iii. diabetes mellitus

8/11/2019 III. Diabetes Mellitus

1/39


2/39

*ge greater than 34 years "though, as noted above, type 2 diabetesmellitus is occurring with increasing frequency in young individuals$

5eight greater than 62- of desirable body weight (amily history of type 2 diabetes in a 7rst/degree relative "eg, parent or

sibling$

+ispanic, 8ative *merican, *frican *merican, *sian *merican, or Paci7c'slander descent +istory of previous impaired glucose tolerance "'9T$ or impaired fasting

glucose "'(9$ +ypertension ":63-; - mm +g$ or dyslipidemia "+ < cholesterol level =

3- mg;d< or triglyceride level :64- mg;d


3/39

+8(/6/beta 8)EF> 6 G


4/39

* population/based, retrospective cohort study of 6,-6-,-JB pregnant womenexamined the association between preeclampsia and gestational hypertensionduring pregnancy and the ris% of developing diabetes post partum. Fesultsshowed the incidence rate of diabetes per 6--- person/years was J.3? forwomen with preeclampsia and 4.2J for those with gestational hypertension,compared with 2.B6 in women with neither condition. Fis% was further elevated

in women with preeclampsia or gesntational hypertension comorbid withgestational diabetes.

Epidemiology

* 2-66 0enters for isease 0ontrol and Prevention "0 0$ report estimated thatnearly 2J million *mericans have diabetes. *dditionally, an estimated ? million*mericans have prediabetes.

iabetes a!ects B.K of *mericans of all ages, 66.K of adults aged 2- yearsand older, and 24 of persons age J4 and older, according to the 8ational

iabetes (act #heet for 2-66. *bout 2? of those with diabetesL? million*mericansLdo not %now that they have the disease. *bout 264,--- peopleyounger than 2- years had diabetes "type 6 or type 2$ in the Enited #tates in2-6-.

'n 2-63, the 0 0 reported that about 3- of E# adults will develop diabetes,primarily type 2, in their lifetime, and more than 4- of ethnic minorities will bea!ected. This is substantially higher than previous estimates. The central reasonfor the increase is obesity.

Prediabetes a!ects K4 of adults aged 2- years and older. Prediabetes, asde7ned by the *merican iabetes *ssociation, is that state in which bloodglucose levels are higher than normal but not high enough to be diagnosed asdiabetes. 't is presumed that most persons with prediabetes will subsequentlyprogress to diabetes. The 0 0 estimated that in 2-6-, ? million *mericansaged 2- years or older had prediabetesLK4 of E# adults aged 2- years orolder and 4- of those aged J4 years or older.

* study by


5/39

largely because of the increase in obesity.

The top 6- countries in number of people with diabetes are currently 'ndia,0hina, the Enited #tates, 'ndonesia, apan, Pa%istan, Fussia, &razil, 'taly, and&angladesh. The greatest percentage increase in rates of diabetes will occur in*frica over the next 2- years. Enfortunately, at least B- of people in *frica

with diabetes are undiagnosed, and many in their K-s to J-s will die fromdiabetes there.

ace!related demographics

The prevalence of type 2 diabetes mellitus varies widely among various racialand ethnic groups. The image below shows data for various populations. Type 2diabetes mellitus is more prevalent among +ispanics, 8ative *mericans, *frican*mericans, and *sians;Paci7c 'slanders than in non/+ispanic whites. 'ndeed, thedisease is becoming virtually pandemic in some groups of 8ative *mericans and+ispanic people. The ris% of retinopathy and nephropathy appears to be greaterin blac%s, 8ative *mericans, and +ispanics.

Prevalence of type 2 diabetes mellitus in various racial and ethnicgroups in the United States (200 !200" data#.

source http ;;emedicine.medscape.com;article;66?B4K/overviewNa-64J

"ge!related demographics Type 2 diabetes mellitus occurs most commonly in adults aged 3- years or older,and the prevalence of the disease increases with advancing age. 'ndeed, theaging of the population is one reason that type 2 diabetes mellitus is becomingincreasingly common. Oirtually all cases of diabetes mellitus in older individualsare type 2.

'n addition, however, the incidence of type 2 diabetes is increasing more rapidlyin adolescents and young adults than in other age groups. The disease is beingrecognized increasingly in younger persons, particularly in highly susceptibleracial and ethnic groups and the obese. 'n some areas, more type 2 than type 6diabetes mellitus is being diagnosed in prepubertal children, teenagers, and


6/39

young adults. The prevalence of diabetes mellitus by age is shown in the imagebelow.

Pre#alence o Dia$etes $y "ge

source http ;;emedicine.medscape.com;article;66?B4K/overviewNa-64J

%lassifcation

%&"SSI'I%"(I)* )' DI"+E(ES ME&&I(,S "*D )(-E %"(EG) IES )'G&,%)SE EG,&"(I)**ssigning a type of diabetes to an individual often depends on thecircumstances present at the time of diagnosis, and many diabetic individuals donot easily 7t into a single class. (or example, a person with gestational diabetesmellitus "9 M$ may continue to be hyperglycemic after delivery and may bedetermined to have, in fact, type 2 diabetes. *lternatively, a person whoacquires diabetes because of large doses of exogenous steroids may becomenormoglycemic once the glucocorticoids are discontinued, but then may developdiabetes many years later after recurrent episodes of pancreatitis. *notherexample would be a person treated with thiazides who develops diabetes yearslater. &ecause thiazides in themselves seldom cause severe hyperglycemia, suchindividuals probably have type 2 diabetes that is exacerbated by the drug. Thus,for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and totreat it e!ectively.

(ype . dia$etes /0!cell destruction1 usually leading to a$solute insulindefciency2


7/39

Immune!mediated dia$etes3

This form of diabetes, which accounts for only 4@6- of those with diabetes,previously encompassed by the terms insulin/dependent diabetes, type 6diabetes, or 1uvenile/onset diabetes, results from a cellular/mediatedautoimmune destruction of the /cells of the pancreas. Mar%ers of the immune

destruction of the /cell include islet cell autoantibodies, autoantibodies toinsulin, autoantibodies to 9* "9* J4$, and autoantibodies to the tyrosinephosphatases '*/2 and '*/2 . >ne and usually more of these autoantibodies arepresent in B4@ - of individuals when fasting hyperglycemia is initiallydetected. *lso, the disease has strong +


8/39

This form of diabetes, which accounts for -@ 4 of those with diabetes,previously referred to as non@insulin/dependent diabetes, type 2 diabetes, oradult/onset diabetes, encompasses individuals who have insulin resistance andusually have relative "rather than absolute$ insulin de7ciency *t least initially,and often throughout their lifetime, these individuals do not need insulintreatment to survive. There are probably many di!erent causes of this form of

diabetes. *lthough the speci7c etiologies are not %nown, autoimmunedestruction of /cells does not occur, and patients do not have any of the othercauses of diabetes listed above or below.

Most patients with this form of diabetes are obese, and obesity itself causessome degree of insulin resistance. Patients who are not obese by traditionalweight criteria may have an increased percentage of body fat distributedpredominantly in the abdominal region. Getoacidosis seldom occursspontaneously in this type of diabetesI when seen, it usually arises inassociation with the stress of another illness such as infection. This form of diabetes frequently goes undiagnosed for many years because thehyperglycemia develops gradually and at earlier stages is often not severeenough for the patient to notice any of the classic symptoms of diabetes.8evertheless, such patients are at increased ris% of developing macrovascularand microvascular complications. 5hereas patients with this form of diabetesmay have insulin levels that appear normal or elevated, the higher bloodglucose levels in these diabetic patients would be expected to result in evenhigher insulin values had their /cell function been normal. Thus, insulinsecretion is defective in these patients and insuUcient to compensate for insulinresistance. 'nsulin resistance may improve with weight reduction and;orpharmacological treatment of hyperglycemia but is seldom restored to normal.

The ris% of developing this form of diabetes increases with age, obesity, and lac%of physical activity. 't occurs more frequently in women with prior 9 M and inindividuals with hypertension or dyslipidemia, and its frequency varies indi!erent racial;ethnic subgroups. 't is often associated with a strong geneticpredisposition, more so than is the autoimmune form of type 6 diabetes.+owever, the genetics of this form of diabetes are complex and not clearlyde7ned.

)ther specifc types o dia$etes

Genetic de ects o the 0!cell3#everal forms of diabetes are associated with monogenetic defects in /cellfunction. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age "generally before age 24 years$. They arereferred to as maturity/onset diabetes of the young "M> D$ and arecharacterized by impaired insulin secretion with minimal or no defects in insulinaction. They are inherited in an autosomal dominant pattern. *bnormalities atsix genetic loci on di!erent chromosomes have been identi7ed to date. Themost common form is associated with mutations on chromosome 62 in a hepatictranscription factor referred to as hepatocyte nuclear factor "+8($/6V. * secondform is associated with mutations in the gluco%inase gene on chromosome ?pand results in a defective gluco%inase molecule. 9luco%inase converts glucose to


9/39


10/39

and impair insulin secretion. (ibrocalculous pancreatopathy may beaccompanied by abdominal pain radiating to the bac% and pancreaticcalci7cations identi7ed on H/ray examination. Pancreatic 7brosis and calciumstones in the exocrine ducts have been found at autopsy.

Endocrinopathies3

#everal hormones "e.g., growth hormone, cortisol, glucagon, epinephrine$antagonize insulin action. )xcess amounts of these hormones "e.g., acromegaly,0ushingSs syndrome, glucagonoma, pheochromocytoma, respectively$ can causediabetes. This generally occurs in individuals with preexisting defects in insulinsecretion, and hyperglycemia typically resolves when the hormone excess isresolved.

#omatostatinoma/ and aldosteronoma/induced hypo%alemia can cause diabetes,at least in part, by inhibiting insulin secretion. +yperglycemia generally resolvesafter successful removal of the tumor.

Drug! or chemical!induced dia$etes3Many drugs can impair insulin secretion. These drugs may not cause diabetes bythemselves, but they may precipitate diabetes in individuals with insulinresistance. 'n such cases, the classi7cation is unclear because the sequence orrelative importance of /cell dysfunction and insulin resistance is un%nown.0ertain toxins such as Oacor "a rat poison$ and intravenous pentamidine canpermanently destroy pancreatic /cells. #uch drug reactions fortunately arerare. There are also many drugs and hormones that can impair insulin action.)xamples include nicotinic acid and glucocorticoids. Patients receiving V/interferon have been reported to develop diabetes associated with islet cellantibodies and, in certain instances, severe insulin de7ciency. The list shown in

Table 6 is not all/inclusive, but reRects the more commonly recognized drug/,hormone/, or toxin/induced forms of diabetes.

In ections30ertain viruses have been associated with /cell destruction. iabetes occurs inpatients with congenital rubella, although most of these patients have +


11/39

insulin resistance, patients with anti/insulin receptor antibodies often haveacanthosis nigricans. 'n the past, this syndrome was termed type & insulinresistance.

)ther genetic syndromes sometimes associated 5ith dia$etes3Many genetic syndromes are accompanied by an increased incidence of

diabetes. These include the chromosomal abnormalities of own syndrome,Glinefelter syndrome, and Turner syndrome. 5olframSs syndrome is anautosomal recessive disorder characterized by insulin/de7cient diabetes and theabsence of /cells at autopsy. *dditional manifestations include diabetesinsipidus, hypogonadism, optic atrophy, and neural deafness. >ther syndromesare listed in Table 6 .

Gestational dia$etes mellitus

(or many years, 9 M has been de7ned as any degree of glucose intolerancewith onset or 7rst recognition during pregnancy. *lthough most cases resolvewith delivery, the de7nition applied whether or not the condition persisted afterpregnancy and did not exclude the possibility that unrecognized glucoseintolerance may have antedated or begun concomitantly with the pregnancy.

This de7nition facilitated a uniform strategy for detection and classi7cation of 9 M, but its limitations were recognized for many years. *s the ongoingepidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2diabetes has increased.

*fter deliberations in 2--B@2-- , the 'nternational *ssociation of iabetes andPregnancy #tudy 9roups "'* P#9$, an international consensus group withrepresentatives from multiple obstetrical and diabetes organizations, includingthe *merican iabetes *ssociation "* *$, recommended that high/ris% womenfound to have diabetes at their initial prenatal visit, using standard criteria,receive a diagnosis of overt, not gestational, diabetes. *pproximately ? of allpregnancies "ranging from 6 to 63 , depending on the population studied andthe diagnostic tests employed$ are complicated by 9 M, resulting in more than2--,--- cases.

Pathophysiology

'mpaired insulin secretion and insulin resistance contribute more or less 1ointlyto the developmentof pathophysiological conditions.

Impaired insulin secretion'mpaired insulin secretion is a decrease in glucose responsiveness, which isobserved before the clinical onset of disease. More speci7cally, impaired glucosetolerance "'9T$ is induced by a decrease in glucose/responsive early/phaseinsulin secretion, and a decrease in additional insulin secretion after mealscauses postprandial hyperglycemia. *n oral glucose tolerance test ">9TT$ in '9T
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797383/table/T1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797383/table/T1/


12/39

cases generally indicates an over/response in 5estern and +ispanic individuals,who have mar%edly high insulin resistance. >n the other hand, apanese patientsoften respond to this test with decreased insulin secretion. )ven when an over/response is seen in persons with obesity or other factors, they show a decreasein early/phase secretory response.

The decrease in early/phase secretion is an essential part of this disease, and isextremely important as a basic pathophysiological change during the onset of disease in all ethnic groups. 'mpaired insulin secretion is generally progressive,and its progression involves glucose toxicity and lipo/toxicity. 5hen untreated,these are %nown to cause a decrease in pancreatic beta cell mass in animalexperiments. The progression of the impairment of pancreatic Y cell functiongreatly a!ects the long/term control of blood glucose. 5hile patients in earlystages after diseaseonset chieRy show an increase in postprandial blood glucoseas a result of increased insulin resistance and decreased early/phase secretion,the progression of the deterioration of pancreatic beta cell function subsequentlycauses permanent elevation of blood glucose.

Insulin resistance'nsulin resistance is a condition in which insulin in the body does not exertsuUcient action proportional to its blood concentration. The impairment of insulin action in ma1or target organs such as liver and muscles is a commonpathophysiological feature of type 2 diabetes. 'nsulin resistance develops andexpands prior to disease onset. The investigation into the molecular mechanismfor insulin action has clari7ed how insulin resistance is related to genetic factorsand environmental factors "hyperglycemia, free fatty acids, inRammatorymechanism, etc.$. Gnown genetic factors, include not only insulin receptor and

insulin receptor substrate "'F#$/6 gene polymorphisms that directly a!ect insulinsignals but also polymorphisms of thrifty genes such as the &eta K adrenergicreceptor gene and the uncoupling protein "E0P$ gene, associated with visceralobesity and promote insulin resistance. 9lucolipotoxicity and inRammatorymediators are also important as the mechanisms for impaired insulin secretionand insulin signaling impairment.

Fecent attention has focused on the involvement of adipocyte/derived bioactivesubstances "adipo%ines$ in insulin resistance. 5hile T8(/alpha, leptin, resistin,and free fatty acids act to increase resistance, adiponectin improves resistance.0linical tests to assess the extent of insulin resistance include homeostasismodel assessment for insulin resistance "+>M*/'F$, insulin sensitivity test"loading test$, steady/state plasma glucose "##P9$, minimal model analysis, andinsulin clamp technique. The Matsuda index3 is now gaining recognition as arelatively simple procedure that can simultaneously evaluate insulin resistancein the liver and muscles. * more convenient way to estimate the degree of resistance is to chec% for the presence of high fasting blood insulin, visceralobesity, hypertriglyceridemia, etc.

%linical Mani estations Type 2 diabetes symptoms often develop slowly. 'n fact, you can have type 2diabetes for years and not %now it.


13/39

Increased thirst and re7uent urination3 )xcess sugar building up inyour bloodstream causes Ruid to be pulled from the tissues. This mayleave you thirsty. *s a result, you may drin% L and urinate L more thanusual.Increased hunger3 5ithout enough insulin to move sugar into your cells,your muscles and organs become depleted of energy. This triggers intensehunger.8eight loss3 espite eating more than usual to relieve hunger, you maylose weight. 5ithout the ability to metabolize glucose, the body usesalternative fuels stored in muscle and fat. 0alories are lost as excessglucose is released in the urine.'atigue3 'f your cells are deprived of sugar, you may become tired andirritable.+lurred #ision3 'f your blood sugar is too high, Ruid may be pulled fromthe lenses of your eyes. This may a!ect your ability to focus.Slo5!healing sores or re7uent in ections3 Type 2 diabetes a!ects

your ability to heal and resist infections. "reas o darkened skin3 #ome people with type 2 diabetes havepatches of dar%, velvety s%in in the folds and creases of their bodies Lusually in the armpits and nec%. This condition, called acanthosisnigricans, may be a sign of insulin resistance.

n the early stages of type 2 diabetes mellitus, there are no symptoms until bloodglucose levels exceed the Zrenal thresholdZ and glucose appears in the urine.Patients may 7rst present with a complication such as neuropathy orretinopathy . People in high/ris% groups, who are obese, who have a familyhistory of type 2 diabetes, or who belong to high/ris% ethnic groups "e.g. *frican*merican, native *merican, +ispanic, Paci7c 'slanders$ should be screened forthe disorder.

5hen the Zrenal thresholdZ for glucose "a blood glucose level of about 6B-mg;d


14/39

The diagnosis of diabetes mellitus is readily entertained when a patient presentswith classic symptoms "ie, polyuria, polydipsia, polyphagia, weight loss$. >thersymptoms that may suggest hyperglycemia include blurred vision, lowerextremity paresthesias, or yeast infections, particularly balanitis in men.+owever, many patients with type 2 diabetes are asymptomatic, and their

disease remains undiagnosed for many years.'n older studies, the typical patient with type 2 diabetes had diabetes for at least3/? years at the time of diagnosis. A 3C*mong patients with type 2 diabetes inthe Enited Gingdom Prospective iabetes #tudy, 24 had retinopathyI ,neuropathyI and B , nephropathy at the time of diagnosis. "(or moreinformation, see iabetic 8europathy .$

Patients 5ith esta$lished dia$etes

'n patients with %nown type 2 diabetes, inquire about the duration of thepatientSs diabetes and about the care the patient is currently receiving for thedisease. The duration of diabetes is signi7cant because the chroniccomplications of diabetes are related to the length of time the patient has hadthe disease.

* focused diabetes history should also include the following questions

's the patientSs diabetes generally well controlled "with near/normal bloodglucose levels$ / Patients with poorly controlled blood glucose levels healmore slowly and are at increased ris% for infection and other complications

oes the patient have severe hypoglycemic reactions / 'f the patient has

episodes of severe hypoglycemia and therefore is at ris% of losingconsciousness, this possibility must be addressed, especially if the patientdrives or has signi7cant underlying neuropathy or cardiovascular disease

oes the patient have diabetic nephropathy that might alter the use of medications or intravenous "'O$ radiographic contrast material

oes the patient have macrovascular disease, such as coronary arterydisease "0* $ that should be considered as a source of acute symptoms

oes the patient self/monitor his or her blood glucose levels / 'f so, notethe frequency and range of values at each time of day5hen was the patientSs hemoglobin *6c "+b*6cI an indicator of long/termglucose control$ last measured, and what was it5hat is the patient[s immunization history / )g, inRuenza, pneumococcal,hepatitis &, tetanus, herpes zoster

*s circumstances dictate, additional questions may be warranted, as follows

oes the patient give a history of recent polyuria, polydipsia, nocturia, orweight loss / These are symptoms of hyperglycemia+as the patient had episodes of unexplained hypoglycemia / 'f so, when,how often, and how does the patient treat these episodes

oes the patient have hypoglycemia unawareness "ie, does the patientlac% the adrenergic warning signs of hypoglycemia$ / +ypoglycemia
http://emedicine.medscape.com/article/1170337http://emedicine.medscape.com/article/1170337


15/39

unawareness indicates an increased ris% of subsequent episodes of hypoglycemiaFegarding retinopathy, when was the patientSs last dilated eyeexamination, and what were the resultsFegarding nephropathy, does the patient have %nown %idney diseaseIwhat were the dates and results of the last measurements of urine proteinand serum creatinine levels

oes the patient have hypertension "de7ned as a blood pressure of :6K-;B-$I what medications are ta%en

oes the patient have 0*Fegarding peripheral vascular disease, does the patient have claudicationor a history of vascular bypass+as the patient had a stro%e or transient ischemic attac%5hat are the patientSs most recent lipid levelsI is the patient ta%ing lipid/lowering medication

oes the patient have a history of neuropathy or are symptoms of

peripheral neuropathy or autonomic neuropathy present "includingimpotence if the patient is male$oes the patient have a history of foot ulcers or amputationsI are any foot

ulcers present*re frequent infections a problemI at what site

Da5n phenomenon

The awn phenomenon, de7ned as a blood glucose increase of over 2- mg;dften, the 7rst hemorrhage is small and is noted by the patient as a Reeting,dar% area, or ZRoater,Z in the 7eld of vision. &ecause subsequent hemorrhagescan be larger and more serious, the patient should be referred immediately to anophthalmologist for possible laser therapy. Patients with retinal hemorrhageshould be advised to limit their activity and %eep their head upright "even whilesleeping$, so that the blood settles to the inferior portion of the retina, thusobscuring less central vision.

Patients with active proliferative diabetic retinopathy are at increased ris% of retinal hemorrhage if they receive thrombolytic therapyI therefore, this conditionis a relative contraindication to the use of thrombolytic agents.

>ne study has shown that individuals with gingival hemorrhaging have a highprevalence of retinal hemorrhage. A6--C Much of this association is driven byhyperglycemia, ma%ing it possible to use gingival tissue to study the naturalcourse of microvascular disease in patients with diabetes.

'oot e6amination

The dorsalis pedis and posterior tibialis pulses should be palpated and theirpresence or absence noted. This is particularly important in patients who havefoot infections, because poor lower/extremity blood Row can slow healing andincrease the ris% of amputation.

ocumenting lower/extremity sensory neuropathy is useful in patients whopresent with foot ulcers because decreased sensation limits the patientSs abilityto protect the feet and an%les. This can be assessed with the #emmes 5einsteinmono7lament or by assessment of reRexes, position, and;or vibration sensation.

'f peripheral neuropathy is found, the patient should be made aware that foot

care "including daily foot examination$ is very important for preventing footulcers and avoiding lower/extremity amputation. "(or more information, see
http://emedicine.medscape.com/article/1224138-overviewhttp://emedicine.medscape.com/article/1224138-overview


18/39

iabetic (oot and iabetic (oot 'nfections .$

Di9erentiation o type 4 rom type . dia$etes

Type 2 diabetes mellitus can usually be di!erentiated from type 6 diabetesmellitus on the basis of history and physical examination 7ndings and simplelaboratory tests "see 5or%up Tests to i!erentiate Type 2 and Type 6 iabetes $.Patients with type 2 diabetes are generally obese, and may have acanthosisnigricans and;or hirsutism in con1unction with thic% nec%s and chubby chee%s.

Di9erential Diagnosis

0orrectly determining whether a patient has type 6 or type 2 diabetes isimportant because patients with type 6 diabetes require continuous exogenousinsulin for survival. 'n contrast, treatment of type 2 diabetes consists of lifestylemeasures and a variety of other medications, with insulin introduced if those

prove inadequate.*s previously stated, patients with type 2 diabetes mellitus can usually bedi!erentiated from those with type 6 disease on the basis of history and physicalexamination 7ndings and through simple laboratory tests. Patients with type 2diabetes are generally obese, and may have acanthosis nigricans and;orhirsutism in con1unction with thic% nec%s and chubby chee%s.

* patient whose diabetes has been controlled with diet or an oral antidiabeticagent for longer than several months generally has type 2 diabetes. * leanpatient who has had diabetes since childhood, who has always been dependent

on insulin, or who has a history of diabetic %etoacidosis " G*$ almost certainlyhas type 6 diabetes.

5hen dealing with patients with %nown diabetes in the emergency department,distinguishing the type of diabetes can be diUcult in 2 groups "6$ patients whoare treated with insulin and are young but clinically appear to have type 2diabetes, and "2$ older patients with late/onset of diabetes who nonethelessta%e insulin and seem to share characteristics of patients with type 6 diabetes."This latter group is now said to have latent autoimmune diabetes of the adultA


19/39

>ften confused with prediabetes is the metabolic syndrome "also calledsyndrome H or the insulin/resistance syndrome$. Metabolic syndrome, thought tobe due to insulin resistance, can occur in patients with overtly normal glucosetolerance, prediabetes, or diabetes. 't is diagnosed when a patient has at least Kof the following 4 conditions

*bdominal obesity)levated triglyceride level9'T$$ 63- mg;dl to 6

mg;dl "?.B / 66.- mmol;l$ A'9TCI ) *60 4.? / J.3 .

Gestational Dia$etes Mellitus /GDM2

#creen at 23/2B wee%s?4g >9TT fasting \ 2mg;dl "4.6 mmol;l$ I )6 hr \ 6B-mg;dl "6-.- mmol;l$I ) 2 hr \ 64Kmg;dl "B.4 mmol;l$.


20/39

(reatment

Pharmacologic $herapy )arly initiation of pharmacologic therapy is associated with improved glycemiccontrol and reduced long/term complications in type 2 diabetes. rug classesused for the treatment of type 2 diabetes include the following

&iguanides#ulfonylureasMeglitinide derivatives*lpha/glucosidase inhibitors

Thiazolidinediones "T] s$9lucagonli%e peptide@6 "9


21/39

in patients with type 2 diabetes mellitus.

Pradhan et al did not 7nd an association between improvement of glycemiccontrol with metformin or insulin and reduction of inRammatory biomar%er levelsin patients with recent/onset type 2 diabetes. Patients were randomized to 6 of 3groups placebo, placebo plus insulin glargine, metformin only, and metformin

and insulin glargine. 8o di!erence in levels of the inRammatory biomar%er high/sensitivity 0/reactive protein was shown between study participants whoreceived insulin or metformin and those who did not.

* retrospective, nationwide cohort study found that metformin is associated witha low ris% of mortality in patients who have diabetes and experience heartfailure compared with treatment that includes a sulfonylurea or insulin. Fousselet al studied the expanded use of metformin in groups of patients with diabetespreviously considered high ris% for possible drug/related adverse outcome andfound a decrease in mortality in these patients.

* study by 9ross et al found no di!erence in bene7t between drug classes inpatients already on metformin and sulfonylurea. The patientSs clinicalcircumstances must guide selection.

'n a meta/analysis of 2- publications comprising 6K,--B cancer patients withconcurrent type 2 diabetes, Din et al found that patients treated with metforminhad better overall and cancer/speci7c survival than those treated with othertypes of glucose/lowering agents. ABB, B C These improvements were observedacross cancer subtypes and geographic locations.

Fis% reduction was signi7cant among patients with prostate, pancreatic, breast,colorectal and other cancers, but not for lung cancer. +owever, it remainsunclear whether metformin can modulate clinical outcomes in cancer patientswith diabetes.

Sul onylureas

#ulfonylureas "eg, glyburide, glipizide, glimepiride$ are insulin secretagoguesthat stimulate insulin release from pancreatic beta cells and probably have thegreatest eUcacy for glycemic lowering of any of the oral agents. +owever, thate!ect is only short/term and quic%ly dissipates. #ulfonylureas may also enhanceperipheral sensitivity to insulin secondary to an increase in insulin receptors or

to changes in the events following insulin/receptor binding.#ulfonylureas are indicated for use as ad1uncts to diet and exercise in adultpatients with type 2 diabetes mellitus. They are generally well/tolerated, withhypoglycemia the most common side e!ect. The 7rst/generation sulfonylureasare acetohexamide, chlorpropamide, tolazamide, and tolbutamideI the second/generation agents are glipizide, glyburide, and glimepiride. The structuralcharacteristics of the second/generation sulfonylureas allow them to be given atlower doses and as once/daily regimens.

>ne study exonerated the sulfonylurea group of oral agents as the chief cause of

cardiovascular death in diabetic patients admitted with acute myocardialinfarction. +owever, even though sulfonylureas were safer in general, within the


22/39

group, the use of glyburide was associated with highest mortality "?.4 $compared with other sulfonylureas, such as gliclazide and glimepiride "2.? $.A62 C This raises an important concern about whether the use of glyburideshould be avoided.

Meglitinide deri#ati#es

Meglitinides "eg, repaglinide, nateglinide$ are much shorter/acting insulinsecretagogues than the sulfonylureas are, with preprandial dosing potentiallyachieving more physiologic insulin release and less ris% for hypoglycemia. A6K-C*lthough meglitinides are considerably more expensive than sulfonylureas, theyare similar in their glycemic clinical eUcacy.

Meglitinides can be used as monotherapyI however, if adequate glycemiccontrol is not achieved, then metformin or a thiazolidinedione may be added.Meglitinides may be used in patients who have allergy to sulfonylureamedications. They have a similar ris% for inducing weight gain as sulfonylureasdo but possibly carry less ris% for hypoglycemia.

"lpha!glucosidase inhi$itors

These agents delay sugar absorption and help to prevent postprandial glucosesurges. *lpha/glucosidase inhibitors prolong the absorption of carbohydrates,but their induction of Ratulence greatly limits their use. They should be titratedslowly to reduce gastrointestinal "9'$ intolerance.

(hiazolidinediones

T] s "eg, pioglitazone A*ctosC, rosiglitazone A*vandiaC$ act as insulin sensitizersIthus, they require the presence of insulin to wor%. They must be ta%en for 62/6Jwee%s to achieve maximal e!ect.

These agents are used as monotherapy or in combination with sulfonylurea,metformin, meglitinide, PP/3 inhibitors, 9)$ trial,glycemic parameters and insulin sensitivity improved in patients ta%ingrosiglitazone and metformin in year 6 but deteriorated in the years thereafter, asin the placebo arm. &eta/cell function remained relatively stable in both groupsfor the 7rst 2 years but then deteriorated progressively in subsequent years. Theinvestigators attributed the lower rate of incident diabetes in therosiglitazone;metformin group to the early e!ect of treatment.

'n a study by e(ronzo et al, pioglitazone was found to reduce the progression tofran% diabetes by ?2 in patients with '9T. +owever, the drug was associatedwith signi7cant edema and weight gain.

'n the iabetes Feduction *ssessment with Famipril and FosiglitazoneMedication " F)*M$ trial, rosiglitazone reduced the incidence of diabetes byJ2 . 't also improved the achievement of normoglycemia by ?- in patientswith '(9 and by J3 in patients with both '(9 and '9T.


23/39

* study by Phung et al investigated oral agents used for prevention of type 2diabetes and found that T] s resulted in a greater ris% reduction thanbiguanides. #ulfonylureas and glinides had no bene7t.

T] s generally decrease triglyceride levels and increase + < cholesterol levels. They increase < < cholesterol, but this increase may involve large, buoyant <


24/39

type 2 diabetes, ris% of fracture in males has since been reported.

osiglitazone restrictions

'n response to data suggesting an elevated ris% of myocardial infarction inpatients treated with rosiglitazone, the ( * has restricted access to this drug.

The use of rosiglitazone is limited to patients already being successfully treatedwith this agent and to patients whose blood sugar cannot be controlled withother antidiabetic medicines and who do not wish to use pioglitazone, the onlyother T] currently available.

+ealth/care providers and patients must be enrolled in the *vandia/FosiglitazoneMedicines *ccess Program in order to prescribe and receive rosiglitazone.Patients who are enrolled in the access program receive their medicine by mailorder through certi7ed pharmacies that participate in the program.

Glucagonlike peptide:. agonists

9ther (actors Through 'ntervention 5ith )xenatide >nce 5ee%ly$

study, the exenatide once/wee%ly formulation provided signi7cantly greaterimprovement in +b*6c and (P9 levels than did the twice/daily preparation.


25/39

*dditionally, less nausea was observed with the once/wee%ly exenatideformulation.

(or patients with type 2 diabetes inadequately controlled with metformin, thein1ectable agent exenatide was found, in one clinical trial, to be more e!ectivethan insulin detemir. A63B, 63 C * clinical trial involving 26J patients with *6c

baseline levels :?.6 despite treatment with metformin found that once/dailyin1ections of exenatide resulted in a signi7cantly greater number of patientsachieving target *6c than treatment with detemir. *t 2J wee%s, 33.6 of theexenatide group had achieved an *6c of ? or less compared to 66.3 of thedetemir group.

The glucagonli%e peptide/6 "9


26/39

'n this study, the incidence of adverse 9' e!ects was lower with sitagliptin thanwith metformin "66.J vs 2-.? $. #peci7cally, diarrhea "K.J vs 6-. $ andnausea "6.6 vs K.6 $ were signi7cantly less common with sitagliptin.

* study by Oilsboll et al in patients receiving stable/dose insulin therapy "with orwithout concomitant metformin$ found that the addition of sitagliptin produced a

greater reduction in (P9 "by 64 mg;d< A-.B mmol;


27/39

0anagliRozin add/on combination therapy to metformin and;or sulfonylureasshowed a reduction in fasting glucose and a greater proportion of patientsachieving an +b*60 level less than ? . *dd/on therapy to insulin andcomparative data to thiazolidinediones and to dipeptidyl peptidase/'O inhibitorshave also shown improved postprandial glucose levels and +b*60 levels.

apagliRozin is ( * approved as an ad1unct to diet and exercise to improveglycemic control in adults with type 2 diabetes mellitus. apagliRozin isindicated as monotherapy, as initial therapy with metformin, or as an add/on toother oral glucose/lowering agents, including metformin, pioglitazone,glimepiride, sitagliptin, and insulin. The ( * is requiring postmar%eting studiesto assess potential safety issues, including a possible increased ris% of bladdercancer.


28/39

e!ects. * reduced dosing frequency may be possible because of its ultralong/action pro7le. 0areful study is needed when ma%ing a decision regardingreduced dosing frequency.

* rapid/acting inhaled insulin powder "*frezza$ for types 6 and 2 diabetesmellitus was approved by the ( * in une 2-63. *pproval was based on a study

involving over K,--- patients over a 23/wee% period. 'n persons with type 6diabetes, the inhaled insulin was found to be noninferior to standard in1ectableinsulin when used in con1unction with basal insulin at reducing hemoglobin *6c.'n persons with type 2 diabetes, the inhaled insulin was compared to placeboinhalation in combination with oral diabetic agents and showed a statisticallysigni7cant lower hemoglobin *6c.

The 7rst inhaled insulin ")xubera$ was approved by the ( * in anuary 2--J as arapid/acting prandial nsulin. 't did not produce better glycemic control than didconventionally in1ected insulins, and it required a mildly cumbersome device ands%ill to deliver an accurate dose "up to a few minutes to deliver 6 dose$ andpulmonary function monitoring due to concerns about lung toxicity over time.)xubera was withdrawn from the mar%et in >ctober 2--?, not because of safetyconcerns but because too few patients were using the product for its continuedsale to be economically feasible.

Insulin and cancer

>n uly 6, 2-- , the ( * issued an early communication regarding a possibleincreased ris% of cancer in patients using insulin glargine "


29/39

associated with lower cancer ris%.

The ( * states that patients should not stop ta%ing insulin without consultingtheir physician. *n ongoing review by the ( * will continue to update themedical community and consumers with additional information as it emerges.#tatements from the * * and the )uropean *ssociation for the #tudy of

iabetes called the 7ndings conRicting and inconclusive and cautioned againstoverreaction.

"mylinomimetics

Pramlintide acetate is an amylin analog that mimics the e!ects of endogenousamylin, which is secreted by pancreatic beta cells. This agent delays gastricemptying, decreases postprandial glucagon release, and modulates appetite.

+ile acid se7uestrants

&ile acid sequestrants were developed as lipid/lowering agents for the treatment

of hypercholesterolemia but were subsequently found to have a glucose/lowering e!ect. The bile acid sequestrant colesevelam is ( */approved as anad1unctive therapy to improve glycemic control. 't has a favorable, butinsigni7cant, impact on (P9 and +b*6c levels.

* study in patients with early type 2 diabetes who were receiving metforminfound that the addition of colesevelam reduced +b*6c levels to a degree thatwas statistically signi7cant but that may have been clinically irrelevant, as nodata show that a -.K reduction of +b*6c produces a better outcome than a-.2 reduction of +b*6c. *chievement of < < cholesterol goals was alsoimproved with the use of colesevelam, but it is not %nown whether that result

correlates with signi7cantly di!erent outcomes in these patients.0olesevelam is a relatively safe addition to the menu of choices available toreduce < < cholesterol in patients with prediabetes. 't should be avoided inpatients with hypertriglyceridemia "a rule that applies to bile acid sequestrantsin general$.

Dopamine agonists

'n 2-- , the ( * approved a quic%/release formulation of bromocriptinemesylate "0ycloset$ as an ad1unct to diet and exercise to improve glycemiccontrol in adults with type 2 diabetes mellitus. &romocriptine is a centrallyacting dopamine 2 receptor agonist. 5hen given in a single timed morningdose, it is thought to act on circadian neuronal activities within thehypothalamus to reset the abnormally elevated drive for increased plasmaglucose, triglyceride, and free fatty acid levels in fasting and postprandial statesin insulin/resistant patients.

Quic%/release bromocriptine may be considered for obese patients who do nottolerate other diabetes medications or who need only a minimal reduction in+b*6c to reach their glycemic goal. This agent has the bene7ts of not causinghypoglycemia and weight gain. 'n addition, a randomized trial of bromocriptine

in K- 4 patients found that cardiovascular events were less frequent in thetreatment arm than in the placebo arm.


30/39

*dverse events most commonly reported in clinical trials of bromocriptineincluded nausea, fatigue, vomiting, headache, and dizziness. These events weremore li%ely to occur during initial titration of the drug and lasted a median of 63days. 8ausea and vomiting were not described as serious.

&romocriptine can cause orthostatic hypotension and syncope, particularly on

initiation of therapy and dose escalation. 0aution is advised when treatingpatients who are receiving antihypertensive therapyI orthostatic vital signsshould be evaluated at baseline and periodically thereafter.

%omparison o oral antidia$etic agents

'n 2--?, the *+FQ compared the e!ectiveness and safety of oral diabetesmedications for adults with type 2 diabetes, with a 2-66 update . The *+FQfound little evidence to support predictions as to whether a particularmedication is more li%ely to be e!ective in a given patient subgroup or to causeadverse e!ects in a particular patient.

The *+FQ concluded that although the long/term bene7ts and harms of diabetesmedications remain unclear, the evidence supports the use of metformin as a7rst/line agent. >n average, monotherapy with many of the oral diabetes drugsreduces +b*6c levels by 6 percentage point "although metformin has beenfound to be more eUcacious than the PP/3 inhibitors$, and 2/drug combinationtherapies reduce +b*6c about 6 percentage point more than do monotherapies.

>ther *+FQ 7ndings included the following

Metformin decreased < < cholesterol levels relative to pioglitazone,sulfonylureas, and PP/3 inhibitorsEnfavorable e!ects on weight were greater with T] s and sulfonylureasthan with metformin "mean di!erence of 2.J %g$Fis% of mild or moderate hypoglycemia was 3/fold higher withsulfonylureas than with metformin aloneI this ris% was more than 4/foldhigher with sulfonylureas plus metformin than with a T] plus metforminFis% of heart failure was higher with T] s than with sulfonylureasFis% of bone fractures was higher with T] s than with metformin

iarrhea was more common with metformin than with glitazones.

%omplications

*cuteDia$etic ketoacidosis

iabetic %etoacidosis " G*$ is an acute and dangerous complication that isalways a medical emergency and requires prompt medical attention.


31/39

The level of consciousness is typically normal until late in the process, whenlethargy may progress to coma. Getoacidosis can easily become severe enoughto cause hypotension , shoc%, and death. Erine analysis will reveal signi7cantlevels of %etone bodies "which have exceeded their renal threshold blood levelsto appear in the urine, often before other overt symptoms$. Prompt, propertreatment usually results in full recovery, though death can result from

inadequate or delayed treatment, or from complications "e.g., brain edema $.Getoacidosis is much more common in type 6 diabetes than type 2.

-yperglycemia hyperosmolar state+yperosmolar non%etotic state "+8#$ is an acute complication sharing manysymptoms with G*, but an entirely di!erent origin and di!erent treatment. *person with very high "usually considered to be above K-- mg;dl "6J mmol;


32/39

neurogenic responses to lower plasma glucose concentrations, antecedenthypoglycemia leads to a vicious cycle of recurrent hypoglycemia and furtherimpairment of glucose counterregulation. 'n many cases "but not all$, short/termavoidance of hypoglycemia reverses hypoglycemia unawareness in a!ectedpatients, although this is easier in theory than in clinical experience.

'n most cases, hypoglycemia is treated with sugary drin%s or food. 'n severecases, an in1ection of glucagon "a hormone with e!ects largely opposite to thoseof insulin$ or an intravenous infusion of dextrose is used for treatment, butusually only if the person is unconscious. 'n any given incident, glucagon willonly wor% once as it uses stored liver glycogen as a glucose sourceI in theabsence of such stores, glucagon is largely ine!ective. 'n hospitals, intravenousdextrose is often used.

Dia$etic comaiabetic coma is a medical emergency in which a person with diabetes mellitus

is comatose "unconscious$ because of one of the acute complications of diabetes

#evere diabetic hypoglycemiaiabetic %etoacidosis advanced enough to result in unconsciousness from

a combination of severe hyperglycemia , dehydration and shoc%, andexhaustion+yperosmolar non%etotic coma in which extreme hyperglycemia anddehydration alone are suUcient to cause unconsciousness.

'n most medical contexts, the term diabetic coma refers to the diagnosticaldilemma posed when a physician is confronted with an unconscious patientabout whom nothing is %nown except that he has diabetes. *n example might bea physician wor%ing in an emergency department who receives an unconsciouspatient wearing a medical identi7cation tag saying '*&)T'0. Paramedics maybe called to rescue an unconscious person by friends who identify him asdiabetic. &rief descriptions of the three ma1or conditions are followed by adiscussion of the diagnostic process used to distinguish among them, as well asa few other conditions which must be considered.

*n estimated 2 to 64 percent of diabetics will su!er from at least one episode of diabetic coma in their lifetimes as a result of severe hypoglycemia.

espiratory in ections The immune response is impaired in individuals with diabetes mellitus. 0ellular

studies have shown that hyperglycemia both reduces the function of immunecells and increases inRammation . The vascular e!ects of diabetes also tend toalter lung function, all of which leads to an increase in susceptibility torespiratory infections such as pneumonia and inRuenza among individuals withdiabetes. #everal studies also show diabetes associated with a worse diseasecourse and slower recovery from respiratory infections.

Periodontal diseaseiabetes is associated with periodontal disease "gum disease$A4C and may ma%e

diabetes more diUcult to treat.AJC 9um disease is frequently related to bacterialinfection by organisms such as Porphyromonas gingivalis and Actinobacillus

actinomycetemcomitans .A?C * number of trials have found improved blood sugarlevels in type 2 diabetics who have undergone peridontal treatment.AJC
http://en.wikipedia.org/wiki/Glucagonhttp://en.wikipedia.org/wiki/Intravenoushttp://en.wikipedia.org/wiki/Dextrosehttp://en.wikipedia.org/wiki/Medical_emergencyhttp://en.wikipedia.org/wiki/Diabetes_mellitushttp://en.wikipedia.org/wiki/Comahttp://en.wikipedia.org/wiki/Diabetic_hypoglycemiahttp://en.wikipedia.org/wiki/Diabetic_ketoacidosishttp://en.wikipedia.org/wiki/Hyperglycemiahttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Shock_(circulatory)http://en.wikipedia.org/wiki/Hyperosmolar_nonketotic_comahttp://en.wikipedia.org/wiki/Hyperglycemiahttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Emergency_departmenthttp://en.wikipedia.org/wiki/Medical_identification_taghttp://en.wikipedia.org/wiki/Paramedichttp://en.wikipedia.org/wiki/Medical_diagnosishttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Influenzahttp://en.wikipedia.org/wiki/Periodontal_diseasehttp://en.wikipedia.org/wiki/Porphyromonas_gingivalishttp://en.wikipedia.org/wiki/Actinobacillus_actinomycetemcomitanshttp://en.wikipedia.org/wiki/Actinobacillus_actinomycetemcomitanshttp://en.wikipedia.org/wiki/Glucagonhttp://en.wikipedia.org/wiki/Intravenoushttp://en.wikipedia.org/wiki/Dextrosehttp://en.wikipedia.org/wiki/Medical_emergencyhttp://en.wikipedia.org/wiki/Diabetes_mellitushttp://en.wikipedia.org/wiki/Comahttp://en.wikipedia.org/wiki/Diabetic_hypoglycemiahttp://en.wikipedia.org/wiki/Diabetic_ketoacidosishttp://en.wikipedia.org/wiki/Hyperglycemiahttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Shock_(circulatory)http://en.wikipedia.org/wiki/Hyperosmolar_nonketotic_comahttp://en.wikipedia.org/wiki/Hyperglycemiahttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Emergency_departmenthttp://en.wikipedia.org/wiki/Medical_identification_taghttp://en.wikipedia.org/wiki/Paramedichttp://en.wikipedia.org/wiki/Medical_diagnosishttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Pneumoniahttp://en.wikipedia.org/wiki/Influenzahttp://en.wikipedia.org/wiki/Periodontal_diseasehttp://en.wikipedia.org/wiki/Porphyromonas_gingivalishttp://en.wikipedia.org/wiki/Actinobacillus_actinomycetemcomitanshttp://en.wikipedia.org/wiki/Actinobacillus_actinomycetemcomitans


33/39

0hronic

'mage of fundus showing scatter laser surgery for diabetic retinopathy

Mechanisms o chronic complications

0hronic elevation of blood glucose level leads to damage of blood vessels"angiopathy $. The endothelial cells lining the blood vessels ta%e in more glucosethan normal, since they do not depend on insulin. They then form more surfaceglycoproteins than normal, and cause the basement membrane to grow thic%erand wea%er. 'n diabetes, the resulting problems are grouped underZmicrovascular disease Z "due to damage to small blood vessels$ andZmacrovascular disease Z "due to damage to the arteries $.

+owever, some research challenges the theory of hyperglycemia as the cause of diabetic complications. The fact that 3- of diabetics who carefully control theirblood sugar nevertheless develop neuropathy,ABC and that some of those with

good blood sugar control still develop nephropathy,A C requires explanation. 'thas been discovered that the serum of diabetics with neuropathy is toxic tonerves even if its blood sugar content is normal.A6-C Fecent research suggeststhat in type 6 diabetics, the continuing autoimmune disease which initiallydestroyed the beta cells of the pancreas may also cause retinopathy,A66Cneuropathy,A62C and nephropathy.A6KC >ne researcher has even suggested thatretinopathy may be better treated by drugs to suppress the abnormal immunesystem of diabetics than by blood sugar control.A63C The familial clustering of the degree and type of diabetic complicationsA64C indicates that genetics mayalso play a role in causing complications such as diabetic retinopathyA6JC andnephropathy.A6?C 8on/diabetic o!spring of type 2 diabetics have been found tohave increased arterial sti!ness and neuropathy despite normal blood glucoselevels,A6BC and elevated enzyme levels associated with diabetic renal diseasehave been found in non/diabetic 7rst/degree relatives of diabetics.A6 CA2-C )venrapid tightening of blood glucose levels has been shown to worsen rather thanimprove diabetic complications, though it has usually been held thatcomplications would improve over time with more normal blood sugar, providedthis could be maintained.A26C +owever, one study continued for 36 monthsfound that the initial worsening of complications from improved glucose controlwas not followed by the expected improvement in the complications.A22C 'n asystematic review with meta/analysis including J randomized controlled trials

involving 2?,J43 patients, tight blood glucose control reduces the ris% for somemacrovascular and microvascular events, without e!ect on all/cause mortality
http://en.wikipedia.org/wiki/Fundus_(eye)http://en.wikipedia.org/wiki/Laser_scalpelhttp://en.wikipedia.org/wiki/Diabetic_retinopathyhttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Angiopathyhttp://en.wikipedia.org/wiki/Endothelial_cellhttp://en.wikipedia.org/wiki/Glycoproteinhttp://en.wikipedia.org/wiki/Basement_membranehttp://en.wikipedia.org/wiki/Microvascular_diseasehttp://en.wikipedia.org/wiki/Macrovascular_diseasehttp://en.wikipedia.org/wiki/Arteryhttp://en.wikipedia.org/wiki/Fundus_(eye)http://en.wikipedia.org/wiki/Laser_scalpelhttp://en.wikipedia.org/wiki/Diabetic_retinopathyhttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Angiopathyhttp://en.wikipedia.org/wiki/Endothelial_cellhttp://en.wikipedia.org/wiki/Glycoproteinhttp://en.wikipedia.org/wiki/Basement_membranehttp://en.wikipedia.org/wiki/Microvascular_diseasehttp://en.wikipedia.org/wiki/Macrovascular_diseasehttp://en.wikipedia.org/wiki/Artery


34/39

and cardiovascular mortality.A2KC 'n terms of pathophysiology, studies show thatthe two main types of M " M6 and M2$ cause a change in balancing of metabolites such as carbohydrates, lipids and blood coagulation factors,A23C andsubsequently bring about complications li%e microvascular and cardiovascularcomplications,A24C

E6amples o chronic complications Aedit C The damage to small blood vessels leads to a microangiopathy , which can causeone or more of the following

!iabetic cardiomyopathy , damage to the heart muscle, leading toimpaired relaxation and 7lling of the heart with blood "diastolicdysfunction$ and eventually heart failure I this condition can occurindependent of damage done to the blood vessels over time from highlevels of blood glucose.A2JC!iabetic nephropathy , damage to the %idney which can lead to chronicrenal failure, eventually requiring dialysis . iabetes mellitus is the mostcommon cause of adult %idney failure worldwide in the developed world.!iabetic neuropathy , abnormal and decreased sensation, usually in aSglove and stoc%ingS distribution starting with the feet but potentially inother nerves, later often 7ngers and hands. 5hen combined with damagedblood vessels this can lead to diabetic "oot "see below$. >ther forms of diabetic neuropathy may present as mononeuritis or autonomicneuropathy . iabetic amyotrophy is muscle wea%ness due to neuropathy.!iabetic retinopathy , growth of friable and poor/quality new blood vesselsin the retina as well as macular edema "swelling of the macula $, which canlead to severe vision loss or blindness. Fetinal damage "frommicroangiopathy$ ma%es it the most common cause of blindness amongnon/elderly adults in the E#.!iabetic encephalopathy A2?C is the increased cognitive decline and ris% of dementia / including "but not limited to$ the *lzheimerSs type/ observed indiabetes. Oarious mechanisms are proposed, including alterations to thevascular supply of the brain and the interaction of insulin with the brainitself.A2BCA2 C

Macrovascular disease leads to cardiovascular disease, to which acceleratedatherosclerosis is a contributor

0oronary artery disease , leading to angina or myocardial infarction "Zheartattac%Z$

iabetic myonecrosis "Smuscle wastingS$Peripheral vascular disease , which contributes to intermittent claudication"exertion/related leg and foot pain$ as well as diabetic foot.AK-C#tro%e "mainly the ischemic type$

iabetic foot, often due to a combination of sensory neuropathy "numbness orinsensitivity$ and vascular damage, increases rates of s%in ulcers "diabetic footulcers $ and infection and, in serious cases, necrosis and gangrene. 't is whydiabetics are prone to leg and foot infections and why it ta%es longer for them toheal from leg and foot wounds. 't is the most common cause of non/traumatic

adult amputation, usually of toes and or feet, in the developed world.AK-C
http://en.wikipedia.org/w/index.php?title=Complications_of_diabetes_mellitus&action=edit&section=10http://en.wikipedia.org/wiki/Microangiopathyhttp://en.wikipedia.org/wiki/Diabetic_cardiomyopathyhttp://en.wikipedia.org/wiki/Heart_failurehttp://en.wikipedia.org/wiki/Diabetic_nephropathyhttp://en.wikipedia.org/wiki/Dialysishttp://en.wikipedia.org/wiki/Diabetic_neuropathyhttp://en.wikipedia.org/wiki/Diabetic_foothttp://en.wikipedia.org/wiki/Autonomic_neuropathyhttp://en.wikipedia.org/wiki/Autonomic_neuropathyhttp://en.wikipedia.org/wiki/Diabetic_amyotrophyhttp://en.wikipedia.org/wiki/Diabetic_retinopathyhttp://en.wikipedia.org/wiki/Retinahttp://en.wikipedia.org/wiki/Macular_edemahttp://en.wikipedia.org/wiki/Maculahttp://en.wikipedia.org/wiki/Vision_losshttp://en.wikipedia.org/wiki/Dementiahttp://en.wikipedia.org/wiki/Macrovascular_diseasehttp://en.wikipedia.org/wiki/Atherosclerosishttp://en.wikipedia.org/wiki/Coronary_artery_diseasehttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Diabetic_myonecrosishttp://en.wikipedia.org/wiki/Peripheral_artery_occlusive_diseasehttp://en.wikipedia.org/wiki/Intermittent_claudicationhttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Skin_ulcerhttp://en.wikipedia.org/wiki/Diabetic_foot_ulcerhttp://en.wikipedia.org/wiki/Diabetic_foot_ulcerhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/w/index.php?title=Complications_of_diabetes_mellitus&action=edit&section=10http://en.wikipedia.org/wiki/Microangiopathyhttp://en.wikipedia.org/wiki/Diabetic_cardiomyopathyhttp://en.wikipedia.org/wiki/Heart_failurehttp://en.wikipedia.org/wiki/Diabetic_nephropathyhttp://en.wikipedia.org/wiki/Dialysishttp://en.wikipedia.org/wiki/Diabetic_neuropathyhttp://en.wikipedia.org/wiki/Diabetic_foothttp://en.wikipedia.org/wiki/Autonomic_neuropathyhttp://en.wikipedia.org/wiki/Autonomic_neuropathyhttp://en.wikipedia.org/wiki/Diabetic_amyotrophyhttp://en.wikipedia.org/wiki/Diabetic_retinopathyhttp://en.wikipedia.org/wiki/Retinahttp://en.wikipedia.org/wiki/Macular_edemahttp://en.wikipedia.org/wiki/Maculahttp://en.wikipedia.org/wiki/Vision_losshttp://en.wikipedia.org/wiki/Dementiahttp://en.wikipedia.org/wiki/Macrovascular_diseasehttp://en.wikipedia.org/wiki/Atherosclerosishttp://en.wikipedia.org/wiki/Coronary_artery_diseasehttp://en.wikipedia.org/wiki/Angina_pectorishttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Diabetic_myonecrosishttp://en.wikipedia.org/wiki/Peripheral_artery_occlusive_diseasehttp://en.wikipedia.org/wiki/Intermittent_claudicationhttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Skin_ulcerhttp://en.wikipedia.org/wiki/Diabetic_foot_ulcerhttp://en.wikipedia.org/wiki/Diabetic_foot_ulcerhttp://en.wikipedia.org/wiki/Infectionhttp://en.wikipedia.org/wiki/Necrosis


35/39

0arotid artery stenosis does not occur more often in diabetes, and there appearsto be a lower prevalence of abdominal aortic aneurysm . +owever, diabetes doescause higher morbidity, mortality and operative ris%s with these conditions.AK6C

'n the developed world, diabetes is the most signi7cant cause of adult blindnessin the non/elderly and the leading cause of non/traumatic amputation in adults,and diabetic nephropathy is the main illness requiring renal dialysis in the Enited#tates.AK2C

* review of type 6 diabetes came to the result that, despite modern treatment,women with diabetes are at increased ris% of female infertility , such as reRectedby delayed puberty and menarche, menstrual irregularities "especiallyoligomenorrhoea $, mild hyperandrogenism , polycystic ovarian syndrome , fewerlive born children and possibly earlier menopause .AKKC *nimal models indicatethat abnormalities on the molecular level caused by diabetes include defectiveleptin , insulin and %isspeptin signalling.AKKC

Festrictive lung defect is %nown to be associated with diabetes.


36/39

treated group demonstrated a continued reduction in microvascular and all/cause mortality, as well as in cardiovascular events, despite early loss of di!erences in glycated hemoglobin levels between the intensive/therapy andconventional/therapy groups. AJJC The total follow/up was 2- years, half while inthe study and half after the study ended.

>ther, shorter studies, such as *ction in iabetes and Oascular isease Preteraxand iamicron Modi7ed Felease 0ontrolled )valuation "* O*80)$ and theOeterans *!airs iabetes Trial "O* T$, showed no improvement in cardiovasculardisease and death with tight control "lower targets than in the EGP #$. AJ?, JB,J C

'n the *ction to 0ontrol 0ardiovascular Fis% in iabetes "*00>F $ study,increased mortality was noted among the poorly/controlled patients in theintensive glycemic armI indeed there was a JJ increase in mortality for each6 increase in +b*6cI the best outcome occurred among patients who achievedthe target of an +b*6c of less than J . The excess mortality between theintensive and conventional glycemic arms occurred for *6c above ? .

i!erences between the patient populations in these studies and the EGP #may account for some of the di!erences in outcome. The patients in these Kstudies had established diabetes and had a prior cardiovascular disease event orwere at high ris% for a cardiovascular disease event, whereas patients in theEGP # study were younger, with new/onset diabetes and low rates of cardiovascular disease.

)arly, intensive, multifactorial "blood pressure, cholesterol$ management inpatients with type 2 diabetes mellitus was associated with a small,nonsigni7cant reduction in the incidence of cardiovascular disease events anddeath in a multinational )uropean study. A?-C The K-4? patients in this study haddiabetes detected by screening and were randomized to receive either standarddiabetes care or intensive management of hyperglycemia "target +b*6c =?.- $, blood pressure, and cholesterol levels.

The bene7ts of intensive intervention were demonstrated in the #teno/2 study inenmar%, which included 6J- patients with type 2 diabetes and persistent

microalbuminuriaI the mean treatment period was ?.B years, followed by anobservational period for a mean of 4.4 years. 'ntensive therapy was associatedwith a lower ris% of cardiovascular events, death from cardiovascular causes,progression to end/stage renal disease, and need for retinal photocoagulation.A?6C

* &ritish study indicated that the +b*6c level achieved K months after the initialdiagnosis of type 2 diabetes mellitus predicts subsequent mortality. 'n otherwords, according to the report, aggressive lowering of glucose after diagnosisbodes well for long/term survival. "'ntensi7ed diabetes control must beintroduced gradually in newly diagnosed patients.$ A?2C

*nother study, a review of randomized clinical trials, showed that intensiveglycemic control reduces the ris% of microvascular complications, but at theexpense of increased ris% of hypoglycemia. *ll/cause mortality and


37/39

cardiovascular mortality in the study did not di!er signi7cantly with intensiveversus conventional glycemic controlI however, trials conducted in usual/caresettings showed a reduction in the ris% of nonfatal myocardial infarction. A?KC

>verall, these studies suggest that tight glycemic control "+b*6c = ? or lower$is valuable for microvascular and macrovascular disease ris% reduction in

patients with recent/onset disease, no %nown cardiovascular diseases, and alonger life expectancy. 'n patients with %nown cardiovascular disease, a longerduration of diabetes "64 or more years$, and a shorter life expectancy, however,tighter glycemic control is not as bene7cial, particularly with regard tocardiovascular disease ris%. )pisodes of severe hypoglycemia may beparticularly harmful in older individuals with poorer glycemic control and existingcardiovascular disease.

;ascular disease considerations

>ne prospective study with a long follow/up challenges the concept of coronarydisease ris% equivalency between nondiabetic patients with a 7rst myocardialinfarction and patients with type 2 diabetes but without any cardiovasculardisease. The study found that patients with type 2 diabetes had lower long/termcardiovascular ris% compared with patients with 7rst myocardial infarction. >therstudies have similarly questioned this ris% equivalency. A?3C

Patients with diabetes have a lifelong challenge to achieve and maintain bloodglucose levels as close to the reference range as possible. 5ith appropriateglycemic control, the ris% of microvascular and neuropathic complications isdecreased mar%edly. 'n addition, if hypertension and hyperlipidemia are treatedaggressively, the ris% of macrovascular complications decreases as well.

These bene7ts are weighed against the ris% of hypoglycemia and the short/termcosts of providing high/quality preventive care. #tudies have shown cost savingsdue to a reduction in acute diabetes/related complications within 6/K years afterstarting e!ective preventive care. #ome studies suggest that broad/based focuson treatment "eg, glycemia, nutrition, exercise, lipids, hypertension, smo%ingcessation$ is much more li%ely to reduce the burden of excess microvascular andmacrovascular events.

Damasa%i et al found that abnormal results on single/photon 0T myocardialperfusion imaging in asymptomatic patients with type 2 diabetes indicated a

higher ris% for cardiovascular events "6K $, including cardiac death. #mo%ingand low glomerular 7ltration rate were signi7cant contributing factors. A?4C+owever, an earlier study questioned the merit of routine screening withadenosine/stress radionuclide myocardial perfusion imaging "MP'$ in otherwiseasymptomatic type 2 diabetic patients "the etection of 'schemia in*symptomatic iabetics A '* C study$. A?JC

'n both diabetic and nondiabetic patients, coronary vasodilator dysfunction is astrong independent predictor of cardiac mortality. 'n diabetic patients withoutcoronary artery disease, those with impaired coronary Row reserve have eventrates similar to those with prior coronary artery disease, while patients withpreserved coronary Row reserve have event rates similar to nondiabeticpatients. A??C


38/39

Dia$etes!associated mortality and mor$idity

'n 2-- , diabetes mellitus was the seventh leading cause of death in the Enited#tates. A?BC'n addition, diabetes is a contributing cause of death in many cases,and it is probably underreported as a cause of death. >verall, the death rateamong people with diabetes is about twice that of people of similar age butwithout diabetes. A6KC

iabetes mellitus causes morbidity and mortality because of its role in thedevelopment of cardiovascular, renal, neuropathic, and retinal disease. Thesecomplications, particularly cardiovascular disease "approximately 4-/?4 of medical expenditures$, are the ma1or sources of expenses for patients withdiabetes mellitus.

The *merican iabetes *ssociation estimated that in 2--?, direct medical costsdue to diabetes in the Enited #tates were 66J billion, with another 4B billionin indirect costs "eg, disability, wor% loss, premature mortality$. *pproximately 6in 4 health care dollars in the Enited #tates was spent caring for someone withdiagnosed diabetes, while 6 in 6- health care dollars was attributed to diabetes.A? C

!iabetic retinopathy

iabetes mellitus is the ma1or cause of blindness in adults aged 2-/?3 years inthe Enited #tatesI diabetic retinopathy accounts for 62,---/23,--- newly blindpersons every year. AB-C The 8ational )ye 'nstitute estimates that laser surgeryand appropriate follow/up care can reduce the ris% of blindness from diabeticretinopathy by - . AB-C

#nd$stage renal disease

iabetes mellitus, and particularly type 2 diabetes mellitus, is the leadingcontributor to end/stage renal disease ")#F $ in the Enited #tates. AB-C*ccording to the 0enters for isease 0ontrol and Prevention, diabetes accountsfor 33 of new cases of )#F . A6KC'n 2--B, 3B,K?3 people with diabetes in theEnited #tates and Puerto Fico began renal replacement therapy, and 2-2,2 -people with diabetes were on dialysis or had received a %idney transplant. AB-C

%europathy and vasculopathy

iabetes mellitus is the leading cause of nontraumatic lower limb amputationsin the Enited #tates, with a 64/ to 3-/fold increase in ris% over that of thenondiabetic population. 'n 2--J, about J4,?-- nontraumatic lower limbamputations were performed related to neuropathy and vasculopathy. AB-C

Cardiovascular disease

The ris% for coronary heart disease "0+ $ is 2/3 times greater in patients withdiabetes than in individuals without diabetes. 0ardiovascular disease is thema1or source of mortality in patients with type 2 diabetes mellitus.*pproximately two thirds of people with diabetes die of heart disease or stro%e.Men with diabetes face a 2/fold increased ris% for 0+ , and women have a K/ to


39/39

3/fold increased ris%.

*lthough type 2 diabetes mellitus, both early onset "= J- y$ and late onset ":J-y$, is associated with an increased ris% of ma1or 0+ and mortality, only theearly onset type "duration :6- y$ appears to be a 0+ ris% equivalent. AB6C

'n patients with type 2 diabetes mellitus, a fasting glucose level of more than6-- mg;d< signi7cantly contributes to the ris% of cardiovascular disease anddeath, independent of other %nown ris% factors. AB2C This is based on a review of

? prospective studies involving B2-, -- patients.

ata from a large population/based study aUrms that worsening glycemiccontrol appears to increase the ris% of heart failure. ABKC

*dolescents with obesity and obesity/related type 2 diabetes mellitusdemonstrate a decrease in diastolic dysfunction. AB3C This suggests that theymay be at increased ris% of progressing to early heart failure compared with

adolescents who are either lean or obese but do not have type 2 diabetesmellitus.

Cancer

* 2-6- 0onsensus Feport from a panel of experts chosen 1ointly by the *mericaniabetes *ssociation and the *merican 0ancer #ociety suggested that people

with type 2 diabetes are at an increased ris% for many types of cancer. AB4CPatients with diabetes have a higher ris% for bladder cancer, particularly thosepatients who use pioglitazone. ABJ, B?C *ge, male gender, neuropathy, andurinary tract infections were associated with this ris%.

'n a meta/analysis of 2- publications comprising 6K,--B cancer patients withconcurrent type 2 diabetes, researchers found that patients treated withmetformin had better overall and cancer/speci7c survival than those treatedwith other types of glucose/lowering agents. ABB, B C These improvements wereobserved across cancer subtypes and geographic locations. Fis% reduction wassigni7cant among patients with prostate, pancreatic, breast, colorectal and othercancers, but not for those with lung cancer. +owever, it remains unclear whethermetformin can modulate clinical outcomes in cancer patients with diabetes.

Pregnancy outcome

Entreated gestational diabetes mellitus can lead to fetal macrosomia,hypoglycemia, hypocalcemia, and hyperbilirubinemia. 'n addition, mothers withgestational diabetes mellitus have increased rates of cesarean delivery andchronic hypertension.

espite advanced age, multiparity, obesity, and social disadvantage, patientswith type 2 diabetes were found to have better glycemic control, fewer large/for/gestational/age infants, fewer preterm deliveries, and fewer neonatal careadmissions compared with patients with type 6 diabetes. This suggests thatbetter tools are needed to improve glycemic control in patients with type 6

iii. diabetes mellitus

Documents