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Diagnosis and Classication of DiabetesMellitusAMERICAN DIABETES ASSOCIATION

DEFINITION ANDDESCRIPTION OF DIABETESMELLITUSdDiabetes is a group ofmetabolic diseases characterized by hy-perglycemia resulting from defects in in-sulin secretion, insulin action, or both.The chronic hyperglycemia of diabetes isassociated with long-term damage, dys-function, and failure of different organs,especially the eyes, kidneys, nerves, heart,and blood vessels.

Several pathogenic processes are in-

volved in the development of diabetes.These range from autoimmune destruc-tion of the b-cells of the pancreas withconsequent insulin deciency to abnor-malities that result in resistance to insulinaction. The basis of the abnormalities incarbohydrate, fat, and protein metabo-lism in diabetes is decient action of in-sulin on target tissues. Decient insulinaction results from inadequate insulin se-cretion and/or diminished tissue respon-ses to insulin at one or more points in thecomplex pathways of hormone action.

Impairment of insulin secretion and de-fects in insulinaction frequently coexist inthe same patient, and it is often unclearwhich abnormality, if either alone, is theprimary cause of the hyperglycemia.

Symptoms of marked hyperglycemia in-cludepolyuria,polydipsia,weightloss,some-times with polyphagia, and blurred vision.Impairment of growth and susceptibility tocertain infections may also accompanychronic hyperglycemia. Acute, life-threaten-ing consequences of uncontrolled diabetesare hyperglycemia with ketoacidosis or thenonketotic hyperosmolar syndrome.

Long-term complications of diabetesinclude retinopathy with potential lossof vision; nephropathy leading to renalfailure; peripheral neuropathy with riskof foot ulcers, amputations, and Charcot

joints; and autonomic neuropathy caus-ing gastrointestinal, genitourinary, and

cardiovascular symptoms and sexual dys-function. Patients with diabetes have anincreased incidence of atherosclerotic car-diovascular, peripheral arterial, and cere-brovascular disease. Hypertension andabnormalities of lipoprotein metabolismare often found in people with diabetes.

The vast majority of cases of diabetesfall into two broad etiopathogenetic cate-gories (discussed in greater detail below).In one category, type 1 diabetes, the causeis an absolute deciency of insulin secre-

tion. Individuals at increased risk of de-veloping this type of diabetes can often beidentied by serological evidence of anautoimmune pathologic process occurringin the pancreatic islets and by geneticmarkers. In the other, much more preva-lent category, type 2 diabetes, the cause is acombination of resistance to insulin actionand an inadequate compensatory insulinsecretory response. In the latter category, adegree of hyperglycemia sufcient to causepathologic and functional changes in var-ious target tissues, but without clinical

symptoms, may be present for a longperiod of time before diabetes is detected.During this asymptomatic period, it ispossible to demonstrate an abnormality incarbohydrate metabolism by measurementof plasma glucose in the fasting state orafter a challenge with an oral glucose load.

The degree of hyperglycemia (if any)may change over time, depending on theextent of the underlying disease process(Fig. 1). A disease process may be presentbut may not have progressed far enoughto cause hyperglycemia. The same diseaseprocess can cause impaired fasting glu-

cose (IFG) and/or impaired glucose toler-ance (IGT) without fullling the criteriafor the diagnosis of diabetes. In some in-dividuals with diabetes, adequate glyce-mic control can be achieved with weightreduction, exercise, and/or oral glucose-lowering agents. These individuals

therefore do not require insulin. Otherindividuals who have some residual insu-

lin secretion but require exogenous insu-lin for adequate glycemic control cansurvive without it. Individuals with ex-tensive b-cell destruction and thereforeno residual insulin secretion require in-sulin for survival. The severity of the met-abolic abnormality can progress, regress,or stay the same. Thus, the degree of hy-perglycemia reects the severity of theunderlying metabolic process and itstreatment more than the nature of theprocess itself.

CLASSIFICATION OFDIABETES MELLITUS ANDOTHER CATEGORIESOF GLUCOSEREGULATIONdAssigning a type ofdiabetes to an individual often dependson the circumstances present at the timeof diagnosis, and many diabetic individ-uals do not easilyt into a single class. Forexample, a person with gestational di-abetes mellitus (GDM) may continue tobe hyperglycemic after delivery and maybe determined to have, in fact, type 2diabetes. Alternatively, a person who

acquires diabetes because of large dosesof exogenous steroids may become nor-moglycemic once the glucocorticoids arediscontinued, but then may develop di-abetes many years later after recurrentepisodes of pancreatitis. Another examplewould be a person treated with thiazideswho develops diabetes years later. Becausethiazides in themselves seldom cause severehyperglycemia, such individuals probablyhave type 2 diabetes that is exacerbated bythedrug.Thus, fortheclinicianand patient,it is less important to label the particular

type of diabetes than it is to understand thepathogenesis of the hyperglycemia and totreat it effectively.

Type 1 diabetes (b-cell destruction,usually leading to absolute insulindeciency)Immune-mediated diabetes. This formof diabetes, which accounts for only510% of those with diabetes, previouslyencompassed by the terms insulin-dependent diabetes, type 1 diabetes, or

juvenile-onset diabetes, results from a cel-lular-mediated autoimmune destruction

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Section on gestational diabetes diagnosis revised Fall 2010.DOI: 10.2337/dc12-s064 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited,theuse iseducationaland notforprot, andthe work is notaltered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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of the b-cells of the pancreas. Markers ofthe immune destruction of the b-cell in-clude islet cell autoantibodies, autoanti-bodies to insulin, autoantibodies to GAD(GAD65), and autoantibodies to the ty-rosine phosphatases IA-2 and IA-2b.One and usually more of these autoanti-bodies are present in 8590% of individ-

uals when fasting hyperglycemia isinitially detected. Also, the disease hasstrong HLA associations, with linkage tothe DQA and DQB genes, and it is inu-enced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing orprotective.

In this form of diabetes, the rate ofb-cell destruction is quite variable, beingrapid in some individuals (mainly infantsand children) and slow in others (mainlyadults). Some patients, particularly chil-dren and adolescents, may present withketoacidosis as the rst manifestation ofthe disease. Others have modest fastinghyperglycemia that can rapidly changeto severe hyperglycemia and/or ketoaci-dosis in the presence of infection or otherstress. Still others, particularly adults,may retain residual b-cell function suf-cient to prevent ketoacidosis for manyyears; such individuals eventually be-come dependent on insulin for survivaland are at risk for ketoacidosis. At thislatter stage of the disease, there is littleor no insulin secretion, as manifested bylow or undetectable levels of plasma

C-peptide. Immune-mediated diabetescommonly occurs in childhood and ado-lescence, but it can occur at any age, evenin the 8th and 9th decades of life.

Autoimmune destruction ofb-cellshas multiple genetic predispositions andis also related to environmental factorsthat are still poorly dened. Although pa-

tients are rarely obese when they presentwith this type of diabetes, the presence ofobesity is not incompatible with the diag-nosis. These patients are also prone toother autoimmune disorders such asGraves disease, Hashimotos thyroiditis,

Addison s disease, vitiligo, celiac sprue,autoimmune hepatitis, myasthenia gravis,and pernicious anemia.Idiopathic diabetes.Some forms of type1 diabetes have no known etiologies.Some of these patients have permanentinsulinopenia and are prone to ketoaci-dosis, but have no evidence of autoim-munity. Although only a minority ofpatients with type 1 diabetes fall intothis category, of those who do, most areof

African or Asian ancestry. Individualswith this form of diabetes suffer fromepisodic ketoacidosis and exhibit varyingdegrees of insulin deciency betweenepisodes. This form of diabetes is stronglyinherited, lacks immunological evidencefor b-cell autoimmunity, and is not HLAassociated. An absolute requirement forinsulin replacement therapy in affectedpatients may come and go.

Type 2 diabetes (ranging frompredominantly insulin resistance

with relative insulin deciency topredominantly an insulin secretorydefect with insulin resistance)This form of diabetes, which accounts for;9095% of those with diabetes, previ-ously referred to as noninsulin-depen-

dent diabetes, type 2 diabetes, or adult-onset diabetes, encompasses individualswho have insulin resistance and usuallyhave relative (rather than absolute) insu-lin deciency At least initially, and oftenthroughout their lifetime, these individu-als do not need insulin treatment to sur-vive. There are probably many differentcauses of this form of diabetes. Althoughthe specic etiologies are not known, au-toimmune destruction ofb-cells does notoccur, and patients do not have any of theother causes of diabetes listed above orbelow.

Most patients with this form of di-abetes are obese, and obesity itself causessome degree of insulin resistance. Patientswho are not obese by traditional weightcriteria may have an increased percentageof body fat distributed predominantly inthe abdominal region. Ketoacidosis sel-dom occurs spontaneously in this type ofdiabetes; when seen, it usually arises inassociation with the stress of anotherillness such as infection. This form ofdiabetes frequently goes undiagnosed formany years because the hyperglycemia

Figure 1dDisorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briey return to normo-glycemia without requiring continuous therapy (i.e., honeymoonremission); **in rare instances, patients in these categories (e.g., Vacor toxicity,type 1 diabetes presenting in pregnancy) may require insulin for survival.

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develops gradually and at earlier stages isoften not severe enough for the patient tonotice any of the classic symptoms ofdiabetes. Nevertheless, such patients areat increased risk of developing macro-vascular and microvascular complica-tions. Whereas patients with this form ofdiabetes may have insulin levels that

appear normal or elevated, the higherblood glucose levels in these diabeticpatients would be expected to result ineven higher insulin values had their b-cellfunction been normal. Thus, insulin se-cretion is defective in these patients andinsufcient to compensate for insulin re-sistance. Insulin resistance may improvewith weight reduction and/or pharmaco-logical treatment of hyperglycemia but isseldom restored to normal. The risk ofdeveloping this form of diabetes increaseswith age, obesity, and lack of physical ac-tivity. It occurs more frequently in womenwith prior GDM and in individuals withhypertension or dyslipidemia, and its fre-quency varies in different racial/ethnic sub-groups. It is often associated with a stronggenetic predisposition, more so than is theautoimmune form of type 1 diabetes. How-ever, the genetics of this form of diabetesare complex and not clearly dened.

Other specic types of diabetesGenetic defects of the b-cell. Severalforms of diabetes are associated withmonogenetic defects in b-cell function.

These forms of diabetes are frequentlycharacterized by onset of hyperglycemiaat an early age (generally before age 25years). They are referred to as maturity-onset diabetes of the young (MODY) andare characterized by impaired insulin se-cretion with minimal or no defects in in-sulin action. They are inherited in anautosomal dominant pattern. Abnormali-ties at six genetic loci on different chro-mosomes have been identied to date.The most common form is associatedwith mutations on chromosome 12 in ahepatic transcription factor referred to ashepatocyte nuclear factor (HNF)-1a. Asecond form is associated with mutationsin the glucokinase gene on chromosome7p and results in a defective glucokinasemolecule. Glucokinase converts glucoseto glucose-6-phosphate, the metabolismof which, in turn, stimulates insulinsecre-tion by the b-cell. Thus, glucokinaseserves as the glucose sensor for theb-cell. Because of defects in the glucoki-nase gene, increased plasma levels of glu-cose are necessary to elicit normal levelsof insulin secretion. The less common

forms result from mutations in other tran-scription factors, including HNF-4a,HNF-1b, insulin promoter factor (IPF)-1, and NeuroD1.

Point mutations in mitochondrialDNA have been found to be associatedwith diabetes and deafness The mostcommon mutation occurs at position

3,243 in the tRNA leucine gene, leadingto an A-to-G transition. An identicallesion occurs in the MELAS syndrome(mitochondrial myopathy, encephalopa-thy, lactic acidosis, and stroke-like syn-drome); however, diabetes is not part ofthis syndrome, suggesting different phe-notypic expressions of this genetic lesion.

Genetic abnormalities that result inthe inability to convert proinsulin to in-sulin have been identied in a few fami-lies, and such traits are inherited in anautosomal dominant pattern. The resul-tant glucose intolerance is mild. Similarly,the production of mutant insulin mole-cules with resultant impaired receptorbinding has also been identied in a fewfamilies and is associated with an autoso-mal inheritance and only mildly impairedor even normal glucose metabolism.Genetic defects in insulin action.Thereare unusual causes of diabetes that resultfrom genetically determined abnormali-ties of insulin action. The metabolic ab-normalities associated with mutations ofthe insulin receptor may range fromhyperinsulinemia and modest hyperglyce-

mia to severe diabetes. Some individualswith these mutations may have acanthosisnigricans. Women may be virilized andhave enlarged, cystic ovaries. In the past,this syndrome was termed type A insulinresistance. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatricsyndromes that have mutations in theinsulin receptor gene with subsequentalterations in insulin receptor functionand extreme insulin resistance. The formerhas characteristic facial features and isusually fatal in infancy, while the latter isassociated with abnormalities of teeth andnails and pineal gland hyperplasia.

Alterations in the structure and func-tion of the insulin receptor cannot bedemonstrated in patients with insulin-resistant lipoatrophic diabetes. Therefore,it is assumed that the lesion(s) must residein the postreceptor signal transductionpathways.Diseases of the exocrine pancreas.Anyprocess that diffusely injures the pancreascan cause diabetes. Acquired processesinclude pancreatitis, trauma, infection, pan-createctomy, and pancreatic carcinoma.

With the exception of that caused bycancer, damage to the pancreas must beextensive for diabetes to occur; adreno-carcinomas that involve only a smallportion of the pancreas have been associ-ated with diabetes. This implies a mech-anism other than simple reduction inb-cell mass. If extensive enough, cystic -

brosis and hemochromatosis will alsodamage b-cells and impair insulin secre-tion. Fibrocalculous pancreatopathy maybe accompanied by abdominal pain radi-ating to the back and pancreatic calcica-tions identied on X-ray examination.Pancreatic brosis and calcium stonesin the exocrine ducts have been found atautopsy.Endocrinopathies. Several hormones(e.g., growth hormone, cortisol, gluca-gon, epinephrine) antagonize insulin ac-tion. Excess amounts of these hormones(e.g., acromegaly, Cushings syndrome,glucagonoma, pheochromocytoma, re-spectively) can cause diabetes. This gen-erally occurs in ind ivid uals withpreexisting defects in insulin secretion,and hyperglycemia typically resolveswhen the hormone excess is resolved.

Somatostatinoma- and aldostero-noma-induced hypokalemia can causediabetes, at least in part, by inhibitinginsulin secretion. Hyperglycemia gener-ally resolves after successful removal ofthe tumor.Drug- or chemical-induced diabetes.

Many drugs can impair insulin secretion.These drugs may not cause diabetes bythemselves, but they may precipitate di-abetes in individuals with insulin resis-tance. In such cases, the classication isunclear because the sequence or relativeimportance ofb-cell dysfunction and in-sulin resistance is unknown. Certain tox-ins such as Vacor (a rat poison) andintravenous pentamidine can perma-nently destroy pancreatic b-cells. Suchdrug reactions fortunately are rare. Thereare also many drugs and hormones thatcan impair insulin action. Examples in-clude nicotinic acid and glucocorticoids.Patients receiving a-interferon have beenreported to develop diabetes associatedwith islet cell antibodies and, in certaininstances, severe insulin deciency. Thelist shown in Table 1 is not all-inclusive,but reects the more commonly recog-nized drug-, hormone-, or toxin-inducedforms of diabetes.Infections. Certain viruses have beenassociated with b-cell destruction. Diabe-tes occurs in patients with congenital ru-bella, although most of these patients


Diagnosis and Classication

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have HLA and immune markers charac-teristic of type 1 diabetes. In addition,coxsackievirus B, cytomegalovirus, ade-novirus, and mumps have been impli-cated in inducing certain cases of thedisease.Uncommon forms of immune-mediateddiabetes. In this category, there are two

known conditions, and others are likelyto occur. The stiff-man syndrome is anautoimmune disorder of the central ner-vous system characterized by stiffness ofthe axial muscles with painful spasms.Patients usually have high titers of theGAD autoantibodies, and approximatelyone-third will develop diabetes.

Anti-insulin receptor antibodies cancause diabetes by binding to the insulinreceptor, thereby blocking the binding ofinsulin to its receptor in target tissues.However, in some cases, these antibodiescan act as an insulin agonist after bindingto the receptor and can thereby causehypoglycemia. Anti-insulin receptor anti-bodies are occasionally found in patientswith systemic lupus erythematosus andother autoimmune diseases. As in otherstates of extreme insulin resistance, pa-tients with anti-insulin receptor antibod-ies often have acanthosis nigricans. In thepast, this syndrome was termed type Binsulin resistance.Other genetic syndromes sometimesassociated with diabetes. Many geneticsyndromes are accompanied by an in-

creased incidence of diabetes. These in-clude the chromosomal abnormalities ofDown syndrome, Klinefelter syndrome,and Turner syndrome. Wolframs syn-drome is an autosomal recessive disordercharacterized by insulin-decient diabe-tes and the absence ofb-cells at autopsy.

Additional manifestations include diabetesinsipidus, hypogonadism, optic atrophy,and neural deafness. Other syndromes arelisted in Table 1.

Gestational diabetes mellitusFor many years, GDM has been dened asany degree of glucose intolerance withonset or rst recognition during preg-nancy. Although most cases resolve withdelivery, the denition applied whetheror not the condition persisted after preg-nancy and did not exclude the possibilitythat unrecognized glucose intolerancemay have antedated or begun concomi-tantly with the pregnancy. This denitionfacilitated a uniform strategy for detectionand classication of GDM, but its limi-tations were recognized for many years.

As the ongoing epidemic of obesity and

Table 1dEtiologic classication of diabetes mellitus

I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deciency)A. Immune mediatedB. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deciencyto a predominantly secretory defect with insulin resistance)

III. Other specic typesA. Genetic defects ofb-cell function

1. Chromosome 12, HNF-1a(MODY3)

2. Chromosome 7, glucokinase (MODY2)3. Chromosome 20, HNF-4a(MODY1)4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)5. Chromosome 17, HNF-1b(MODY5)6. Chromosome 2, NeuroD1(MODY6)7. Mitochondrial DNA8. Others

B. Genetic defects in insulin action1. Type A insulin resistance2. Leprechaunism3. Rabson-Mendenhall syndrome4. Lipoatrophic diabetes5. Others

C. Diseases of the exocrine pancreas1. Pancreatitis2. Trauma/pancreatectomy

3. Neoplasia4. Cysticbrosis5. Hemochromatosis6. Fibrocalculous pancreatopathy7. Others

D. Endocrinopathies1. Acromegaly2. Cushings syndrome3. Glucagonoma4. Pheochromocytoma5. Hyperthyroidism6. Somatostatinoma7. Aldosteronoma8. Others

E. Drug or chemical induced1. Vacor2. Pentamidine

3. Nicotinic acid4. Glucocorticoids5. Thyroid hormone6. Diazoxide7. b-adrenergic agonists8. Thiazides9. Dilantin

10. g-Interferon11. Others

F. Infections1. Congenital rubella2. Cytomegalovirus3. Others

G. Uncommon forms of immune-mediated diabetes1. Stiff-mansyndrome2. Anti-insulin receptor antibodies

3. OthersH. Other genetic syndromes sometimes associated with diabetes1. Down syndrome2. Klinefelter syndrome3. Turner syndrome4. Wolfram syndrome5. Friedreich ataxia6. Huntington chorea7. Laurence-Moon-Biedl syndrome8. Myotonic dystrophy9. Porphyria

10. Prader-Willi syndrome11. Others

IV. Gestational diabetes mellitus

Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use ofinsulin does not, of itself, classify the patient.


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Acc ordin gly, int erven tions should bemost intensive and follow-up should beparticularly vigilant for those with A1Clevels above 6.0%, who should be consid-ered to be at very high risk. However, justas an individual with a fasting glucose of98 mg/dl (5.4 mmol/l) may not be at neg-ligible risk for diabetes, individuals with

A1C levels below 5.7% may still be atrisk, depending on level of A1C and pres-ence of other risk factors, such as obesityand family history.

Table 2 summarizes the categories ofincreased risk for diabetes. Evaluation ofpatients at risk should incorporate aglobal risk factor assessment for both di-abetes and cardiovascular disease. Screen-ing for and counseling about risk ofdiabetes should always be in the prag-matic context of the patients comorbidi-ties, life expectancy, personal capacity toengage in lifestyle change, and overallhealth goals.

DIAGNOSTIC CRITERIA FORDIABETES MELLITUSdFor deca-des, the diagnosis of diabetes has beenbased on glucose criteria, either the FPGor the 75-g OGTT. In 1997, the rstExpert Committee on the Diagnosis andClassication of Diabetes Mellitus revisedthe diagnostic criteria, using the observedassociation between FPG levels and pres-ence of retinopathy as the key factor withwhich to identify threshold glucose level.

The Committee examined data from threecross-sectional epidemiologic studies thatassessed retinopathy with fundus pho-tography or direct ophthalmoscopy andmeasured glycemia as FPG, 2-h PG, and

A1C. These studies demonstrated glyce-mic levels below which there was littleprevalent retinopathy and above whichthe prevalence of retinopathy increased inan apparently linear fashion. The decilesof the three measures at which retinopa-thy began to increase were the same foreach measure within each population.Moreover, the glycemic values abovewhich retinopathy increased were similaramong the populations. These analyseshelped to inform a new diagnostic cutpoint of $126 mg/dl (7.0 mmol/l) forFPG and conrmed the long-standing di-agnostic 2-h PG value of $200 mg/dl(11.1 mmol/l).

A1C is a widely used marker ofchronic glycemia, reecting averageblood glucose levels over a 2- to 3-monthperiod of time. The test plays a critical rolein the management of the patient withdiabetes, since it correlates well with both

microvascular and, to a lesser extent,macrovascular complications and iswidely used as the standard biomarkerfor the adequacy of glycemic manage-ment. Prior Expert Committees have notrecommended use of the A1C for diag-nosis of diabetes, in part due to lack ofstandardization of the assay. However,

A1C assays are now highly standardizedso that their results can be uniformlyapplied both temporally and across pop-ulations. In their recent report (3), an In-ternational Expert Committee, after anextensive review of both established andemerging epidemiological evidence, rec-ommended the use of the A1C test to di-agnose diabetes, with a threshold of$6.5%, and ADA afrms this decision.The diagnostic A1C cut point of 6.5% isassociated with an inection point for ret-

inopathy prevalence, as are the diagnosticthresholds for FPG and 2-h PG (3). Thediagnostic test should be performedusing a method that is certied by the Na-tional Glycohemoglobin StandardizationProgram (NGSP) and standardized ortraceable to the Diabetes Control andComplications Trial reference assay.Point-of-care A1C assays are not suf-ciently accurate at this time to use for di-agnostic purposes.

There is an inherent logic to using amore chronic versus an acute marker ofdysglycemia, particularly since the A1C isalready widely familiar to clinicians as amarker of glycemic control. Moreover,the A1C has several advantages to theFPG, including greater convenience,since fasting is not required, evidence tosuggest greater preanalytical stability, andless day-to-day perturbations during pe-riods of stress and illness. These advan-tages, however, must be balanced bygreater cost, the limited availability of

A1C testing in certain regions of thedeveloping world, and the incompletecorrelation between A1C and average

glucose in certain individuals. In addi-tion, the A1C can be misleading in pa-tients with certain forms of anemia andhemoglobinopathies, which may alsohave unique ethnic or geographic distri-butions. For patients with a hemoglobin-opathy but normal red cell turnover, suchas sickle cell trait, an A1C assay withoutinterference from abnormal hemoglobinsshould be used (an updated list is avail-able at www.ngsp.org/prog/index3.html). For conditions with abnormal redcell turnover, such as anemias from he-molysis and iron deciency, the diagnosisof diabetes must employ glucose criteriaexclusively.

The established glucose criteria forthe diagnosis of diabetes remain valid.These include the FPG and 2-h PG.

Additionally, patients with severe hyper-

glycemia such as those who present withsevere classic hyperglycemic symptomsor hyperglycemic crisis can continue to bediagnosed when a random (or casual)plasma glucose of $200 mg/dl (11.1mmol/l) is found. It is likely that in suchcases the health care professional wouldalso measure an A1C test as part of theinitial assessment of the severity of the di-abetes and that it would (in most cases) beabove the diagnostic cut point for diabe-tes. However, in rapidly evolving diabe-tes, such as the development of type 1diabetes in some children, A1C may notbe signicantly elevated despite frankdiabetes.

Just as there is less than 100% con-cordance between the FPG and 2-h PGtests, there is not full concordance be-tween A1C and either glucose-basedtest. Analyses of NHANES data indicatethat, assuming universal screening of theundiagnosed, the A1C cut point of$6.5% identies one-third fewer casesof undiagnosed diabetes than a fastingglucose cut point of $126 mg/dl (7.0mmol/l) (cdc website tbd). However, in

Table 3dCriteria for the diagnosis of diabetes

A1C $6.5%. The test should be performed in a laboratory using a method that is NGSP certied

and standardized to the DCCT assay.*

OR

FPG $126 mg/dl (7.0 mmol/l). Fasting is dened as no caloric intake for at least 8 h.*

OR

2-h plasma glucose$200 mg/dl (11.1mmol/l) duringan OGTT. Thetestshould be performedas

described by theWorld HealthOrganization,usinga glucose load containing theequivalent of

75 g anhydrous glucose dissolved in water.*

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma

glucose $200 mg/dl (11.1 mmol/l).

*In the absence of unequivocal hyperglycemia, criteria 13 should be conrmed by repeat testing.


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practice, a large portion of the populationwith type 2 diabetes remains unaware oftheir condition. Thus, it is conceivablethat the lower sensitivity of A1C at thedesignated cut point will be offset by thetests greater practicality, and that widerapplication of a more convenient test(A1C) may actually increase the number

of diagnoses made.Further research is needed to better

characterize those patients whose glyce-mic status might be categorized differ-ently by two different tests (e.g., FPG and

A1C), obtained in close temporal approx-imation. Such discordance may arise frommeasurement variability, change overtime, or because A1C, FPG, and post-challenge glucose each measure differentphysiological processes. In the setting ofan elevated A1C but nondiabetic FPG,the likelihood of greater postprandial glu-cose levels or increased glycation ratesfor a given degree of hyperglycemia maybe present. In the opposite scenario (highFPG yet A1C below the diabetes cutpoint), augmented hepatic glucose pro-duction or reduced glycation rates maybe present.

As with most diagnostic tests, a testresult diagnostic of diabetes should berepeated to rule out laboratory error,unless the diagnosis is clear on clinicalgrounds, such as a patient with classicsymptoms of hyperglycemia or hypergly-cemic crisis. It is preferable that the same

test be repeated for conrmation, sincethere will be a greater likelihood of con-currence in this case. For example, if the

A1C is 7.0% and a repeat result is 6.8%,the diagnosis of diabetes is conrmed.However, there are scenarios in which re-sults of two different tests (e.g., FPG and

A1C) are available for the same patient. Inthis situation, if the two different tests areboth above the diagnostic thresholds, thediagnosis of diabetes is conrmed.

On the other hand, when two differ-ent tests are available in an individual andthe results are discordant, the test whoseresult is above the diagnostic cut pointshould be repeated, and the diagnosis ismade on the basis of the conrmed test.That is, if a patient meets the diabetescriterion of the A1C (two results $6.5%)but not the FPG (,126 mg/dl or 7.0mmol/l), or vice versa, that person shouldbe considered to have diabetes. Admit-tedly, in most circumstance the nondia-betic test is likely to be in a range veryclose to the threshold that denes diabetes.

Since there is preanalytic and analyticvariability of all the tests, it is also possible

that when a test whose result was abovethe diagnostic threshold is repeated, thesecond value will be below the diagnosticcut point. This is least likely for A1C,somewhat more likely for FPG, and mostlikely for the 2-h PG. Barring a laboratoryerror, such patients are likely to have testresults near the margins of the threshold

for a diagnosis. The healthcare profes-sional might opt to follow the patientclosely and repeat the testing in 36months.

The decision about which test to useto assess a specic patient for diabetesshould be at the discretion of the healthcare professional, taking into account theavailability and practicality of testing anindividual patient or groups of patients.Perhaps more important than which di-agnostic test is used, is that the testing fordiabetes be performed when indicated.There is discouraging evidence indicatingthat many at-risk patients still do not re-ceive adequate testing and counseling forthis increasingly common disease, or for itsfrequently accompanying cardiovascularrisk factors. The current diagnostic criteriafor diabetes are summarized in Table 3.

Diagnosis of gestational diabetesGDM carries risks for the mother andneonate. The Hyperglycemia and AdversePregnancy Outcomes (HAPO) study(11), a large-scale (;25,000 pregnantwomen) multinational epidemiologic

study, demonstrated that risk of adversematernal, fetal, and neonatal outcomescontinuously increased as a function ofmaternal glycemia at 24-28 weeks, evenwithin ranges previously considered nor-mal for pregnancy. For most complica-tions, there was no threshold for risk.These results have led to careful reconsid-eration of the diagnostic criteria for GDM.

Aft er del iberat ion s in 2008-2009, theIADPSG, an international consensusgroup with representatives from multipleobstetrical and diabetes organizations, in-cluding ADA, developed revised recom-mendations for diagnosing GDM. Thegroup recommended that all women notknown to have diabetes undergo a 75-gOGTT at 24-28 weeks of gestation. Addi-tionally, the group developed diagnosticcutpoints for the fasting, 1-h, and 2-hplasma glucose measurements that con-veyed an odds ratio for adverse outcomesof at least 1.75 compared with womenwith mean glucose levels in the HAPOstudy. Current screening and diagnosticstrategies, based on the IADPSG state-ment (12), are outlined in Table 4.

These new criteria will signicantlyincrease the prevalence of GDM, primar-ily because only one abnormal value, nottwo, is sufcient to make the diagnosis.The ADA recognizes the anticipated sig-nicant increase in the incidence of GDMto be diagnosed by these criteria and issensitive to concerns about the medical-ization of pregnancies previously catego-rized as normal. These diagnostic criteriachanges are being made in the context ofworrisome worldwide increases in obe-sity and diabetes rates, with the intent ofoptimizing gestational outcomes forwomen and their babies.

Admittedly, there are few data fromrandomized clinical trials regarding ther-

apeutic interventions in women who willnow be diagnosed with GDM based ononly one blood glucose value above thespecied cutpoints (in contrast to theolder criteria that stipulated at least twoabnormal values). Expected benets totheir pregnancies and offspring is inferredfrom intervention trials that focused onwomen with more mild hyperglycemiathan identied using older GDM diag-nostic criteria and that found modestbenets (13,14). The frequency of theirfollow-up and blood glucose monitoringis not yet clear but likely to be less inten-sive than women diagnosed by the oldercriteria. Additional well-designed clinicalstudies are needed to determine the op-timal intensity of monitoring and treat-ment of women with GDM diagnosedby the new criteria (that would nothave met the prior denition of GDM).It is important to note that 80-90% ofwomen in both of the mild GDM studies(whose glucose values overlapped withthe thresholds recommended herein)could be managed with lifestyle therapyalone.

Table 4dScreening for and diagnosis of

GDM

Perform a 75-g OGTT, with plasma glucose

measurement fasting and at 1 and 2 h, at

24-28 of weeks gestation in women not

previously diagnosed with overt diabetes.

The OGTT should be performed in the

morning after an overnight fast of at least

8 h.

The diagnosis ofGDM ismade whenany ofthe

following plasma glucose values are

exceeded

c Fasting: $92 mg/dl (5.1 mmol/l)c 1 h: $180 mg/dl (10.0 mmol/l)c 2 h: $153 mg/dl (8.5 mmol/l)


Diagnosis and Classication

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