell PJ, Caplin ME,Bomanji J. The impact of 68Ga-DOTATATE PET/CTimaging on management of patients with neuroen-docrine tumors: experience from a national referralcenter in the United Kingdom. J Nucl Med.2016;57:34-40. [Crossref] [PubMed]

5. Kulke MH, Shah MH, Benson AB, 3rd, Bergsland E,Berlin JD, Blaszkowsky LS, Emerson L, Engstrom PF,

Fanta P, Giordano T, Goldner WS, Halfdanarson TR,Heslin MJ, Kandeel F, Kunz PL, Kuvshinoff BW 2nd,Lieu C, Moley JF, Munene G, Pillarisetty VG, Saltz L,Sosa JA, Strosberg JR, Vauthey JN, Wolfgang C, YaoJC, Burns J, Freedman-Cass D; National compre-hensive cancer network. Neuroendocrine tumors,version 1.2015. J Natl Compr Canc Netw. 2015;13:78-108. [Crossref] [PubMed]

6. Deppen SA, Blume J, Bobbey AJ, Shah C, GrahamMM, Lee P, Delbeke D, Walker RC. 68Ga-DOTATATEcompared with 111In-DTPA-Octreotide and conven-tional imaging for pulmonary and gastroenteropan-creatic neuroendocrine tumors: a systematic reviewand meta-analysis. J Nucl Med. 2016;57:872-878.[Crossref] [PubMed] [PMC]

7. Herrmann K, Czernin J, Wolin EM, Gupta P, BarrioM, Gutierrez A, Schiepers C, Mosessian S, PhelpsME, Allen-Auerbach MS. Impact of 68Ga-DOTATATE PET/CT on the management of neu-roendocrine tumors: the referring physician'sperspective. J Nucl Med. 2015;56:70-75. [Crossref][PubMed] [PMC]

8. Yamaga LYI, Wagner J, Funari MBG. 68Ga-DOTATATE PET/CT in nonneuroendocrine tumors: apictorial essay. Clin Nucl Med. 2017;42:e313-e316.[Crossref] [PubMed]

9. Ruuska T, Ramírez Escalante Y, Vaittinen S, Gard-berg M, Kiviniemi A, Marjamäki P, Kemppainen J,Jyrkkiö S, Minn H. Somatostatin receptor expres-sion in lymphomas: a source of false diagnosis oftumor at 68Ga-DOTANOC PET/CT imaging. ActaOncol. 2017;57:283-289. [Crossref] [PubMed]

10.Strosberg J, El-Haddad G, Wolin E, Hendifar A, YaoJ, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H,Bushnell D, O’Dorisio TM, Baum RP, Kulkarni HR,Caplin M, Lebtahi R, Hobday T, Delpassand E,Van Cutsem E, Benson A, Srirajaskanthan R, PavelM, Mora J, Berlin J, Grande E, Reed N, Seregni E,Öberg K, Lopera Sierra M, Santoro P, Thevenet T,Erion JL, Ruszniewski P, Kwekkeboom D, KrenningE. Phase 3 trial of 177lu-dotatate for midgut neu-roendocrine tumors. N Engl J Med. 2017;376:125-135. [Crossref] [PubMed] [PMC]

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Address for Correspondence: Müge Keskin, University of Health Sciences Keçiören Training and Research Hospital,Clinic of Endocrinology and Metabolism, Ankara, Turkey

Phone: +90 312 356 90 00 E-mail: keskinmuge@hotmail.comReceived: 08/11/2018 Received in revised form: 19/12/2018 Accepted: 09/01/2019 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Case Report: Fixed Drug Eruption Causedby Dapagliflozin

Vaka Sunumu: Dapagliflozine Bağlı Fiks İlaç Erüpsiyonu

Clinic of Endocrinology and Metabolism, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey*Clinic of Dermatology, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey

**Clinic of Pathology, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey

IntroductionThe latest treatment modality for T2DM in-cludes SGLT2 inhibitors, which exert an in-sulin-independent action by blocking there-absorption of filtered glucose in kidneys.Dapagliflozin, an SGLT2 inhibitor, is con-

sumed orally, once-daily, and has a half lifeof about 17 hours. SGLT2 inhibitors causethe loss of calories, helping in subsequentweight loss (1). Weight loss is associatedwith the reduction of visceral or subcuta-neous fat. SGLT2 inhibitors provide cardio-

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Type 2 diabetes mellitus (T2DM) is a global health concern. Ithas multifactorial pathophysiology and its incidence is increa-sing day by day. The treatment is mainly targeted at main-taining cardiovascular and renal functions. Administration ofsodium-glucose co-transporter-2 (SGLT2) inhibitors is one ofthe emerging medications for T2DM. It improves glycemia byemploying insulin-independent mechanisms that increase uri-nary glucose excretion. The authors hereby report a case ofa 62-year-old male with T2DM, who was referred to our out-patient clinic for glycemic control. The patient was taking met-formin and gliclazide for five years in addition to dapagliflozin,an SGLT-2 inhibitor, for one year. Physical examination re-vealed a few, sharply-demarcated erythematous plaques onthe patient’s forearm for fifteen days. The patient previouslyhad psoriasis, and to rule out this diagnosis a skin punch bi-opsy was taken from one of the lesions. The histopathologi-cal evaluation was found to be compatible with drug eruption;however, skin patch test performed with dapagliflozin wasnon-reactive. After performing oral provocation test with da-pagliflozin, new erythematous plaques appeared around thesame sites on the forearm. On withdrawing dapagliflozin, thelesions resolved completely. This case gives an insight thatdapagliflozin may also cause drug eruptions, which should bekept in mind, especially in a patient with psoriasis.

Keywords: Dapagliflozin; fixed drug eruption;sodium-glucose co-transporter-2 inhibitors;type 2 diabetes mellitus

Tip 2 diabetes mellitus (Tip 2 DM), global bir sağlık prob-lemidir. Patofizyolojisi multifaktöriyeldir ve insidansı gün-den güne artmaktadır. Tedavide temel hedef, kardiyovas-küler ve renal fonksiyonların korunmasıdır. Sodyum glukozko-transporter-2 (SGTL2) inhibitörleri, Tip 2 DM tedavi-sinde yeni ortaya çıkan ilaçlardan biridir. SGLT-2 inhibitör-leri, insülinden bağımsız mekanizma ile üriner glukozatılımını artırarak glisemiyi düzeltmektedir. Bu çalışmada,glisemik kontrol amaçlı polikliniğimize başvuran 62 yaşın-daki Tip 2 DM’li erkek hasta sunulmuştur. Hasta beş yıldırmetformin, gliklazid; beraberinde bir yıldır da dapagliflo-zin tedavisi almakta idi. Fizik muayenesinde, ön kol üze-rinde keskin sınırlı eritematöz plaklar saptandı. Psöriyazistanısı olan hastada, psöriyazisi ekarte etmek için lezyon-lardan birinden deri biyopsisi alındı. Histopatolojik değer-lendirme ilaç erüpsiyonu ile uyumlu bulunmasına rağmen,dapagliflozin ile yapılan deri yama testi reaktif değildi. Da-pagliflozin ile oral provokasyon testi yapıldığında, ön koldaeski lezyonların yerlerinde eritemli yeni plakların ortayaçıktığı gözlendi. Dapagliflozin tedavisinin kesilmesi ile lez-yonlar tamamen düzeldi. Bu hasta, dapagliflozinin fiks ilaçerüpsiyonuna neden olabileceği ve önceden psöriyazis ta-nısı almış olsa bile bu hastalarda akılda tutulması gerek-tiği konusunda fikir vermektedir.

Anahtar kelimeler: Dapagliflozin; fiks ilaç erüpsiyonu;sodyum glukoz ko-transporter-2 (SGTL2);tip 2 diyabetes mellitus

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vascular protection with other beneficial ef-fects like weight loss, decrease in bloodpressure and triglycerides, and also diminishthe progression of kidney diseases (2).SGLT2 inhibitors are generally well-toler-ated; yet, the typical adverse effects includegenital mycotic infections and lower urinarytract infections (3). The available current lit-erature does not report any case of fixeddrug eruption caused by SGLT2 inhibitors.Only a few cutaneous adverse events suchas intense and severe pruritus (4), an in-creased rate of vaginal colonization by can-dida species, and vulvovaginal adverseevents in women with T2DM caused bycanagliflozin (5) have been reported.Drug eruptions can either result from im-munological or non-immunological mecha-nisms. In immunologically mediated drugeruptions, drugs or their metabolites mayact as haptens, thus causing either a spe-cific cell-mediated or humoral response.Fixed drug eruptions (FDE) are the cell-me-diated, delayed type of drug reactions. Itmay present as a single or a few, round,sharply demarcated erythematous and ede-matous plaques anywhere on the body. Afterre-administration of the causative drug, thelesions recur at exactly the same sites.Patch testing and oral provocation havebeen used to identify the suspected agentand check for cross-sensitivities to medica-tions. Management starts with the with-drawal of the suspected drug (6).

Case ReportThe authors hereby report a case of a 62-year-old male having coronary artery dis-ease, with a history of T2DM for 20 years,who was referred to our outpatient clinic forglycemic control. He was on metformin andgliclazide for five years, and dapagliflozinwas given for one year. His initial anthropo-metric measurements were weight: 81 kg,height: 163 cm, and body mass index(BMI): 30.4 kg/m². His blood test showed:fasting blood glucose:118 mg/dL, creati-nine: 1.0 mg/dL, serum alanine amino-transferase: 22 U/L, HbA1c: 7.1%. Aftertreatment with dapagliflozin for 12 months,the patient has lost 6 kg. Physical examina-tion revealed a few, sharply-demarcatederythematous plaques on his forearms,present for fifteen days (Figure 1). The pa-

tient’s past medical history revealed that hehad been affected with psoriasis, and to ruleout this diagnosis a skin punch biopsy wasperformed on one of the lesions. Histopatho-logical evaluation showed parakeratosis,loss in granular layer, subcorneal neu-trophilic infiltration, irregular acanthosis andspongiosis, perifollicular and perivasculareosinophilic and lymphocytic inflammation.Though the skin biopsy was compatible withdrug eruption (Figure 2); however, skinpatch test performed with dapagliflozin wasobserved to be non-reactive. After oralprovocation test with dapagliflozin, new ery-thematous plaques appeared near the samesites on the forearms (Figure 3). When da-pagliflozin was withdrawn, the lesions re-solved completely in seven days. No lesionwas observed after one month of withdrawalof the drug (Figure 4).

DiscussionSGLT2 inhibitors like dapagliflozin,canagliflozin, empagliflozin, and ipragliflozinform the novel therapeutic approach forT2DM. The most common adverse effects ofthese drugs include female genital mycoticinfections and benign urinary tract infections(7). These drugs can be classified as ‘nutri-ent load reducer’s’ group among the antihy-perglycemic agents, which have been shownto improve cardiovascular and renal out-comes, with low hypoglycemia risk (8). De-spite all these beneficial effects, skin lesionswhich may develop due to SGLT2 inhibitorsshould not be overlooked. To the bestknowledge of the authors, this study is thefirst report showing fixed drug eruption

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Figure 1: Erythematous plaques on his forearms.

caused by dapagliflozin. Drug eruptionmechanisms with dapagliflozin have notbeen investigated earlier. In a previousstudy on Japanese population, six SGLT-2

inhibitors have been evaluated for possibleskin reactions wherein serious generalizedrashes, eruptions, urticaria, erythema, andeczema and subcutaneous tissue disorderswith ipragliflozin alone were observed.Ipragliflozin is stored in the skin tissue, andinteracts with melanin; therefore skin reac-tions might be related to the disturbed skintissue homeostasis (9). Such reactions,however, were not observed with da-pagliflozin in the present study.Recent studies have also reported fixed drugeruptions with SGLT2 inhibitors (10), for ex-ample, drug eruptions with ipragliflozin (11)and Fournier’s gangrene with empagliflozin,though not with dapagliflozin (12). U.S.Food and Drug Administration (FDA) re-cently issued a safety warning about a rare,but serious, skin infection in patients treatedwith SGLT2 inhibitors, i.e., necrotizing fasci-itis (gangrene) of the perineum on andaround the genitals, also referred to asFournier’s gangrene (13). Adverse cuta-neous drug reactions are recognized asmajor health problems worldwide, causing aconsiderable financial burden for the health-care systems. SGLT2 inhibitors are in use inEurope since only a few years, and their ad-verse effects are yet to be clarified. The au-thors suggest that FDE must be added tothe list of side-effects of SGTL2 inhibitors asa rare cutaneous reaction. Though drugeruption caused by dapagliflozin is a rarecondition, this possibility should be kept inmind, especially while dealing with psoriasispatients.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

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Figure 2: Psoriasiform epidermal hyperplasia and der-mal perivascular inflammation with eosinophilic infiltra-tion (40X HE).

Figure 4: No lesion was observed after one month of da-pagliflozin withdrawal.

Figure 3: Recurrens after oral provocation test near thesame sites of former lesions

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Authorship ContributionsIdea/Concept: Müge Keskin; Design: MügeKeskin, Arzu Or Koca; Control/Supervision:Müge Keskin, Derun Taner Ertuğrul; DataCollection and/or Processing: Müge Keskin,Mustafa Altay; Analysis and/or Interpreta-tion: Müge Keskin, Arzu Or Koca; LiteratureReview: Müge Keskin, Murat Dağdeviren;Writing the Article: Müge Keskin, DerunTaner Ertuğrul; Critical Review: Müge Ke-skin, Murat Dağdeviren; References andFundings: Müge Keskin, Mustafa Altay.

References1. Kim Y, Babu AR. Clinical potential of sodium-glucose

cotransporter 2 inhibitors in the management oftype 2 diabetes. Diabetes Metab Syndr Obes.2012;5:313-327. [PubMed] [PMC]

2. Santos LL, Lima FJC, Sousa-Rodrigues CF, BarbosaFT. Use of SGLT-2 inhibitors in the treatment of type2 diabetes mellitus. Rev Assoc Med Bras (1992).2017;63:636-641. [Crossref] [PubMed]

3. Nauck MA. Update on developments with SGLT2 in-hibitors in the management of type 2 diabetes.Drug Des Devel Ther. 2014;8:1335-1380. [Cros-sref] [PubMed] [PMC]

4. Vasapollo P, Cione E, Luciani F, Gallelli L. General-ized İntense pruritus during canagliflozin treatment:İs it an adverse drug reaction? Curr Drug Saf.2018;13:38-40. [Crossref] [PubMed]

5. Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation ofvulvovaginal symptoms and Candida colonization inwomen with type 2 diabetes mellitus treated withcanagliflozin, a sodium glucose co-transporter 2 in-hibitor. Curr Med Res Opin. 2012;28:1173-1178.[Crossref] [PubMed]

6. Shear NH, Knowles SR. Cutaneous reactions todrugs. In: Goldsmith LA, Katz SI, Gilchrest BA,

paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Der-matology in General Medicine (8th ed). New York:Mc Graw-Hill; 2012;2121-2610.

7. Scheen AJ. Pharmacodynamics, efficacy and safetyof sodium-glucose co-transporter type 2 (SGLT2) in-hibitors for the treatment of type 2 diabetes melli-tus. Drugs. 2015;75:33-59. [Crossref] [PubMed]

8. Kalra S, Ghosh S, Aamir AH, Ahmed T, Amin MF,Bajaj S, Baruah MP, Bulugahapitiya U, Das AK, GiriM, Gunatilake S, Mahar SA, Pathan MF, Qureshi NK.Raza SA, Sahay R, Shakya S, Shreshta D, Soma-sundaram N, Sumanatilleke M, Unnikrishnan AG,Wijesinghe AM. Safe and pragmatic use of sodium-glucose co transporter 2 inhibitors in type 2 dia-betes mellitus: South Asian Federation of EndocrineSocieties consensus statement. Indian J EndocrinolMetab. 2017;21:210-230. [Crossref] [PubMed][PMC]

9. Sakaeda T, Kobuchi S, Yoshioka R, Haruna M, Taka-hata N, Ito Y, Sugano A, Fukuzawa K, Hayase T,Hayakawa T, Nakayama H, Takaoka Y, Tohkin M.Susceptibility to serious skin and subcutaneous tis-sue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2)inhibitors. Int J Med Sci. 2018;15:937-943. [Cros-sref] [PubMed] [PMC]

10.Damiani G, Loite U, Ramoni S, Marzano AV. Possiblenew inflammatory side-effect of SGLT2-inhibitors:fixed drug eruption. J Diabetes Complications.2016;30:1530-1531. [Crossref] [PubMed]

11.Saito-Sasaki N, Sawada Y, Nishio D, Nakamura M.First case of drug eruption due to ipragliflozin: casereport and review of the literature. Dermatol.2017;58:236-238. [Crossref]

12.Kumar S, Costello AJ, Colman PG. Fournier’s gan-grene in a man on empagliflozin for treatment ofType 2 diabetes. Diabet Med. 2017;34:1646-1648.[Crossref] [PubMed]

13.U.S. Food and Drug Administration. Drug safetycommunication: FDA warns about rare occurrencesof a serious infection of the genital area with SGLT2inhibitors for diabetes. 2018 Aug 29.

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Address for Correspondence: Arzu Or Koca, University of Health Sciences, Keçiören Health Application and Research Center,Department of Endocrinology and Metabolism, Ankara, TurkeyPhone: +90 312 356 90 00 E-mail: drarzuor@hotmail.com

Received: 06/10/2018 Received in revised form: 20/12/2018 Accepted: 21/12/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Transient Elevation of CA 19-9 Due toCessation of Levothyroxine in a Patient with

Hashimoto’s ThyroiditisHashimoto Tiroiditi Olan Bir Hastada

Levotiroksinin Kesilmesi Nedeni ile Geçici CA 19-9 Yükselmesi

University of Health Sciences, Keçiören Health Application and Research Center,Department of Endocrinology and Metabolism, Ankara, Turkey

IntroductionSerum CA 19-9 (carbohydrate antigen 19-9) is a tumor marker that is expressed as amonosialoganglioside and a mucosal proteinin tissues. CA 19-9, which is secreted intothe blood, saliva, bronchial secretions, andin stomach and bile fluids, has found appli-cation in the follow-up of recurrence of cer-tain malignant diseases post tumor

resection, primarily in the biliopancreaticmalignancies (1). However, CA 19-9 mayalso exhibit elevated levels in non-malignantdiseases, such as biliary obstruction, chronicviral hepatitis, chronic pancreatitis, or idio-pathic pulmonary fibrosis, as its specificityis not very high (2-5). Although there is nodefinite limit for CA 19-9 elevation that oc-curs in benign and malignant diseases, cer-

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Serum CA 19-9 (carbohydrate antigen 19-9) is a tumormarker with monosialoganglioside structure. Its levels aremeasured frequently for screening purposes in daily prac-tice by physicians, while its main application is in the studyof tumor recurrence and the follow-up of the recurrences.Although significant elevation in the levels of CA 19-9 indi-cates malignancy, an underlying malignant disease may notalways be determined, and benign pathologies may also beobserved. A 45-year-old female patient who was undergoinga follow-up for Hashimoto’s thyroiditis applied to our clinicwith complaints of fatigue, tiredness, and hair loss. Elevati-ons in the levels of both thyroid-stimulating hormone (TSH)and CA 19-9 were observed. The levels of TSH and CA 19-9were observed to be normal after the patient was treatedfor hypothyroidism, and the results of the analysis conduc-ted for malignancy were also determined to be normal. Onthe basis of the present case study, we propose thathypothyroidism should be considered while making a diffe-rential diagnosis for patients with elevated levels of CA 19-9.

Keywords: Hashimoto’s thyroiditis; hypothyroidism;CA 19-9

Serum CA 19-9 (karbonhidrat antijeni 19-9); monosialo-gangliosid yapıda bir tümör belirtecidir. Günümüzde asılkullanım amacı olan tümörün rekürrens ve nüks takibi dı-şında günlük pratikte hekimler tarafından sıklıkla taramaamaçlı olarak da düzeyine bakılmaktadır. Her ne kadar CA19-9 düzeyindeki belirgin yükseklikler maligniteye yönlen-dirme açısından şüphe uyandırsa da her zaman altta yatanmalign hastalık saptanmayıp, benign patolojiler de görüle-bilmektedir. Hashimoto tiroiditi ile takipli 45 yaşındakikadın hasta; hâlsizlik, yorgunluk ve saç dökülmesi şikâ-yetleri ile kliniğimize başvurdu. Yapılan incelemelerde, TSHve CA 19-9 yüksekliği olduğu görüldü. Malignite taramayayönelik yapılan tetkik sonuçları normal saptanan hastada,hipotiroidi tedavisi sonrası normal TSH ve CA 19-9 düzeyiolduğu bulundu. Hastamızda da olduğu gibi, CA 19-9yüksekliği saptanan bir bireyde ayırıcı tanı yapılır iken hi-potiroidinin de akılda bulundurulması gerektiği düşünül-mektedir.

Anahtar kelimeler: Hashimoto tiroiditi; hipotiroidi;CA 19-9

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tain studies have reported that the elevationvalues above certain thresholds are sugges-tive of malignant pancreatobiliary diseases(2, 6, 7). The earlier studies have revealedthat CA 19-9 elevation may also occur inHashimoto’s thyroiditis in proportion to theelevation in the thyroid-stimulating hormone(TSH), even in the absence of any underly-ing malignant disease (8, 9). The presentstudy was, therefore, aimed at demonstrat-ing the relationship between the levels of CA19-9 and thyroid function disorder in a pa-tient undergoing a follow-up for the diagno-sis of Hashimoto’s thyroiditis.

Case ReportA 45-year-old female patient, who had beenundergoing a follow-up for the diagnosis ofHashimoto’s thyroiditis for 20 years, appliedto our clinic with complaints of fatigue, tired-ness, and hair loss. She had a history ofsmoking (five packs/year), although she hadquit and been a non-smoker for the last tenyears. She had no known diseases, her de-ceased mother had suffered from malignantesophagus neoplasm, and her father hadbeen diagnosed with hypertension. The pa-tient stated that she was on a replacementtreatment with levothyroxine at a daily doseof 100 µg when she applied to our clinic. Thefindings of her physical examination werenormal, except for the dry skin and frozenglance. In the laboratory analyses, it wasdetermined that the TSH level was 17.08µIU/mL (normal range: 0.55-4.78), serumfree thyroxin level was 0.7 ng/mL (0.78-1.48), and the level of anti-thyroid peroxi-

dase antibody was 720 U/mL (0-35). Theannual routine controls conducted forscreening purposes revealed high (52 U/mL)CA 19-9 levels (normal: <30.9). The CA 19-9 levels were determined to be high even onrepeated measurements (Figure 1). The lev-els of carcinoembryonic antigen, carbohy-drate antigen 15-3, carbohydrate antigen125, alpha fetoprotein, and serum free tri-iodothyronine were observed to be withinthe normal limits, and the renal functiontests and the liver function tests were alsoobserved to be normal. She, therefore, con-sulted with the relevant department regard-ing the elevated levels of CA 19-9, followingwhich, whole-body positron-emission to-mography/computed tomography analysiswas performed as the results of certain ex-aminations such as mammography andupper gastrointestinal endoscopy were ob-served to be normal, and no increasedmetabolic activity uptake was determinedfor any organ. Physical examination, labora-tory analyses, and imaging methods couldprovide no explanation for the elevated Ca-19-9 levels, and it was considered that thepossible reason for the elevation in the Ca-19-9 levels was hypothyroidism.The detailed study of the medical history ofthis patient with apparent hypothyroidismrevealed that she had been using her med-ication irregularly for the last one month.Subsequently, her daily dose of levothyrox-ine was increased to 117.85 µg, and shewas scheduled for a control visit six weekslater. Investigations in the control visit reg-istered a significant decrease in the initial

Figure 1: Patient’s TSH and CA 19-9 measurements (TSH normal reference range: 0.55-4.78 µIU/mL; Ca 19-9 nor-mal reference range: 0-30.9 U/mL).

complaints of fatigue, tiredness, and hairloss. Laboratory analysis determined thatshe was euthyroid. A decrease in the levelsof CA 19-9, which reached 8.2 U/mL, wasobserved to accompany this improvement inthe thyroid function (Figure 1).

DiscussionThe American Association of Clinical Oncol-ogy has suggested that tumor markersshould not be used in research on malignan-cies as even though they are relatively highin sensitivity, they exhibit low specificity (8).Tumor markers are nonetheless studied fre-quently with the belief that the unusuallyhigh values of the markers may assist inidentifying malignancies. However, elevationin the levels of CA 19-9 (a tumor marker)may also be observed in benign diseases, asoccurred in the case reported in the presentstudy. Such a situation may cause anxiety toboth the clinician and the patient, and maylead to unnecessary screening analyses. Inthe case reported in the present study, thereduced levels of CA 19-9 post the treatmentfor hypothyroidism demonstrated that theelevated value observed initially was not aresult of any underlying malignancy. The lit-erature indicates that thyroiditis may in-crease the levels of CA 19-9, Hashimoto’sthyroiditis may elevate the CA 19-9 levelswithout disturbing the thyroid function tests,and an increase in the CA 19-9 levels mayalso occur in benign or malignant thyroid dis-eases (8, 10-15). However, contrary datawere also reported suggesting that therewas no relationship between Hashimoto’sthyroiditis and CA 19-9 levels. In a studyconducted in 2009 by Sezer et al., 71 pa-tients with a diagnosis of Hashimoto’s thy-roiditis were examined, and no statisticallysignificant difference was observed in thelevels of CA 19-9 between the euthyroid andhypothyroid subjects. However, the numberof patients included in that study was not re-ported, and no correlation was addressedbetween the serum CA 19-9 levels and TSHlevels (16). Although the influence of thyroiddiseases on CA 19-9 elevation has not beenelucidated to date, it is commonly believedto be multifactorial (9). A previous studyused immunohistochemical staining todemonstrate that the inflamed thyroid tissueproduced CA 19-9 (11). However, CA 19-9

elevation could not be demonstrated in allthe cases of inflammatory thyroid disease.The association between thyroid diseasesand CA 19-9 levels remains a mystery dueto a number of reasons, such as lack of CA19-9 elevation in certain cases of thyroiditis,the observed elevations not always being inproportion to thyroid function disorder, andthe complete absence of CA 19-9 elevationin certain malignant thyroid diseases (16).Therefore, it is suggested that screening forthyroid diseases in addition to the routinescreening parameters would serve as a suit-able approach to diagnosis for the patientsexhibiting CA 19-9 elevations. In addition,further studies investigating the associationbetween CA 19-9 and thyroid diseases arerequired to elucidate the details of this asso-ciation.Informed consent of the patient was ob-tained for the case report.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Arzu Or Koca, Mustafa Altay;Design: Arzu Or Koca, Mustafa Altay;Control/Supervision: Arzu Or Koca, MustafaAltay; Data Collection and/or Processing:Arzu Or Koca, Mustafa Altay; Analysis and/orInterpretation: Arzu Or Koca, Mustafa Altay;Literature Review: Arzu Or Koca, MustafaAltay; Writing the Article: Arzu Or Koca,Mustafa Altay; Critical Review: Arzu Or Koca,Mustafa Altay; References and Fundings:Arzu Or Koca, Mustafa Altay; Materials: ArzuOr Koca, Mustafa Altay.

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References1. Ventrucci M, Pozzato P, Cipolla A, Uomo G. Persist-

ent elevation of serum CA 19-9 with no evidence ofmalignant disease. Dig Liver Dis. 2009;41:357-363.[Crossref] [PubMed]

2. Kim MS, Jeon TJ, Park JY, Choi J, Shin WC, Park SE,Seo JY, Kim YM. Clinical interpretation of elevated CA19-9 levels in obstructive jaundice following benignand malignant pancreatobiliary disease. Korean JGastroenterol. 2017;70:96-102. [Crossref] [PubMed]

3. Bertino G, Ardiri AM, Calvagno GS, Malaguarnera G,Interlandi D, Vacante M, Bertino N, Lucca F,Madeddu R, Motta M. Carbohydrate 19.9 antigenserum levels in liver disease. Biomed Res Int.2013;2013:531640. [Crossref] [PubMed] [PMC]

4. Fania C, Pezzilli R, Melzi d’Eril G, Gelfi C, Barassi A.Identification of small proteins and peptides in thedifferentiation of patients with intraductal mucinousneoplasms of the pancreas, chronic pancreatitis andpancreatic adenocarcinoma. Dig Dis Sci.2018;63:920-933. [Crossref] [PubMed]

5. Romero Estarlich V, González-Senac NM, YulissaPeña Lora D, Vidán Astiz MT, Serra Rexach JA. [Pro-gressive elevation of CA 19-9 tumour marker in anonagenarian with advanced idiopathic pulmonaryfibrosis]. Rev Esp Geriatr Gerontol. 2018;53:360-361. [Crossref] [PubMed]

6. Kim HJ, Kim MH, Myung SJ, Lim BC, Park ET, YooKS, Seo SK, Min YI. A new strategy for the applica-tion of CA19-9 in the differentiation of pancreatico-biliary cancer: analysis using a receiver operatingcharacteristic curve. Am J Gastroenterol.1999;94:1941-1946. [Crossref] [PubMed]

7. Morris-Stiff G, Teli M, Jardine N, Puntis MC. CA19-9antigen levels can distinguish between benign andmalignant pancreaticobiliary disease. HepatobiliaryPancreat Dis Int. 2009;8:620-626. [PubMed]

8. Parra JL, Kaplan S, Barkin JS. Elevated CA 19-9caused by Hashimoto’s thyroiditis: review of the be-nign causes of increased CA 19-9 level. Dig Dis Sci.2005;50:694-695. [Crossref] [PubMed]

9. Jamaludin AZ, Metassan MM, Zainal-Abidin Z,Chong VH. Elevated serum CA 19-9 in associationwith Hashimoto’s thyroiditis. Singapore Med J.2010;51:e143-145. [PubMed]

10.Takahashi N, Shimada T, Ishibashi Y, Oyake N, Mu-rakami Y. Transient elevation of serum tumor mark-ers in a patient with hypothyroidism. Am J Med Sci.2007;333:387-389. [Crossref] [PubMed]

11.Tekin O. Hypothyroidism-related CA 19-9 eleva-tion. Mayo Clin Proc. 2002;77:398. [Crossref][PubMed]

12.Hashimoto T, Matsubara F. Changes in the tumormarker concentration in female patients withhyper-, eu-, and hypothyroidism. Endocrinol Jpn.1989;36:873-7879. [Crossref] [PubMed]

13.Kamoshida S, Ogane N, Yasuda M, Muramatsu T,Bessho T, Kajiwara H, Osamura RY. Immunohisto-chemical study of type-1 blood antigen expressionsin thyroid tumors: the significance for papillary car-cinomas. Mod Pathol. 2000;13:736-741. [Crossref][PubMed]

14.Ogawa M, Hori H, Hirayama M, Kobayashi M, Shi-raishi T, Watanabe Y, Komada Y. Anaplastic trans-formation from papillary thyroid carcinoma withincreased serum CA19-9. Pediatr Blood Cancer.2005;45:64-67. [Crossref] [PubMed]

15.Leaes CG, Sperb D, Garcia E, Barra MB, Lima JP, daOliveira MC. Elevated CA 19-9 associated with thy-roid follicular adenoma. Endocrinologist.2008;18:176-177. [Crossref]

16.Sezer K, Cakal E, Ozkaya M, Yaman E, Akbay E. Nor-mal CA 19-9 levels in Hashimoto’s thyroiditis. AsianPac J Cancer Prev. 2009;10:315-318. [PubMed]

Case ReportTurk J Endocrinol Metab 2019;23:72-75

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Address for Correspondence: Elif Sevil Alagüney, Eskişehir Osmangazi University Faculty of Medicine,Department of Endocrinology, Eskişehir, Turkey

Phone: +90 5304334626 E-mail: elifsevilaktas@gmail.comReceived: 28/08/2018 Accepted: 26/11/2018 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Hypoglycemia Due to the Presence ofAnti-insulin Antibodies: A Case Report

Anti-insülin Antikorlarının Varlığına BağlıHipoglisemi: Bir Olgu Sunumu

Department of Endocrinology, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey*Department of Radiology, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey

**Department of Internal Medicine, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, Turkey

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A 50-year-old male was referred to our clinic for hypogly-cemic attacks. He denied using oral antidiabetic drugs, in-sulin, or herbal substances but admitted using proton pumpinhibitors, pregabalin, and alpha lipoic acid. Venous bloodglucose level was 44 mg/dL, C-peptide was 15.6 ng/mL, andinsulin levels were >1.000 µIU/mL. His BMI was 21.4. Noevidence of pancreatic or extra pancreatic insulinoma wasfound in imaging studies. No diagnostic results were ob-tained in the selective calcium receptor stimulation test.Anti-insulin antibody test was positive. The insulin autoim-mune syndrome was diagnosed with low glucose levels. Thesymptoms were associated with very high serum insulin lev-els, and the patient was positive for the anti-insulin anti-body. Alpha lipoic acid and proton pump inhibitors, whichmay cause insulin autoimmune syndrome, were discontin-ued and alpha glucosidase inhibitor and diet therapy werestarted. During follow-up, the patient did not report hypo-glycemia. Insulin autoimmune hypoglycemia should be keptin mind in patients with very high levels of insulin and with-out evidence of insulinoma.

Keywords: Autoimmune; hypoglycemia;anti-insulin antibody

Elli yaşındaki erkek hasta, hipoglisemik ataklar nedeni ile kli-niğimize yönlendirildi. Hasta oral antidiyabetik ilaç, insülinveya bitkisel maddeler kullanmadığını; ancak proton pompainhibitörü, pregabalin ve alfa lipoik asit kullandığını belirtti.Hastanın venöz kan glukoz seviyesi 44 mg/dL iken, C-peptitdüzeyi 15,6 ng/mL ve insülin seviyesi 1.000 µIU/mL üzerindeidi. Beden kitle indeksi 21,4 bulundu. Görüntüleme çalış-malarında, pankreatik veya ekstra pankreatik insülinomalehine kanıt bulunmadı. Selektif kalsiyum reseptörstimülasyon testinde tanısal sonuç alınamadı. Anti-insülin an-tikor testi pozitif saptandı. Düşük glukoz seviyeleri ile birlikteinsülin otoimmün sendrom tanısı konuldu. Belirtiler çok yük-sek serum insülin seviyeleri ile ilişkili idi ve hastada anti-in-sülin antikoru pozitifti. İnsülin otoimmün sendromuna nedenolabilecek alfa lipoik asit ve proton pompa inhibitörleri kesildive alfa glukozidaz inhibitörü ile diyet tedavisi başladı. Takipsırasında hasta hipoglisemi tarif etmedi. İnsülin otoimmünhipoglisemi, çok yüksek düzeyde insülin seviyesi ile birlikteinsülinoma lehine bulgu olmayan hastalarda akılda tutul-malıdır.

Anahtar kelimeler: Otoimmün; hipoglisemi;anti-insülin antikoru

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This case report has been a poster presentation in 19th European Congress of Endocrinology in 2017,Portugal, EP No: 427.

IntroductionThe most common causes of hypoglycemiain non-diabetic patients are insulinoma,extra pancreatic tumors, and autoimmunehypoglycemia (1). The autoimmunity thatcauses hypoglycemia occurs in two ways: in-

sulin receptor antibodies with insulin mimeticeffects or insulin autoimmune syndromecharacterized by insulin antibodies (1). Theinsulin autoimmune syndrome is character-ized by spontaneous hypoglycemia, in-creased insulin levels, and increased

circulating insulin antibodies, first describedby Hirata et al. in 1970 (2). It may causepostprandial hypoglycemia but rarely causesfasting hypoglycemia. Despite adequate in-sulin secretion following ingestion of food ororal glucose loading, hyperglycemia and ahypoglycemic reaction occur after 2-3 h. Thereason is that there is less increase in freeinsulin initially and a slower decrease overtime, when compared with total insulin and cpeptide. Insulin-antibodies binding insulinthat is possibly secreted in response to hy-perglycemia reduces the initial insulin re-sponse and, consequently, hyperglycemia isexacerbated. This causes further insulin se-cretion. As the glucose level decreases, in-sulin secretion and total insulin concentrationalso decrease. The release of the antibody-bond insulin causes the free insulin to be in-appropriately elevated irrespective of theglucose level, and this results in hypo-glycemia (3). Insulin autoimmune syndromehas a strong association with sulfhydrylgroup drug use, some autoimmune diseases,plasma cell dyscrasias, and presence of HLA-DR4. There are also publications showing as-sociation with other drugs, which mostfrequently include methimazole, along withothers such as D-penicillamine, pro-cainamide, isoniazid, hydralazine, glu-tathione, captopril, and imipenem (4). Inaddition, incidences related to alpha lipoicacid (5) and proton pump inhibitor (1, 2)have also been reported.

Case ReportA 50-year-old man was referred to our clinicon the occasion of fever, sweating and pal-pitations, which started about a month ago,and a low blood glucose level was detectedin another clinic. The patient described thesymptoms being aggravated with hungerand 2-3 h after the meal. He had food crav-ings 2 or 3 times a night.However, the patient stated that he hadfasted in Ramadan about five months agoand the duration of the fasting periodreached 17 h and his complaints were ab-sent at that time.The patient denied any chronic disease;however, pregabalin was prescribed in aclinic due to chills and tingling in the feetand the hands. During this period, he ad-mitted intermediate usage of proton pump

inhibitors (esomeprazole and rabeprazole)and vitamin complexes including B1 +B6 +B12 + alpha lipoic acid.On physical examination, his general condi-tion was good, body temperature was 36.6degrees, pulse rate was 80/min, blood pres-sure was 110/70 mmHg. The patient’s bodymass index was calculated as 21.4, with aheight of 174 cm and a weight of 65 kg. Nopathology was detected in the systemic ex-amination. At the time of admission, theblood glucose level was 54 mg/dL. Renalfunction, liver function, thyroid functiontests, and complete blood count values werenormal. The patient was negative for thyroidauto antigens, ANA, and RF values; theHbA1c value was 5.74.He was hospitalized and followed up for thesigns of hypoglycemia. The tests which wereperformed during a hypoglycemic period didnot show pathology with counter insulin sys-tem function to show endogenous hyperin-sulinemia.The blood glucose level was 44 mg/dL, insulinlevel >1000 µl/mL, c peptide 15.6 ng/mL,growth hormone 16.49 ng/mL, and cortisolresponse was 26.41 µg/dL. These tests wereperformed using a Cobas 8000 Autoanalyzer(Roche Diagnostics, Mannheim, Germany)and the enzymatic colorimetric method. ACTHlevel was 66.4 pg/mL. The ACTH test wasperformed using the electrochemilumines-cence immunoassay (ECLIA) method in aRoche Hitachi Cobas e411 Analyzer (RocheDiagnostics, Mannheim, Germany).The prolactin and parathormone levels werein the normal limits ruling out MEN. Ultra-sound of the pancreas with a preliminary di-agnosis of insulinoma showed normalhomogeneous appearance and pathologywas not detected in other organs. No pathol-ogy was detected in dynamic pancreas com-puterized tomography. Abdomen/pelvis MRIand Ga-68 DOTATATE PET/CT examinationswere normal and an extra pancreatic focuswas ruled out. In order to rule out insuli-noma, selective calcium receptor stimulationtest was performed. During the test, 0.015mEq/kg of calcium was delivered via thecatheterized arteries (hepatic artery, splenicartery, gastroduodenal artery, and superiormesenteric artery). A blood sample of 5 mLwas taken from the hepatic vein, before cal-cium injection and at 30 s and at 1, 1.5, 2,

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3 min. At least a two-fold increase in insulinlevels in blood samples taken at 30 s andfirst minute after calcium injection suggeststhe presence of an insulin secreting tumorin the artery-fed region (6). In our patient,insulin levels were >1000 units in all sam-ples. The results obtained when the serumsamples were diluted and reworked areshown in Table 1. The results obtained werenot conclusive in terms of localizing thepresence of an insulin secreting tumor.The baseline blood glucose level was 57mg/dL and the insulin level was 2939 unitsin the 75 g OGTT test. At the first hour, theblood glucose level was 201 mg/dL, insulinlevel was 4038 u/mL, blood glucose levelwas 39 mg/dL, and insulin level was 4655u/mL at the 4th hour when the lowest bloodsugar of the patient was reached.The insulin autoantibody test was positive.The patient was diagnosed with insulin au-toimmune syndrome. The dietary arrange-ment was made available at the hospital andacarbose treatment was started. Hypo-glycemia complaints did not recur in the fol-low-up under current treatment.

DiscussionEndogenous hyper insulinemia hypoglycemia(EHH) is a condition resulting in the excessivelow levels of glucose due to endogenous ex-cess insulin production. The most commoncause of EHH is insulinoma, though insulinautoimmune syndrome should also be takeninto account as a rare cause of EHH (4).This study presents a case of insulin au-toimmune syndrome resulting in high seruminsulin levels, while the positivity of insulinautoantibodies during hypoglycemia and im-aging methods were completely normal interms of insulinoma.

Earlier studies have shown much higher lev-els of insulin in insulin auto immune syn-drome in contrast to insulinoma. Woo CY andcolleagues analyzed 84 patients with EHHduring 1998-2012 and observed that the pa-tients with insulinoma had a mean insulinlevel of 14.1 mIU/mL; however, it was over1000 mlU/mL in insulin autoantibody posi-tive patients (7). This elevation in insulin lev-els is explained by the delay in clearance ofinsulin in the absence of auto antibodieswhich bind insulin (8). In our patient Insulinlevels were also >1000 mlU/mL as expected.Our patient did not show symptoms despitethe fact that he was fasting for a long timeduring the month of Ramadan (threemonths before the admission) and he hadhypoglycemic symptoms at 4th hour in OGTT.This also supports the diagnosis of insulinautoimmune hypoglycemia. In a case reportby Pooja and colleagues, neuroglycopenicsymptoms in a patient with insulin autoim-mune hypoglycemia were observed after 2h of a meal (2).The drugs containing sulfhydryl groups areknown to be associated with insulin autoim-mune hypoglycemia (2, 6). In addition, casereports showing association with alpha lipoicacid (5) and with proton pump inhibitorscontaining sulfhydryl groups (2) have beenreported. The mechanism of how sulfhydrylgroup containing drugs develop insulin au-toimmune hypoglycemia is unclear (2).Gopal et al. reported a case report of insulinautoimmune hypoglycemia due to pantopra-zole use. When pantoprazole is activated inthe acidic medium, sulfonic acid is formedand is attached to the sulfhydryl group of H+

K+ ATPase. This is related to the fact that theactive form of the drug binds to the disulfidebond in the insulin molecule and makes the

GDA: Gastroduodenal artery; SMA: Superior mesenteric artery; HA: Hepatic artery; SA: Splenic artery.

GDA SMA HA SA right SA left

0. sec 4224 5669 3922 3614 5173

30. sec 6218 4339 5900 3981 3524

1. min 6325 6263 6833 6295 5808

1,5 min 6369 6272 5903 6216 5860

2. min 6418 7687 6340 5599 6060

3. min 6540 6160 6490 4001 5883

Table 1. The results of selective calcium receptor stimulation test.

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insulin immunogenic (1). In a case reportpublished by Pooja et al., omeprazole usewas associated with insulin autoimmune hy-poglycemia (2). Our patient also had a his-tory of vitamin complex containing alphalipoic acid and esomeprazole usage in thelast three months. Insulin autoantibody pos-itivity that we detected in our patient maybe associated with the use of these drugs.Insulin autoimmune hypoglycemia is usuallya self-limiting disease. Many patients re-spond to a high frequency diet well. Alphaglycosidase inhibitors reduce postprandialinsulin levels and thus reduce postprandialhypoglycemic episodes. Steroid, diazoxide,octreotide and plasmapheresis treatmentscan be tried in patients who do not respondto these treatments (1).In our patient, hypoglycemia did not occurunder dietary management and acarbosetherapy.In conclusion, in patients with hypoglycemiashowing very high levels of insulin and noother diagnosis could be made with imagingmodalities, insulin autoimmune syndromeshould be considered for further differentialdiagnosis as a rare cause of EHH.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Belgin Efe; Design: BelginEfe, Elif Sevil Alagüney; Control/Supervi-sion: Belgin Efe, Elif Sevil Alagüney; DataCollection and/or Processing: Belgin Efe, ElifSevil Alagüney, İnsaf Durmuş; Analysisand/or Interpretation: Belgin Efe, GöknurYorulmaz, Elif Sevil Alagüney; Literature Re-view: Belgin Efe, Elif Sevil Alagüney; Writ-ing the Article: Elif Selvi Alagüney; CriticalReview: Belgin Efe.

References1. Gopal K, Priya G, Gupta N, Praveen EP, Khadgawat

R. A case of autoimmune hypoglycemia outsideJapan: Rare, but in the era of expanding drug-list,important to suspect. Indian J Endocrinol Metab.2013;17:1117-1119. [Crossref] [PubMed] [PMC]

2. Sahni P, Trivedi N, Omer A. Insulin autoimmunesyndrome: a rare cause of postprandial hypo-glycemia. Endocrinol Diabetes Metab Case Rep.2016;1-4. [Crossref]

3. Türkiye Endokrinoloji ve Metabolizma Dernegi(TEMD). Baskal N. Hipoglisemi. Klinik Endokrinoloji.Ankara: Miki Matbaacılık San ve Tic Ltd Şti;2000:69-75.

4. Alam S, Ozair M, Ahmad J. Hypoglycemia due to in-sulin autoimmune syndrome: a rare cause not to beforgotten. Journal of Clinical and Translational En-docrinology: Case Reports. 2016:7-9.

5. Gullo D, Evans JL, Sortino G, Goldfine ID, Vigneri R.Insulin autoimmune syndrome (Hirata Disease) inEuropean Caucasians taking alpha-lipoic acid. ClinEndocrinol (Oxf). 2014;81:204-209. [Crossref][PubMed]

6. Pereira PL, Roche AJ, Maier GW, Huppert PE,Dammann F, Farnsworth CT, Duda S, Claussen CD.Insulinoma and islet cell hyperplasia: value of thecalcium intraarterial stimulation test when findingsof other preoperative studies are negative. Radiol-ogy. 1998;206:703-709. [Crossref] [PubMed]

7. Woo CY, Jeong JY, Jang JE, Leem J, Jung CH, KohEH, Lee WJ, Kim MS, Park JY, Lee JB, Lee KU. Clin-ical features and causes of endogenous hyperinsu-linemic hypoglycemia in Korea. Diabetes Metab J.2015;39:126-131. [Crossref] [PubMed] [PMC]

8. Ma WY, Won JG, Tang KT, Lin HD. Severe hypo-glycemic coma due to insulin autoimmune syn-drome. J Chin Med Assoc. 2005;68:82-86.[Crossref]