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REVISTA ROMNDE PEDIATRIE VOLUMUL LIX, NR. 4, AN 2010274

REFERATE GENERALE5

Adresa de coresponden:Dr. Ionela Tman, Universitatea de Medicini Farmacie Victor Babe, P-a Eftimie Murgu, Nr. 2, 300041, Timioara

DIABETUL ZAHARAT TIP 2 LA COPILI ADOLESCENT O REALITATE N

PATOLOGIA PEDIATRICDr. Ionela Tman, Conf. Dr. I. Velea, Dr. Corina Paul, Prof. Dr. I. Popa

Clinica II Pediatrie, UMF Victor Babe, Timioara

REZUMAT

Pn nu demult, majoritatea cazurilor de diabet zaharat al copilului erau ncadrate ca i DZ tip 1.n ultimii 20 de ani ns, creterea incidenei obezitii a dus la o cretere sporire a numrului cazurilor de DZtip 2 la copil i adolescent.Se pare c insulino-rezistena reprezint punctul cheie n dezvoltarea DZ tip 2 att la copil, ct i la adult.

Avnd n vedere acest lucru, personalul medical trebuie avizat s efectueze teste screening la copiii cu riscde a dezvolta DZ tip 2, acest lucru determinnd implicit un diagnostic precoce i un management adecvat albolii.

Cuvinte cheie: diabet zaharat tip 2, obezitate, copil

1. INTRODUCERE

La sfritul secolului XX, incidena DZ tip 2 lacopil a crescut dramatic. Considerat pn nu demulto afeciune caracteristic persoanelor suprapon-derale/obeze de vrsta medie, DZ tip 2 prezint nultimii ani o inciden a crei cretere a devenitalarmant n rndul copiilor i adolescenilor dinntreaga lume dar mai ales n anumite grupuri popu-laionale (hispanici, indienii Pima, afro-americanii asiatici) (1, 2). Aceast tendin de cretere aprevalenei DZ tip 2 la copil este atribuit spoririiratei obezitii n rndul persoanelor de vrsttnr (3).

n ultimii 30 de ani, numrul copiilor diagnosti-cai cafiind obezi a crescut cu 100 %. (4). n Europa,

conform datelor raportate de Lobstein & Frelut n2003, rile din sudul continentului au raportat celmai mare numr de cazuri de suprapondere i obe-zitate la copil i adolescent. La adolesceni (grupade vrst 13-17 ani) apte ri din UE raporteaz oprevalen a obezitii de aproximativ 20%, cu unvrf de 35% n Creta (Grecia) (5).

Supraponderea/obezitatea reprezint cel maiimportant factor de risc n dezvoltarea DZ tip 2 latineri. ntra-devr, creterea prevalenei obezitiise coreleaz ndeaproape cu nmulirea numrului

de cazuri de DZ tip 2 (6,7). Tot mai multe cazuri de

DZ nou diagnosticat la copil sunt reprezentate deDZ tip 2 (pn la 50% din total n anumite centredin S.U.A) (8, 9).

Creterea incidenei DZ tip 2 n rndul copiilori adolescenilor are implicaii majore pe termen

lung, att pentru individ, ct i pentru societate isistemul de sntate public (10, 11). Debutul DZtip 2 la vrste tinere duce la instalarea precoce acomplicaiilor cronice degenerative (neuropatieprogresiv, retinopatie ce poate determina chiarpierderea vederii, nefropatie ce poate evolua pnla insuficiena renal cronic, complicaii atero-sclerotice).

2. FIZIOPATOLOGIA DZ TIP 2

DZ tip 2 apare n momentul n care secreia deinsulin devine inadecvat pentru asigurarea nece-sarului crescut impus de insulino-rezisten (12).

2.1 Insulino-rezistena (IR)

Reprezint de fapt un rspuns deficitar la efectelefiziologice ale insulinei (afectate fiind metabolismulglucidic, lipidic, proteic precum i funcia endo-teliului vascular). Astfel, se observ c DZ tip 2este n mod frecvent asociat cu alte semne de IR:

hipertensiunea arterial, dislipidemie, acanthosis

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REVISTA ROMNDE PEDIATRIE VOLUMUL LIX, NR. 4, AN 2010 275

nigricans, hiperandrogenismul ovarian, steatozahepatic non-alcoolic (13).

Att apariia IR, ct i a DZ tip 2, sunt influenatede factori genetici i de mediu. Printre factoriiimplicai n apariia DZ tip 2 amintim: greutateamic la natere (< 2500 g), nou-nscutul macrosom

din mam diabetic (> 4000 g), pubarha precoce(apariia pilozitii pubiene sub vrsta de 8 ani) (14,15). Instalarea pubertaii contribuie, de asemenea,la apariia IR (cu o scdere de aproximativ 30% asensibilitii periferice la insulini o cretere com-pensatorie a secreiei). Hormonul de cretere (GH)este considerat un factor ce contribuie la dezvoltareaIR la pubertate, existnd o corelaie invers pro-porional ntre nivelul GH i nivelul de aciune ainsulinei (16).

Secreia de insulin depinde de durata i stadiulbolii, i poate varia de la o cretere marcat dartardiv n timpul testului de provocare cu glucoz(TTGO), pn la valori mult sczute (12).

Amintim c DZ tip 2 este doar una dintre mani-festrile sindromului de insulino-rezisten (sindro-mul metabolic). Acesta mai include: obezitatea;nefropatia (albuminuria); hipertensiunea arterial;dislipidemia: TG i HDLc; sindromul ovarelorpolichistice; steatoza hepatic non-alcoolic; semnesistemice de inflamaie ( PCR, a citokinelor proin-

flamatorii i a numarului de leucocite).

2.2. Genetica n DZ tip 2

n patogeneza DZ tip 2 este recunoscut oputernic component genetic. Cei care au rude degradul I cu DZ tip 2, au un risc mult crescut de adezvolta aceast afeciune. Concordana la gemeniimonozigoi, de exemplu, este de aproape 100%.

Au fost studiate mai multe gene asociate cu dez-voltarea DZ tip 2: ABCC8 (gena ce codific recep-torul pentru sulfoniluree), CAPN10 (The Calpain10 Enzyme enzim activat de calciu implicat ndescompunerea proteinelor), GCGR (receptorulpentru glucagon), GCK (gena ce codific gluco-kinaza), GLUT2 SLC2A2 (gena ce codific trans-portorul pentru glucoz la nivelul celulei beta rolde senzor glicemic), factorul de trancripieHNF4A, gena ce codific insulina (INS), genareceptorului pentru insulin (INSR), gena ce co-dific lipoprotein-lipaza, KCNJ11 (gen situat lanivelul cromozomului 11, ce codific canalele de

potasiu Kir 6.2 ATP dependente), TCF7L2 unfactor de transcripie ce regleaz gena de expresie aproglucagonului, fiind astfel implicat n produciapeptidului gucagon-like 1. Se pare c, la populaiaeuropean este factorul de risc determinant n

apariia DZ tip 2 (19). Mai mult dect att, obezitatea(ca i factor de risc independent n apariia DZ tip2) are o important component genetic (17).

Amintim aici i diabetul monogenic (MODY),form relativ rar de diabet (aproximativ 1-5% dinnumrul total de cazuri). Formele de diabet mono-

genic rezult din mutaia unei singure gene; poate fitransmis dominant autosomal, recesiv autosomal,dar sunt descrise i mutaii de novo. La copil,cazurile de diabet monogenic rezult din mutaiiale genelor ce regleaz funcia beta celulari mairar din mutaii ce induc o insulino-rezisten sever(18). Prima gen MODY a fost descris n 1991, iarn prezent sunt 6 gene a cror mutaie poate duce laapariia diabetului monogenic i cteva genecandidate (MODY 7 MODY 9).

2.3. Ipoteza acceleratoruluiSusintorii acestei teorii pleac de la premiza

cDZ tip 1 i DZ tip 2 reprezint, de fapt, o tulburarea IR ce survine pe teren genetic diferit. Sunt re-cunoscui 3 factori care accelereaz n mod variabildistrucia beta celular: constituionali/genetici, IRi rspunsul imun indus de aceasta. Nici unul dintreaceti acceleratori nu duce la apariia diabetului nabsena creterii n greutate. Se presupune c doarritmul (tempoul) n care se distrug celulele beta

face distincia ntre DZ tip 1 i DZ tip 2.Patru postulate stau la baza acestei teorii:1. Rspunsul imun n DZ tip 1 i insulina asociat

duc n final la IR. Acest concept este esenialpentru strategiile de prevenie n DZ tip 1.

2. n condiii de IR, tempo-ul (ritmul) dedistrucie beta celular va fi mai accelerat lacei cu genotip mai reactiv ceea ce ar ex-plica de ce DZ cu debut n copilrie se aso-ciaz mai frecvent cu genotip DR3/DR4.

3. DZ tip 1 i DZ tip 2 sunt privite (cel mai

frecvent) ca dou entiti separate cu un gradde suprapunere n cazul celor cu DZ tip 2 cedevin n timp insulinodependeni.

4. Distrucia beta celular este rezultatul aciuniicombinate a IR i a rspunsului imun laaceasta. Dac IR este suficient de severpoate accelera singur apoptoza beta celularfr a fi nevoie de prezena semnificativ acelui de-al doilea accelerator.

2.4. Progresia de la IR la DZ tip 2

Sensibilitatea la insulini secreia de insulinsunt invers proporionale. Cu ct sensibilitatea lainsulin este mai mic (de exemplu n cazurile cuIR), cu att se secret mai mult insulin. La un

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anumit moment secreia compensatorie a celulelorbeta devine ineficient, i indicele de utilizareperiferic a glucozei scade (19).

Eecul celulelor beta pancreatice (tradus printr-osecreie insuficient de insulin), st la baza tran-ziiei de la IR la debutul diabetului. Prin urmare,

debutul bolii este silenios, i scap astfel eforturilormedicale de a interveni precoce. Diagnosticul sestabilete, de obicei, cnd exist o deteriorare afunciei beta celulare care necesit de cele maimulte ori tratament medicamentos i/sau insulin.

3. SCREENINGUL PACIENILOR CU RISCDE A DEZVOLTA DZ TIP 2

DZ tip 2 este de cele mai multe ori asimptomatic.Factorii de risc n dezvoltarea DZ tip 2 includ:

supraponderea/obezitatea i semne ale IR: acan-thosis nigricans, pubertate precoce, hipertensiunearterial, dislipidemie, sindromul ovarelor polichis-tice (13). Asociatia Americana de Diabet (ADA)recomand ca toi copiii cu IMC peste percentila 85corespunztoare vrstei i sexului i care au ali doifactori de risc pentru DZ tip 2 sfie supui screenin-gului pentru aceast afeciune (Tabelul 1).

Pentru optimizarea terapiei, este important dife-renierea ct mai precoce ntre DZ tip 1 i DZ tip 2.Semnele clinice utile n diagnosticul diferenial, suntobezitatea i markerii IR (acanthosis nigricans, HTA,sindromul ovarelor polichistice). Pacienii cu DZ tip2 au, de obicei, nivel seric crescut al peptidului C.

Absena anticorpilor anti-insulin (IAA), a celor anti-celul pancreatic (ICA) i/sau a anti GAD (de-carboxilaza acidului glutamic) este de asemeneatipic pentru majoritatea cazurilor de DZ tip 2 (21).

Dificulti de ncadrare diagnostic

Clinicianul este obligat s cntreasc cu mareatenie dovezile ce vin n sprijinul diagnosticului is ncadreze corect, nc de la debut, tipul de diabet.Acest lucru este tot mai dificil de realizat din maimulte considerente:

Odat cu creterea incidenei obezitii la copil,

10-15% dintre cazurile nou diagnosticate cuDZ tip 1 sau MODY prezint exces ponderal.Un numr semnificativ de copii cu DZ tip 2 potprezenta cetonurie i cetoacidoz diabetic.Amintim, de asemenea, i alte forme de diabetcare pot face diagnosticul diferenial dificil:DZ tip 2 autoimun: are o fiziopatologie ncneclar. Cel mai probabil, reprezint un DZtip 1 autoimun ce survine la persoane supra-ponderale/obeze (acest lucru stnd la bazainsulino-rezistenei) (22). Funcia celulelor

beta este semnificativ redus la indivizii cuanticorpi, cea mai dramatic diferenfiindraportat la adulii tineri (25-34 ani) la carese dezvolt o dependen rapid de insulin de obicei n 3 ani (23, 24).Diabetul zaharat atipic: apare n timpul co-pilriei (debuteaz rar dup vrsta de 40 deani). A fost descris doar la descendenii popu-laiei africane. Cetoza i cetoacidoza suntprezente la debut. Secreia de insulin esteprezent dar diminuati fr alterarea func-iei pe termen lung; interesant este c insulinanu este necesar pentru supravieuire duptratamentul alterrilor metabolice acute, deicontrolul diabetului poate fi srac i ceto-acidoza diabetic poate aprea n absenasubstituiei cu insulin (de exemplu n caz deboal sau sarcin). Nu este asociat cu obe-zitate, i nici cu insulinorezisten.

5. OPIUNI TERAPEUTICE N CAZUL COPIILOR

CU DZ TIP 2Eforturile de ncadrare diagnostic a unui copil

cu DZ la debut urmresc de fapt stabilirea unei ati-tudini terapeutice ct mai corecte.

TABELUL 1. Recomandri de screening pentru DZ tip 2

Suprapondere sau risc de suprapondere

IMC > percentila 85 pentru vrsti sex; sau Greutatea corespunztoare taliei > percentila 85; sau Greutate >120% fa de cea ideal pentru talie.

Plus oricare 2 dintre urmtoarele

istoric familial de DZ tip 2 la rudele de gradul I sau II,

apartenena etnic/ras (indieni americani, rasaneagr, hispanici, asiatici/locuitori ai insulelor din Pacific), semne clinice de insulino-rezisten sau afeciuniasociate acesteia (acanthosis nigricans, HTA,

dislipidemie, sindromul ovarelor polichistice),

vrsta de iniiere a screeningului: 10 ani sau debutulpubertii (dac acesta se instaleaz mai devreme).

Dispensarizare:

Frecvena testrii: la fiecare 2 ani; Test utilizat: glicemia a jeun (TTGO poate fi utilizat de

asemenea pentru confirmarea diabetului).

4. DIAGNOSTICUL DZ TIP 2

Criteriile de diagnostic pentru DZ se bazeaz pedeterminarea valorilor glicemice, precum i peprezena/absena simptomelor.

Conform ISPAD, aceste criterii sunt (20):Glicemie a jeun 7,0 mmol/l (126 mg/dl);

Glicemie la 2 ore n timpul TTGO 11,1mmol/l (200 mg/dl);Simptome sugestive pentru diabet i glicemiedeterminat ocazional 11,1 mmol/l (200mg/dl).

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5.1. n DZ tip 2 obiectivele tratamentului vizeaz:

Scderea n greutate1.Creterea capacitii de a face sport2.Normalizarea glicemiei3.Controlul comorbidittilor (HTA, dislipi-4.demia, nefropatia, steatoza hepatic).

5.2. Mijloacele terapeutice recomandate n DZ tip 2sunt:

a) Modificarea stilului de viat

n 2005, n SUA au fost publicate rezultatele adou trialuri clinice randomizate, care au demonstratbeneficiile modificrii stilului de via asupra pro-gresiei de la alterarea toleranei la glucoz la DZ(25).

Scderea n greutate sau prevenirea i stoparea

procesului de ngrare par a fi cele mai bune metodede prevenie ale DZ tip 2 la copiii cu risc (26).

n orice caz, modificarea stilului de via estepiatra de temelie n tratamentul DZ tip 2. Attcopilul, ct i prinii trebuie sperceap implicaiilemedicale importante pe care le are excesul ponderal.Modificrile se fac treptat, iar copilul i familiaacestuia trebuie s neleag c toate aceste schim-bri, pentru a fi benefice, vorfi permanente. Ideal arfi ca n managementul DZ tip 2 sfie inclui unnutriionist i un psiholog.

b) Terapia farmacologic:

Vafiutilizat concomitent cu modificarea stiluluide viai are drept scop:

scderea rezistenei la insulin;creterea secreiei de insulin;ncetinirea absorbiei postprandiale a glu-cozei.

Terapia copilului cu DZ tip 2 este srac nopiuni, dac ne gndim c singurul antidiabeticoral aprobat pentru utilizare sub vrsta de 18 ani

este Metforminul (sulfonilureicelefi

ind aprobatepentru utilizare la copii n foarte puine ri).b.1. Metforminul singurul antidiabetic oral

aprobat pentru uz pediatric.

n 1922 s-a sintetizat pentru prima dat 1-1-dimetilbiguanida (Metforminul), pornind dela structura chimic a unei plante numiteGalega Officinalis Galegine (plantutilizatn tratamentul DZ nc de la nceputul se-colului XX);n 1950, dup un hiatus n dezvoltarea anti-

diabeticelor orale (hiatus produs din cauzadescoperirii insulinei), se redeteapt inte-resul vizavi de efectele hipoglicemiante alebiguanidelor n general (i ale metforminuluin special).

n Europa, metforminul este recomandat ntratamentul copiilor cu DZ tip 2 cu vrsta maimare de 10 ani;poate fi utilizat ca monoterapie, dar i nasociere cu insulina;acioneaz asupra receptorilor insulinici din

ficat, muchi i esutul adipos (cu aciunepredominant n ficat);reduce producia hepatic de glucoz prininhibarea gluconeogenezei;crete captarea de glucoz (stimulat deinsulin) n muchi i ficat;doza iniial este de obicei de 1 tb/zi (500mg). La 10-15 zile de la iniierea tratamen-tului, doza poate fi ajustat n funcie de va-lorile glicemiei;doza maxim recomandat/24 ore = 2000 mg.

Avantajele terapiei:Un efect anorexic iniial poate duce la scdereponderal;Utilizarea pe timp ndelungat duce la scdereaHbA1c cu 1-2%;Are avantajul, comparativ cu sulfonilureicele,de a reduce n egal msur HbA1c, dar frrisc de hipoglicemie;Greutatea scade sau rmne stabil;LDLc i trigliceridele scad pe perioada trata-mentului;Risc sczut de acidoz lactic.

Efecte adverse: gastrointestinale: dureri abdo-minale, diaree, greuri.

Eecul monoterapiei cu Metformin dupa 3 luni,impune asocierea de glitazon, sulfoniluree sauinsulin.

b.2. Insulina:

n ciuda hiperinsulinismuluii a IR (caracteristiceDZ tip 2), doze relative mici de insulin pot fiadeseori utile.

Dac nu se obine controlul metabolic optim cu ajutorul antidiabeticelor orale, un analogde insulin cu aciune lung poate fi util (fra avea legtur cu mesele). Metforminul tre-buie continuat, deoarece mbuntete sensi-bilitatea la insulin.Nu se recomand asocierea tiazolidindionelorcu insulin din cauza riscului de apariie aedemelor;Dac persist hiperglicemia postprandial,poate fi necesar asocierea insulinei cu aci-

une rapid la mese;Efectele adverse ale terapiei cu insulin:hipoglicemia;La adolescenii cu DZ tip 2, cu control ina-decvat al bolii, s-a instituit terapie cu insulin

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glargine, o singur injecie/zi (tratament do-vedit a fi la fel de eficient ca i cel cu 3 injeciide insulin rapid) (27).

CONCLUZII

La nivel mondial, incidena obezitii a crescutn toate segmentele populaiei. Aceast epidemie,precum i complicaiile ei reprezint un consumatormajor din fondurile alocate sntii.

Prevenia DZ tip 2 are la baz prevenia obezitiila cei care nu sunt supraponderali, respectiv trat-amentul obezitii la cei cu IMC peste percentila85.

Prevenia primar a DZ tip 2 este direcionatspre obezitatea pandemici presupune, n primulrnd, modificarea obiceiurilor alimentare i de vianc din perioada de copil mic.

Multiple studii au artat c o minim scdere ngreutate duce la scderea ratei de apariie a dia-

betului la persoanele cu risc (28, 29). La populaiaadult, interveniile de modificare a stilului de viasunt mult mai dificil de nfptuit dect la copil(30).

Societatea, familia, ntreaga comunitate, dar ipersonalul medical sunt direct implicate n pre-venirea sau ntrzierea apariiei DZ tip 2 i a altormanifestri ale insulino-rezistenei.

Type 2 diabetes in children and adolescents a reality in pediatric pathology

Ionela Tamasan, I. Velea, Corina Paul, I. Popa2nd Clinic of Pediatrics V. Babes University of Medicine and Pharmacy,

Timisoara, Romania

ABSTRACT

Until recently, the majority of cases of diabetes mellitus among children and adolescents were considered

type 1 diabetes.Obesity has led to a dramatic increase in the incidence of type 2 diabetes (T2DM) among children andadolescents over the past 2 decades.The hallmark of type 2 diabetes in the young, as in most adults, is insulin resistance.Health care professionals are advised to perform the appropriate screening in children at risk for T2DM,diagnose the condition as early as possible, and provide rigorous management of the disease.

Key words: type 2 diabetes,obesity, child

1. INTRODUCTION

By the end of the 20th century the incidence of

type 2 diabetes mellitus (T2DM) in children hadincreased dramatically. Once considered a diseaseof the overweight, middle age person, the incidenceof type 2 diabetes is rising rapidly in children and ado-lescents worldwide, with the highest prevalence inthose of American-Indian, Hispanic, African-Ameri-can, and Asian descent (1, 2). The alarming incidenceand prevalence of diabetes has been attributed to in-creasing obesity among younger people (3).

During the past 30 years, the number of childrendiagnosed as being overweight has increased by

100 %. (4). In Europe, according to data reportedby Lobstein & Freult in 2003, the countries of thesouth have reported the highest number of cases ofoverweight and obesity in children and adolescents.In adolescents (age group 13-17 years), severel EU

countries reported a prevalence of obesity about20%, with a peak of 35% in Crete (Greece) (5).

Overweight/obesity is the most important risk

factor in developing T2DM in young people. In-deed, the increasing prevalence of obesity is closelycorrelated with increasing number of cases of type2 diabetes (6,7).

More and more cases of diagnosed diabetesamong children represent T2DM (up to 50% of atotal in some parts of the USA) (8, 9).

Increasing rates of T2DM among children andadolescents will have considerable long-term im-plications for the affected individuals, society, andthe public health system as a whole (10,11). Earlier

onset of T2DM leads to earlier onset of complica-tions including progressive neuropathy, retinopathyleading to blindness, nephropathy leading to chron-ic renal failure, and atherosclerotic cardiovasculardisease.

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2. PATHOPHISYOLOGY IN T2DM

Type 2 diabetes occurs when insulin secretion isinadequate for ensuring increased requirements im-posed by insulin resistance (12).

2.1. Insulin resistanceInsuline resistance is an impaired response to

the physiologic effects of insulin, including effectson glucose, lipid, and protein metabolism, and onvascular endothelial function. Thus, T2DM is com-monly associated with other features of the insulinresistance syndrome [hyperlipidemia, hypertension,acanthosis nigricans, ovarian hyperandrogenismnon-alcoholic fatty liver disease (NAFLD)] (13).

Genetic and environmental factors influence thedevelopment of insulin resistance and T2DM.Among the factors involved in the occurrence oftype 2 diabetes recall: children born small for ges-tational age (< 2500 g), newborn macrosomia ofdiabetic mother (> 4000 g), premature adrenarchein girls (pubic hair appearing before the age of 8years) (14, 15). The onset of puberty also contrib-utes to insulin resistance, with insulin sensitivitydecreasing by approximately 30% and compensa-tory increases in insulin secretion. Growth hormonehas been considered a contributing factor in the de-

velopment of insulin resistance during puberty,with an inverse correlation between growth hor-mone levels and insulin action (16).

Insulin secretion depends on the duration anddisease stage, and can vary from a delayed butmarked increase during glucose challenge test(OGTT), to values lower than (12).

Diabetes is only one manifestation of the insulinresistance syndrome or the MS (metabolic syn-drome). Other associations include: obesity, hyper-tension, nephropaty (albuminuria), dyslipidemia(hypertriglyceridemia and decreased high-densitylipoprotein cholesterol), ovarian hyperandrogenismand premature adrenarche, NAFLD (non-alcoholicfatty liver disease), systemic inflammation: elevat-ed C-reactive protein, inflammatory cytokines.

2.2. Genetics in Type 2 diabetes

There is an important genetic component recog-nized in the T2DM pathogenesis. Those who havefirst degree relatives suffering of T2DM, have a

much higher risk of developing this disease. In thecase of identical twins, the concordance is for ex-ample of almost 100%.

There have been studies conducted regardingthe genes associated to the development of DM

type 2: ABCC8 (the gene that codifies the receiverfor sulfonylurea), CAPN 10 (the Calpain 10 En-zyme an enzyme activated by the Calcium, relat-ed to the protein decomposition), GCGR (the re-ceptor for glucagon), GCK (the gene that codifiesthe glucokinasis), GLUT2 SLC2A3 (the gene that

codifies the glucose transporter at the beta celllevel having a role of a glycaemic sensor), thetranscription factor HNF4A, the gene that codifiesthe insulin (INS), the receptor gene for insulin(INSR), the gene that codifies the lipoprotein-li-pase, KCNJ11 (the gene situated at the level of the11th chromosome, that encoding the Kir 6.2 ATP-sensitive K+ channel), TCF7L2 a transcriptionfactor that regulates the expression gene of the pro-glucagon, being likewise involved in the produc-tion of the glucagons-like peptide. It seems that the

determinant risk factor in developing T2DM, ap-pears in the case of European population. Furthermore, the obesity (as a risk factor independent ofT2DM) has a valuable genetic component (17).

We mention here also the monogenic diabetes(Maturity Onset Diabetes of the Young MODY),a relatively rare form of diabetes (appreciative-ly1-5% of the whole nimble of cases). Monogenicdiabetes results from the inheritance of a mutationor mutations in a single gene. It may be dominantlyor recessively inherited or may be a de novo muta-

tion and hence a spontaneous case. In children, al-most all monogenic diabetes results from mutationsin genes that regulate beta-cell function althoughdiabetes can rarely occur from mutations resultingin very severe insulin resistance (18). The firstMODY gene was described in 1991 and at the mo-ment there are 6 genes whose mutations can lead tothe monogenetic diabetes apparition. (MODY 7 MODY 9)

2.3. The accelerator hypotesis

The accelerator hypothesis argues that type 1and type 2 diabetes are the same disorder of insulinresistance set against different genetic backgrounds.The Accelerator Hypothesis identifies three pro-cesses which variably accelerate the loss of betacells through apoptosis: constitution, insulin resis-tance and autoimmunity. None of the acceleratorsleads to diabetes without excess weight gain. It issupposed that only the rhythm (the tempo) inwhich the beta cells are destroyed makes the dis-

tinction between T1DM and T2DM.There are four postulates that fundament this

theory:1. The immune response in the case of T1DM

and the islet-cell inflamation can finally bring

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to insulino-resistance (IR). This concept isessential for the prevention strategies inT1DM.

2. In IR conditions the tempo of beta cellular de-struction will be more accelerated in the caseof those who have a more reactive genotype-

circumstance that will explain also why DMthat appeared in childhood is more frequentlyassociated with the DR3/DR4 genotype.

3. T1DM and T2DM are most frequently re-garded as two separate entities with a degreeof superposition in the case of T2DM that be-come in time dependent to insulin.

4. The beta cellular destruction is the result ofthe combined action of the IR and the im-mune response. If IR is severe enough it canindependently accelerate the beta cellular

apoptosis. Without being necessary the pres-ence of the second accelerant.

2.4. Progression From Insulin Resistance to T2DM

Insulin sensitivity and insulin secretion are in-versely and proportionately related. The lower theinsulin sensitivity (ie. the greater the insulin resis-tance), the more insulin is secreted. At a certainpoint, this compensatory-cell response fails and theglucose-disposition index decreases. (19)

The failure of beta pancreatic cells (regarded as

an insufficient insulin secretion), lies at the basis ofthe transition from IR to the start of diabetes. There-fore, the beginning of the illness is silent and thus iteludes the medical efforts of early intervention. Thediagnosis is usually established when there is al-ready a deterioration of the beta cellular functionthat needs a medicinal treatment and/or insulin inmost of the cases.

3. SCREENING OF INDIVIDUALS AT RISKFOR T2DM

T2DM is often asymptomatic. Risk factors forT2DM include overweight and obesity, and signsof insulin resistance including acanthosis nigricans,precocious puberty, hypertension, dyslipidemia,and polycystic ovary syndrome (13). The AmericanDiabetes Association recommends screening fordiabetes among children with a BMI of 85th per-centile for age and gender, with 2 additional riskfactors for T2DM (Tabel 1).

4. DIAGNOSIS OF TYPE 2 DIABETESDiagnostic criteria for diabetes are based on BG

measurements and the presence or absence ofsymptoms.

Diabetes is diagnosed when (20):A fasting plasma glucose (FPG) is 7.0mmol/l (126 mg/dl) orThe post challenge plasma glucose is >11.1mmol/l (200 mg.dl) orSymptoms of diabetes and a casual plasmaglucose 200 mg/dl (11.1 mmol/L).

Early in the evaluation of a new patient with dia-betes mellitus, it is important to distinguish between

T1DM and T2DM to optimize therapy. Clinicalsigns helpful in distinguishing T2DM from T1DMare obesity and signs of insulin resistance (acantho-sis nigricans, hypertension, polycystic ovary syn-drome). Patients with T2DM frequently have ele-vated C-peptide levels. The absence of insulinautoantibodies, the islet cell and/or glutamic aciddecarboxylase is also typical in most (but not all)cases of diabetes that are classified as T2DM (21).

Uncertainties of Classification

The clinician is obliged to weigh the evidence ineach individual patient to distinguish betweenT1DM and T2DM. The realization of this desider-ate is more and more difficult to be made becauseof different reasons:

with increasing obesity in childhood, as manyas 1525% of newly diagnosed T1DM (ormonogenic diabetes) patients may be obese;the significant number of pediatric patientswith T2DM demonstrating ketonuria orketoacidosis at diagnosis;

We also add different other diabetes forms thatcan make the differential diagnosis difficult to bemade:

Autoimmune T2DM: The pathophysiologyof autoimmune T2DM is unclear. It most

TABLE 1. Testing Guidelines for T2DM

Overweight or at risk for overweight

BMI >85th percentile for age and gender; or

Body weight for height >85th percentile; or

Body weight >120% of ideal for height

+ Plus any 2 of the following

Family history of T2DM in first or second-degree

relatives

Race/ethnicity (American Indian, black, Hispanic,

Asian/Pacific Islander)

Signs of insulin resistance or conditions associated with

insulin resistance (acanthosis nigricans, hypertension,

dyslipidemia, polycystic ovary syndrome)

Age of screening initiation: 10 y or at onset of puberty if

puberty occurs at a younger age

Medical attendance:

Frequency of testing: Every 2 years

Test: Fasting plasma glucose (OGTT can also be used

to confirm diabetes)

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likely represents autoimmune T1DM in over-weight or obese individuals with underlyinginsulin resistance. (22). The function of betacells is significantly less in antibody positiveindividuals. The most dramatic differencehas been observed among young adults (25-

34 years old), where a rapid insulin dependenceis developed usually in about 3 years(23,24).Atypical diabetes mellitus or Flatbushdiabetes: occurs throughout childhood, butrarely begins past age 40. It has only beendescribed in young people of African descent.Ketosis or ketoacidosis is typical at onset.Insulin secretion is present but diminishedand without long-term deterioration offunction. Interestingly, insulin is often not

required for survival after treatment of acutemetabolic deterioration, although diabetescontrol may be poor and ketoacidosis mayrecur without insulin, e.g. with illness orpregnancy. It is not associated with obesityand with insulino resistance.

5. THERAPEUTICAL OPTIONS FOR CHILDRENWITH T2DM

The efforts to establish the right diagnosis of achild with DM in an early stage, follows in fact thedetermination of a therapeutically attitude as accu-rate as possible.

5.1. Treatament goals in T2DM:

1. Weight loss2. Increase in exercise capacity3. Normalization of glycemia4. Control of comorbidities: including hyper-

tension, dyslipidemia, nephropathy, and he-

patic steatosis

5.2. Recommended therapeutic means in T2DM:

a) Lifestyle modifications

Two recent randomized (USA 2005), con-trolled clinical trials on the prevention of diabetesamong adults have demonstrated the benefits oflifestyle intervention on the prevention of progres-sion from impaired glucose tolerance to T2DM(25).

Weight loss and/or prevention of weight gain isthe best way to prevent T2DM among children withrisk factors for the disease (26).

Lifestyle change is the corner-stone of treatmentof T2DM. The family and child should understand

the medical implications of obesity and T2DM. Themodifications are done gradually and the patientsfamily has to understand that all these changesshould be permanent in order to be beneficial. Itwould be ideal that a nutritionist and a psychologistwere included in DM type 2 management.

b) Pharmacologic therapy:It would be done in the same time as the lifestyle

changes, its purpose is:To decrease insulin resistance;To increase insulin secretion;To slow postprandial glucose absorption.

The therapy of a child with T2DM is short onoptions, if we think that the only approved oral an-tidiabetic is Metformin (the sulfonylurea has theapproval to be used in child treatment only in a fewcountries).

b.1. Metformin the only oral medicine that has theapproval to be used in pediatrics.

In 1922 there has been synthesized for thevery first time the dimethylbiguanmide (theMetformin). The process started from thechemical structure of a plant called GalegaOfficinalis Galegine (a plant that has beenused in the treatment of diabetes since thebeginning of the 20th century);

In 1950, after a hiatus in the development of oral antidiabetics (due to the insulindiscovery) the general interest regarding thehypoglyceminates effects of biguanides isrenewed (and the interest for Metformin inparticular);In Europe the treatment with Metformin isrecommended as a treatment for children thathave more than 10 years old;It can be used either as a single therapy or inassociation with insulin;

Hepatic glucose production is reduced bydecreasing gluconeogenesis;Insulin stimulated glucose uptake is increasedin muscle and fat;The initial dose is usually of 1 tb/ a day. After10-15 days from the beginning of thetreatment the dose can be adjusted accordingto the glycaemia values;The maximum recommended dose /24=2000mg;

The advantages of the therapy: An initial anorexic effect may promoteweight loss;Its use for a long period of time can reducethe HbAlc with 1-2%;

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In comparison to the sulfonylurea, it has theadvantages of reducing the HbAlc withoutany hypoglycemic risk;The corporeal weight is reduced or it remainsthe same;LDLc and the triglycerides are reduced

during the treatment;Reduced risk of lactic acidosis;Side effects: gastrointestinal: abdominalpain, diarrhea, nausea.

The failure of single Metphormin treatment af-ter 3 months, imposes its association with Glita-sone, sulfonylurea or insulin.

b.2. Insulin:

Despite hyperinsulinemia and insulin resistance,relatively small doses of supplemental insulin areoften effective.

If glycemic control on oral agents isinadequate, a long-acting insulin analoguemay provide satisfactory therapy withoutmeal related therapy. Metformin should becontinued to improve insulin sensitivity. TheMetformin should still be taken as it improvesthe sensitivity to insulin.It is not recommended to associate thi-azolidinodines with insulin because of

increased risk forfl

uid retention.If the postprandial hyperglycemia still per-sists the association with insulin might benecessary in order to have a quick effect during meals.The side effects of the insulin therapy: hypo-glycemia;

In adolescents with T2DM that proved tohave an inadequate control over the illness, ithas been considered a glargine insulin therapywith a single injection a day (the treatmentproved to be as efficient as the 3 injectionswith rapid insulin) (27).

CONCLUSIONS

At a global level, the incidence of obesity hasraised in all the segments of the population. Theepidemic of obesity and its complications accountsfor a substantial and increasing proportion of directand indirect health care costs.

Prevention of T2DM requires prevention of obe-sity in those who are not overweight and treatmentof obesity in those who have a BMI > 85th percen-

tile.The primary prevention of T2DM is leaded to

pandemic obesity and supposes the change of life-style and alimentary habits from a young age in thefirst place.

Many studies have shown that a minimumweight loss can be followed up by the reduction ofthe diabetes rate among the persons exposed to risk(28, 29). For the adult population, it is much harderto change the lifestyle, than it is for children (30).

The society, the family, the whole society andalso the health care professionals are directly in-volved in the prevention or the delaying of theT2DM and other manifestations of insulin resis-tance.

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