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2. Classification and Diagnosis of Diabetes Diabetes Care 2017;40(Suppl. 1):S11S24 | DOI: 10.2337/dc17-S005 CLASSIFICATION Diabetes can be classied into the following general categories: 1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to ab- solute insulin deciency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specic types of diabetes due to other causes, e.g., monogenic diabetes syn- dromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic brosis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation) This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position state- ment Diagnosis and Classication of Diabetes Mellitus(1). Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classication is im- portant for determining therapy, but some individuals cannot be clearly classied as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, patients with type 2 diabetes may present with diabetic ketoacidosis (DKA), particularly ethnic minorities (2). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with DKA (3). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in children. Although difculties in distin- guishing diabetes type may occur in all age-groups at onset, the true diagnosis becomes more obvious over time. In October 2015, the ADA, JDRF, the European Association for the Study of Di- abetes, and the American Association of Clinical Endocrinologists convened the Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Re- search Symposium (4). The goals of the symposium were to discuss the genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, to determine appropriate therapeutic approaches based on disease pathophysiology and stage, and to dene research gaps hindering a personalized approach to treat- ment. The experts agreed that in both type 1 and type 2 diabetes, various genetic and environmental factors can result in the progressive loss of b-cell mass and/or function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, patients with all forms of diabetes are at risk for developing the same complications, although rates of progression may differ. They concluded that the identication of individualized therapies for diabetes in the future will require better characteriza- tion of the many paths to b-cell demise or dysfunction. Characterization of the underlying pathophysiology is much more developed in type 1 diabetes than in type 2 diabetes. It is now clear from studies of rst-degree relatives of patients with type 1 diabetes that the persistent presence of two or Suggested citation: American Diabetes Associa- tion. Classication and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetesd 2017. Diabetes Care 2017;40(Suppl. 1):S11S24 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for prot, and the work is not altered. More infor- mation is available at http://www.diabetesjournals .org/content/license. American Diabetes Association Diabetes Care Volume 40, Supplement 1, January 2017 S11 2. CLASSIFICATION AND DIAGNOSIS OF DIABETES

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2. Classification and Diagnosisof DiabetesDiabetes Care 2017;40(Suppl. 1):S11–S24 | DOI: 10.2337/dc17-S005

CLASSIFICATION

Diabetes can be classified into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to ab-solute insulin deficiency)

2. Type 2 diabetes (due to a progressive loss ofb-cell insulin secretion frequently onthe background of insulin resistance)

3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or thirdtrimester of pregnancy that was not clearly overt diabetes prior to gestation)

4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syn-dromes (such as neonatal diabetes and maturity-onset diabetes of the young[MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- orchemical-induced diabetes (such as with glucocorticoid use, in the treatment ofHIV/AIDS, or after organ transplantation)

This section reviews most common forms of diabetes but is not comprehensive. Foradditional information, see the American Diabetes Association (ADA) position state-ment “Diagnosis and Classification of Diabetes Mellitus” (1).Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical

presentation and disease progression may vary considerably. Classification is im-portant for determining therapy, but some individuals cannot be clearly classified ashaving type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigmsof type 2 diabetes occurring only in adults and type 1 diabetes only in children are nolonger accurate, as both diseases occur in both cohorts. Occasionally, patients withtype 2 diabetes may present with diabetic ketoacidosis (DKA), particularly ethnicminorities (2). Children with type 1 diabetes typically present with the hallmarksymptoms of polyuria/polydipsia, and approximately one-third present with DKA(3). The onset of type 1 diabetes may be more variable in adults, and they may notpresent with the classic symptoms seen in children. Although difficulties in distin-guishing diabetes type may occur in all age-groups at onset, the true diagnosisbecomes more obvious over time.In October 2015, the ADA, JDRF, the European Association for the Study of Di-

abetes, and the American Association of Clinical Endocrinologists convened theDifferentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Re-search Symposium (4). The goals of the symposium were to discuss the genetic andenvironmental determinants of type 1 and type 2 diabetes risk and progression, todetermine appropriate therapeutic approaches based on disease pathophysiologyand stage, and to define research gaps hindering a personalized approach to treat-ment. The experts agreed that in both type 1 and type 2 diabetes, various geneticand environmental factors can result in the progressive loss of b-cell mass and/orfunction that manifests clinically as hyperglycemia. Once hyperglycemia occurs,patients with all forms of diabetes are at risk for developing the same complications,although rates of progression may differ. They concluded that the identification ofindividualized therapies for diabetes in the future will require better characteriza-tion of the many paths to b-cell demise or dysfunction.Characterization of the underlying pathophysiology is much more developed in

type 1 diabetes than in type 2 diabetes. It is now clear from studies of first-degreerelatives of patients with type 1 diabetes that the persistent presence of two or

Suggested citation: American Diabetes Associa-tion. Classification and diagnosis of diabetes.Sec. 2. In Standards ofMedical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S11–S24

© 2017 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

American Diabetes Association

Diabetes Care Volume 40, Supplement 1, January 2017 S11

2.CLA

SSIFICATIO

NANDDIAGNOSIS

OFDIABETES

more autoantibodies is an almost cer-tain predictor of clinical hyperglycemiaand diabetes. The rate of progression isdependent on the age at first detectionof antibody, number of antibodies, anti-body specificity, and antibody titer. Glu-cose and A1C levels rise well before theclinical onset of diabetes, making diag-nosis feasible well before the onset ofDKA. Three distinct stages of type 1 di-abetes can be identified (Table 2.1) andserve as a framework for future researchand regulatory decision making (4,5).The paths to b-cell demise and dys-

function are less well defined in type 2diabetes, but deficient b-cell insulin se-cretion frequently in the setting of insu-lin resistance appears to be the commondenominator. Characterization of sub-types of this heterogeneous disorderhave been developed and validated inScandinavian and Northern Europeanpopulations, but have not been con-firmed in other ethnic and racial groups.Type 2 diabetes is primarily associatedwith insulin secretory defects relatedto inflammation and metabolic stressamong other contributors includinggenetic factors. Future classificationschemes for diabetes will likely focuson the pathophysiology of the under-lying b-cell dysfunction and the stageof disease as indicated by glucose status(normal, impaired, or diabetes) (4).

DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based onplasma glucose criteria, either the fast-ing plasma glucose (FPG) or the 2-hplasma glucose (2-h PG) value after a75-g oral glucose tolerance test (OGTT)or A1C criteria (1,6) (Table 2.2).FPG, 2-h PG after 75-g OGTT, and A1C

are equally appropriate for diagnostictesting. It should be noted that the testsdo not necessarily detect diabetes inthe same individuals. The efficacy of

interventions for primary prevention oftype 2 diabetes (7,8) has primarily beendemonstrated among individuals withimpaired glucose tolerance (IGT), notfor individuals with isolated impairedfasting glucose (IFG) or for those withprediabetes defined by A1C criteria.

The same tests may be used to screenfor and diagnose diabetes and to detectindividuals with prediabetes. Diabetesmay be identified anywhere along thespectrum of clinical scenarios: in seem-ingly low-risk individuals who happento have glucose testing, in individualstested based on diabetes risk assess-ment, and in symptomatic patients.

Fasting and 2-Hour Plasma GlucoseThe FPG and 2-h PG may be used to di-agnose diabetes (Table 2.2). The concor-dance between the FPG and 2-h PG testsis imperfect, as is the concordance be-tween A1C and either glucose-basedtest. Numerous studies have confirmedthat, compared with FPG and A1C cutpoints, the 2-h PG value diagnosesmore people with diabetes.

A1CThe A1C test should be performedusing a method that is certified by theNGSP (www.ngsp.org) and standardizedor traceable to the Diabetes Control andComplications Trial (DCCT) reference as-say. Although point-of-care A1C assaysmay be NGSP certified, proficiency test-ing is not mandated for performing thetest, so use of point-of-care assays fordiagnostic purposes is not recommen-ded but may be considered in the futureif proficiency testing is performed anddocumented.

The A1C has several advantages com-pared with the FPG and OGTT, includinggreater convenience (fasting not re-quired), greater preanalytical stability,and less day-to-day perturbations dur-ing stress and illness. However, these

advantages may be offset by the lowersensitivity of A1C at the designated cutpoint, greater cost, limited availabilityof A1C testing in certain regions of thedeveloping world, and the imperfectcorrelation between A1C and averageglucose in certain individuals. NationalHealth andNutrition Examination Survey(NHANES) data indicate that an A1C cutpoint of $6.5% (48 mmol/mol) identifiesone-third fewer cases of undiagnosed di-abetes than a fasting glucose cut pointof$126 mg/dL (7.0 mmol/L) (9).

When using A1C to diagnose diabetes,it is important to recognize that A1C isan indirectmeasure of average blood glu-cose levels and to take other factors intoconsiderationthatmayimpacthemoglobinglycation independently of glycemia in-cluding age, race/ethnicity, and anemia/hemoglobinopathies.

Age

The epidemiological studies that formedthe basis for recommending A1C to di-agnose diabetes included only adult pop-ulations. Therefore, it remains unclear ifA1C and the same A1C cut point shouldbe used to diagnose diabetes in childrenand adolescents (9,10).

Race/Ethnicity

A1C levels may vary with race/ethnicityindependently of glycemia (11,12). Forexample, African Americans may havehigher A1C levels than non-Hispanicwhites despite similar fasting and post-glucose load glucose levels (13). Thoughthere is some conflicting data, AfricanAmericans may also have higher levelsof fructosamine and glycated albuminand lower levels of 1,5-anhydroglucitol,suggesting that their glycemic burden(particularly postprandially) may behigher (14,15). The association of A1Cwith risk for complications appears tobe similar in African Americans andnon-Hispanic whites (16).

Table 2.1—Staging of type 1 diabetes (4,5)

Stage 1 Stage 2 Stage 3

Stage c Autoimmunityc Normoglycemiac Presymptomatic

c Autoimmunityc Dysglycemiac Presymptomatic

c New-onset hyperglycemiac Symptomatic

Diagnostic criteria c Multiple autoantibodiesc No IGT or IFG

c Multiple autoantibodiesc Dysglycemia: IFG and/or IGTc FPG 100–125 mg/dL (5.6–6.9 mmol/L)c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L)c A1C 5.7–6.4% (39–47 mmol/mol) or $10%increase in A1C

c Clinical symptomsc Diabetes by standard criteria

S12 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

Hemoglobinopathies/Red Blood Cell

Turnover

Interpreting A1C levels in the presenceof certain hemoglobinopathies may beproblematic. For patients with an abnor-mal hemoglobin but normal red bloodcell turnover, such as those with thesickle cell trait, an A1C assay withoutinterference from abnormal hemoglo-bins should be used. An updated list ofinterferences is available at www.ngsp.org/interf.asp.In conditions associated with in-

creased red blood cell turnover, suchas pregnancy (second and third trimes-ters), hemodialysis, recent blood loss ortransfusion, or erythropoietin therapy,only blood glucose criteria should beused to diagnose diabetes.

Confirming the DiagnosisUnless there is a clear clinical diagnosis(e.g., patient in a hyperglycemic crisis orwith classic symptoms of hyperglycemiaand a random plasma glucose $200mg/dL [11.1 mmol/L]), a second test is re-quired for confirmation. It is recom-mended that the same test be repeatedwithout delay using a new blood samplefor confirmation because there will be agreater likelihood of concurrence. For ex-ample, if the A1C is 7.0% (53 mmol/mol)and a repeat result is 6.8% (51mmol/mol),the diagnosis of diabetes is confirmed. Iftwo different tests (such as A1C and FPG)are both above the diagnostic threshold,this also confirms the diagnosis. On theother hand, if a patient has discordantresults from two different tests, then thetest result that is above the diagnostic cutpoint should be repeated. The diagnosisis made on the basis of the confirmedtest. For example, if a patient meetsthe diabetes criterion of the A1C (tworesults $6.5% [48 mmol/mol]) but not

FPG (,126 mg/dL [7.0 mmol/L]), thatperson should nevertheless be consid-ered to have diabetes.

Since all the tests have preanalyticand analytic variability, it is possiblethat an abnormal result (i.e., above thediagnostic threshold), when repeated,will produce a value below the diagnos-tic cut point. This scenario is likely forFPG and 2-h PG if the glucose samplesremain at room temperature and arenot centrifuged promptly. Because ofthe potential for preanalytic variability,it is critical that samples for plasma glu-cose be spun and separated immedi-ately after they are drawn. If patientshave test results near the margins ofthe diagnostic threshold, the healthcare professional should follow the pa-tient closely and repeat the test in3–6 months.

CATEGORIES OF INCREASED RISKFOR DIABETES (PREDIABETES)

Recommendations

c Screening for prediabetes and riskfor future diabetes with an infor-mal assessment of risk factors orvalidated tools should be consid-ered in asymptomatic adults. B

c Testing for prediabetes and riskfor future diabetes in asymptom-atic people should be consideredin adults of any age who are over-weight or obese (BMI $25 kg/m2

or $23 kg/m2 in Asian Ameri-cans) and who have one or moreadditional risk factors for diabe-tes. B

c For all people, testing should be-gin at age 45 years. B

c If tests are normal, repeat testingcarried out at a minimum of 3-yearintervals is reasonable. C

c To test for prediabetes, fastingplasma glucose, 2-h plasma glucoseafter 75-g oral glucose tolerancetest, and A1C are equally appropri-ate. B

c In patients with prediabetes,identify and, if appropriate, treatother cardiovascular disease riskfactors. B

c Testing for prediabetes should beconsidered in children and ado-lescents who are overweight orobese and who have two or moreadditional risk factors for diabe-tes. E

DescriptionIn 1997 and 2003, the Expert Committeeon the Diagnosis and Classification ofDiabetes Mellitus (17,18) recognized agroup of individuals whose glucose lev-els did not meet the criteria for diabetesbut were too high to be considered nor-mal. “Prediabetes” is the term used forindividuals with IFG and/or IGT and/orA1C 5.7–6.4% (39–47 mmol/mol). Pre-diabetes should not be viewed as a clin-ical entity in its own right but rather asan increased risk for diabetes (Table 2.3)and cardiovascular disease (CVD).Prediabetes is associated with obe-sity (especially abdominal or visceralobesity), dyslipidemia with high triglyc-erides and/or low HDL cholesterol, andhypertension.

DiagnosisThe Expert Committee on the Diagnosisand Classification of Diabetes Mellitus(17,18) defined IFG as FPG levels be-tween 100 and 125 mg/dL (between5.6 and 6.9 mmol/L) and IGT as 2-h PGafter 75-g OGTT levels between 140 and199mg/dL (between7.8and11.0mmol/L).It should be noted that the World HealthOrganization (WHO) and numerous otherdiabetes organizations define the IFGcutoff at 110 mg/dL (6.1 mmol/L).

As with the glucose measures, severalprospective studies that used A1C topredict the progression to diabetes asdefined by A1C criteria demonstrated astrong, continuous association betweenA1C and subsequent diabetes. In a sys-tematic review of 44,203 individualsfrom 16 cohort studies with a follow-upinterval averaging 5.6 years (range 2.8–12 years), those with A1C between 5.5and 6.0% (between 37 and 42 mmol/mol)

Table 2.2—Criteria for the diagnosis of diabetesFPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*

OR

2-h PG$200mg/dL (11.1mmol/L) during anOGTT. The test should be performed as describedby the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucosedissolved in water.*

OR

A1C$6.5% (48 mmol/mol). The test should be performed in a laboratory using a method thatis NGSP certified and standardized to the DCCT assay.*

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasmaglucose $200 mg/dL (11.1 mmol/L).

*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.

care.diabetesjournals.org Classification and Diagnosis of Diabetes S13

had a substantially increased risk of diabe-tes (5-year incidence from 9 to 25%). AnA1C range of 6.0–6.5% (42–48 mmol/mol)had a 5-year risk of developing diabetesbetween 25 and 50% and a relative risk20 times higher compared with A1C of5.0% (31 mmol/mol) (19). In a community-based study of African American andnon-Hispanic white adults without diabe-tes, baseline A1C was a stronger predictorof subsequent diabetes and cardiovascu-lar events than fasting glucose (20).Other analyses suggest that A1C of5.7% (39 mmol/mol) or higher is associ-ated with a diabetes risk similar to thatof the high-risk participants in the Di-abetes Prevention Program (DPP) (21),and A1C at baseline was a strong pre-dictor of the development of glucose-defined diabetes during the DPP and itsfollow-up (22).Hence, it is reasonable to consider an

A1C range of 5.7–6.4% (39–47mmol/mol)as identifying individuals with prediabe-tes. Similar to those with IFG and/or IGT,individuals with A1C of 5.7–6.4% (39–47 mmol/mol) should be informed oftheir increased risk for diabetes andCVD and counseled about effective strat-egies to lower their risks (see Section5 “Prevention or Delay of Type 2 Diabe-tes”). Similar to glucose measurements,the continuum of risk is curvilinear, so asA1C rises, the diabetes risk rises dispro-portionately (19). Aggressive interven-tions and vigilant follow-up should bepursued for those considered at veryhigh risk (e.g., those with A1C .6.0%[42 mmol/mol]).

Table 2.4 summarizes the categoriesof prediabetes and Table 2.3 the criteriafor prediabetes testing. The ADA diabe-tes risk test is an additional option forscreening (Fig. 2.1). For recommenda-tions regarding risk factors and screen-ing for prediabetes, see pp. S17–S18(“Screening and Testing for Type 2 Di-abetes and Prediabetes in Asymptom-atic Adults” and “Screening and Testingfor Type 2 Diabetes and Prediabetes inChildren and Adolescents”).

TYPE 1 DIABETES

Recommendations

c Bloodglucose rather thanA1C shouldbe used to diagnose the acute onsetof type 1 diabetes in individuals withsymptoms of hyperglycemia. E

c Screening for type 1 diabetes with apanel of autoantibodies is currentlyrecommended only in the settingof a research trial or in first-degreefamily members of a proband withtype 1 diabetes. B

c Persistence of two or more autoan-tibodies predicts clinical diabetes

and may serve as an indication forintervention in the setting of a clini-cal trial. Outcomes may include re-version of autoantibody status,prevention of glycemic progressionwithin the normal or prediabetesrange, prevention of clinical diabe-tes, or preservation of residualC-peptide secretion. A

DiagnosisIn a patient with classic symptoms, mea-surement of blood glucose is sufficientto diagnose diabetes (symptoms of hy-perglycemia or hyperglycemic crisisplus a random plasma glucose $200mg/dL [11.1 mmol/L]). In these cases,knowing the blood glucose level is criti-cal because, in addition to confirmingthat symptoms are due to diabetes, itwill inform management decisions.Some providers may also want to knowthe A1C to determine how long a patienthas had hyperglycemia.

Immune-Mediated DiabetesThis form, previously called “insulin-dependent diabetes” or “juvenile-onsetdiabetes,” accounts for 5–10% of diabe-tes and is due to cellular-mediated au-toimmune destruction of the pancreaticb-cells. Autoimmunemarkers include is-let cell autoantibodies and autoanti-bodies to GAD (GAD65), insulin, thetyrosine phosphatases IA-2 and IA-2b,and ZnT8. Type 1 diabetes is definedby the presence of one or more of theseautoimmune markers. The disease hasstrong HLA associations, with linkageto the DQA and DQB genes. TheseHLA-DR/DQ alleles can be either predis-posing or protective.

The rate of b-cell destruction is quitevariable, being rapid in some individuals(mainly infants and children) and slow inothers (mainly adults). Children and ado-lescents may present with ketoacidosis asthe first manifestation of the disease.Others havemodest fasting hyperglycemia

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults1. Testing should be considered in overweight or obese (BMI$25 kg/m2 or$23 kg/m2 in Asian

Americans) adults who have one or more of the following risk factors:c A1C $5.7% (39 mmol/mol), IGT, or IFG on previous testingc first-degree relative with diabetesc high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American,Pacific Islander)

c women who were diagnosed with GDMc history of CVDc hypertension ($140/90 mmHg or on therapy for hypertension)c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL(2.82 mmol/L)

c women with polycystic ovary syndromec physical inactivityc other clinical conditions associatedwith insulin resistance (e.g., severe obesity, acanthosisnigricans).

2. For all patients, testing should begin at age 45 years.

3. If results are normal, testing should be repeated at a minimum of 3-year intervals, withconsideration of more frequent testing depending on initial results (e.g., those withprediabetes should be tested yearly) and risk status.

Table 2.4—Categories of increased risk for diabetes (prediabetes)*FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG)

OR

2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT)

OR

A1C 5.726.4% (39247 mmol/mol)

*For all three tests, risk is continuous, extending below the lower limit of the range andbecoming disproportionately greater at the higher end of the range.

S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

that can rapidly change to severe hyper-glycemia and/or ketoacidosis with infec-tion or other stress. Adults may retainsufficient b-cell function to prevent

ketoacidosis for many years; such indi-viduals eventually become dependenton insulin for survival and are at risk forketoacidosis. At this latter stage of the

disease, there is little or no insulin secre-tion, asmanifested by lowor undetectablelevelsofplasmaC-peptide. Immune-mediateddiabetes commonly occurs in childhood

Figure 2.1—ADA risk test.

care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

and adolescence, but it can occur at anyage, even in the 8th and9th decades of life.Autoimmune destruction of b-cells

has multiple genetic predispositionsand is also related to environmental fac-tors that are still poorly defined. Al-though patients are not typically obesewhen they present with type 1 diabetes,obesity should not preclude the diag-nosis. Patients with type 1 diabetes arealso prone to other autoimmune disor-ders such as Hashimoto thyroiditis,Graves disease, Addison disease, celiacdisease, vitiligo, autoimmune hepatitis,myasthenia gravis, and pernicious ane-mia (see Section 3 “ComprehensiveMedical Evaluation and Assessment ofComorbidities”).

Idiopathic Type 1 DiabetesSome forms of type 1 diabetes have noknown etiologies. These patients havepermanent insulinopenia and are proneto ketoacidosis, but have no evidence ofb-cell autoimmunity. Although only aminority of patients with type 1 diabetesfall into this category, of those who do,most are of African or Asian ancestry.Individuals with this form of diabetessuffer from episodic ketoacidosis andexhibit varying degrees of insulin defi-ciency between episodes. This form ofdiabetes is strongly inherited and is notHLA associated. An absolute requirementfor insulin replacement therapy in affectedpatients may be intermittent.

Testing for Type 1 Diabetes RiskThe incidence and prevalence of type 1diabetes is increasing (23). Patients withtype 1 diabetes often present with acutesymptoms of diabetes and markedly el-evated blood glucose levels, and ap-proximately one-third are diagnosedwith life-threatening ketoacidosis (3).Several studies indicate that measuringislet autoantibodies in relatives of thosewith type 1 diabetes may identify indi-viduals who are at risk for developingtype 1 diabetes (5). Such testing, cou-pled with education about diabetessymptoms and close follow-up, may en-able earlier identification of type 1 di-abetes onset. A study reported the riskof progression to type 1 diabetes fromthe time of seroconversion to autoanti-body positivity in three pediatric co-horts from Finland, Germany, and theU.S. Of the 585 children who developedmore than two autoantibodies, nearly

70% developed type 1 diabetes within10 years and 84% within 15 years (24).These findings are highly significantbecause, while the German group wasrecruited from offspring of parents withtype 1 diabetes, the Finnish and Americangroups were recruited from the generalpopulation. Remarkably, the findings inall three groupswere the same, suggestingthat the same sequence of events led toclinical disease in both “sporadic” and fa-milial cases of type 1 diabetes. Indeed, therisk of type 1 diabetes increases as thenumber of relevant autoantibodies de-tected increases (25–27).

Although there is currently a lack ofaccepted screening programs, one shouldconsider referring relatives of those withtype 1 diabetes for antibody testing forrisk assessment in the setting of a clinicalresearch study (http://www.diabetestrialnet.org). Widespread clinical testing ofasymptomatic low-risk individuals is notcurrently recommended due to lack ofapproved therapeutic interventions. In-dividuals who test positive will be coun-seled about the risk of developingdiabetes, diabetes symptoms, and DKAprevention. Numerous clinical studiesare being conducted to test variousmethods of preventing type 1 diabetesin those with evidence of autoimmunity(www.clinicaltrials.gov).

TYPE 2 DIABETES

Recommendations

c Screening for type 2 diabetes withan informal assessment of risk fac-tors or validated tools shouldbe con-sidered in asymptomatic adults. B

c Testing for type 2 diabetes in asymp-tomatic people should be consideredin adults of any age who are over-weight or obese (BMI $25 kg/m2

or $23 kg/m2 in Asian Americans)andwhohaveoneormoreadditionalrisk factors for diabetes. B

c For all people, testing should be-gin at age 45 years. B

c If tests are normal, repeat testingcarried out at a minimum of 3-yearintervals is reasonable. C

c To test for type 2 diabetes, fastingplasma glucose, 2-h plasma glucoseafter 75-g oral glucose tolerance test,and A1C are equally appropriate. B

c In patientswithdiabetes, identify andtreat other cardiovascular diseaserisk factors. B

c Testing for type 2 diabetes shouldbe considered in children and ado-lescents who are overweight orobese andwhohave twoormore ad-ditional risk factors for diabetes. E

DescriptionType 2 diabetes, previously referred toas “noninsulin-dependent diabetes” or“adult-onset diabetes,” accounts for90–95% of all diabetes. This form en-compasses individuals who have relative(rather than absolute) insulin deficiencyand have peripheral insulin resistance. Atleast initially, and often throughout theirlifetime, these individuals may not needinsulin treatment to survive.

There are various causes of type 2 di-abetes. Although the specific etiologiesare not known, autoimmune destruc-tion of b-cells does not occur, and pa-tients do not have any of the otherknown causes of diabetes. Most, butnot all, patients with type 2 diabetesare overweight or obese. Excess weightitself causes some degree of insulin re-sistance. Patients who are not obese oroverweight by traditional weight criteriamay have an increased percentage ofbody fat distributed predominantly inthe abdominal region.

Ketoacidosis seldom occurs sponta-neously in type 2 diabetes; when seen,it usually arises in association with thestress of another illness such as infec-tion. Type 2 diabetes frequently goesundiagnosed for many years becausehyperglycemia develops gradually and,at earlier stages, is often not severeenough for the patient to notice theclassic diabetes symptoms. Neverthe-less, even undiagnosed patients are atincreased risk of developing macrovas-cular and microvascular complications.

Whereas patients with type 2 diabe-tes may have insulin levels that appearnormal or elevated, the higher bloodglucose levels in these patients wouldbe expected to result in even higher in-sulin values had their b-cell functionbeen normal. Thus, insulin secretion isdefective in these patients and insuffi-cient to compensate for insulin resis-tance. Insulin resistance may improve withweight reduction and/or pharmacologicaltreatment of hyperglycemia but is seldomrestored to normal.

The risk of developing type 2 diabetesincreases with age, obesity, and lack of

S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

physical activity. It occurs more fre-quently in women with prior GDM, inthose with hypertension or dyslipide-mia, and in certain racial/ethnic sub-groups (African American, AmericanIndian,Hispanic/Latino, andAsianAmerican).It is often associated with a stronggenetic predisposition, more so thantype 1 diabetes. However, the geneticsof type 2 diabetes is poorly understood.In adults without traditional risk factorsfor type 2 diabetes and/or younger age,consider antibody testing for type 1 di-abetes (i.e., GAD).

Screening and Testing for Type 2Diabetes and Prediabetes inAsymptomatic AdultsScreening for prediabetes and type 2 di-abetes through an informal assessmentof risk factors (Table 2.3) or with an as-sessment tool, such as the ADA risk test(Fig. 2.1), is recommended to guide pro-viders on whether performing a diag-nostic test (Table 2.2) is appropriate.Prediabetes and type 2 diabetes meetcriteria for conditions in which early de-tection is appropriate. Both conditionsare common and impose significant clin-ical and public health burdens. There isoften a long presymptomatic phase be-fore the diagnosis of type 2 diabetes.Simple tests to detect preclinical diseaseare readily available. The duration ofglycemic burden is a strong predictorof adverse outcomes. There are effec-tive interventions that prevent progres-sion from prediabetes to diabetes (seeSection 5 “Prevention or Delay of Type 2Diabetes”) and reduce the risk of diabe-tes complications (see Section 9 “Cardio-vascular Disease and Risk Management”and Section 10 “Microvascular Complica-tions and Foot Care”).Approximately one-quarter of people

with diabetes in the U.S. and nearly halfof Asian and Hispanic Americans withdiabetes are undiagnosed (28). Althoughscreening of asymptomatic individuals toidentify thosewithprediabetesordiabetesmight seem reasonable, rigorous clinicaltrials to prove the effectiveness of suchscreening have not been conducted andare unlikely to occur.A large European randomized con-

trolled trial compared the impact ofscreening for diabetes and intensivemultifactorial intervention with that ofscreening and routine care (29). Generalpractice patients between the ages of

40 and 69 years were screened for di-abetes and randomly assigned by prac-tice to intensive treatment of multiplerisk factors or routine diabetes care. Af-ter 5.3 years of follow-up, CVD risk fac-tors were modestly but significantlyimproved with intensive treatmentcompared with routine care, but the in-cidence of first CVD events or mortalitywas not significantly different betweenthe groups (29). The excellent care pro-vided to patients in the routine caregroup and the lack of an unscreenedcontrol arm limited the authors’ abilityto determine whether screening andearly treatment improved outcomescompared with no screening and latertreatment after clinical diagnoses. Com-puter simulation modeling studies sug-gest that major benefits are likely toaccrue from the early diagnosis and treat-ment of hyperglycemia and cardiovas-cular risk factors in type 2 diabetes(30); moreover, screening, beginningat age 30 or 45 years and independentof risk factors, may be cost-effective(,$11,000 per quality-adjusted life-yeargained) (31).

Additional considerations regardingtesting for type 2 diabetes and predia-betes in asymptomatic patients includethe following.

Age

Screening recommendations for diabe-tes in asymptomatic adults are listed inTable 2.3. Age is a major risk factor fordiabetes. Testing should begin at age45 years for all patients. Screeningshould be considered in overweight orobese adults of any age with one ormore risk factors for diabetes.

BMI and Ethnicity

In general, BMI $25 kg/m2 is a risk fac-tor for diabetes. Data and recommenda-tions from the ADA position statement“BMI Cut Points to Identify At-RiskAsian Americans for Type 2 DiabetesScreening” (32,33) suggest that theBMI cut point should be lower for theAsian American population. The BMI cutpoints fall consistently between 23 and24 kg/m2 (sensitivity of 80%) for nearlyall Asian American subgroups (with levelsslightly lower for Japanese Americans).This makes a rounded cut point of23 kg/m2 practical. In determining a sin-gle BMI cut point, it is important to bal-ance sensitivity and specificity so as toprovide a valuable screening tool without

numerous false positives. An argumentcan be made to push the BMI cut pointto lower than 23 kg/m2 in favor of in-creased sensitivity; however, this wouldlead to an unacceptably low specificity(13.1%). Data from the WHO also suggestthat a BMI of$23 kg/m2 should be usedto define increased risk in Asian Ameri-cans (34). The finding that half of diabe-tes in Asian Americans is undiagnosedsuggests that testing is not occurring atlower BMI thresholds (28).

Evidence also suggests that otherpopulations may benefit from lowerBMI cut points. For example, in a largemultiethnic cohort study, for an equiva-lent incidence rate of diabetes, a BMI of30 kg/m2 in non-Hispanic whites wasequivalent to a BMI of 26 kg/m2 in Afri-can Americans (35).

Medications

Certain medications, such as glucocorti-coids, thiazide diuretics, and atypical an-tipsychotics (36), are known to increasethe risk of diabetes and should be consid-ered when deciding whether to screen.

Testing Interval

The appropriate interval betweenscreening tests is not known (37). Therationale for the 3-year interval is thatwith this interval, the number of false-positive tests that require confirmatorytesting will be reduced and individualswith false-negative tests will be retestedbefore substantial time elapses andcomplications develop (37).

Community Screening

Ideally, testing should be carried outwithin a health care setting because ofthe need for follow-up and treatment.Community screening outside a healthcare setting is not recommended be-cause people with positive tests maynot seek, or have access to, appropriatefollow-up testing and care. Communitytesting may also be poorly targeted; i.e.,it may fail to reach the groups most atrisk and inappropriately test those atvery low risk or even those who havealready been diagnosed (38).

Screening in Dental Practices

Because periodontal disease is associ-ated with diabetes, the utility of chair-side screening and referral to primarycare as a means to improve the diagno-sis of prediabetes and diabetes has beenexplored (39–41), with one study esti-mating that 30% of patients $30 years

care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

of age seen in general dental practiceshad dysglycemia (41). Further researchis needed to demonstrate the feasibility,effectiveness, and cost-effectiveness ofscreening in this setting.

Screening and Testing for Type 2Diabetes and Prediabetes in Childrenand AdolescentsIn the last decade, the incidence andprevalence of type 2 diabetes in ado-lescents has increased dramatically,especially in racial and ethnic minoritypopulations (23). Recent studies ques-tion the validity of A1C in the pediatricpopulation, especially among certainethnicities, and suggest OGTT or FPGas more suitable diagnostic tests (42).However, many of these studies do notrecognize that diabetes diagnostic crite-ria are based on long-term health out-comes, and validations are not currentlyavailable in the pediatric population(43). The ADA acknowledges the limiteddata supporting A1C for diagnosingtype 2 diabetes in children and adoles-cents. Although A1C is not recom-mended for diagnosis of diabetes inchildren with cystic fibrosis or symptomssuggestive of acute onset of type 1 di-abetes and only A1C assays withoutinterference are appropriate for childrenwith hemoglobinopathies, the ADA con-tinues to recommend A1C for diagnosisof type 2 diabetes in this cohort (44,45).The modified recommendations of theADA consensus report “Type 2 Diabetesin Children and Adolescents” are sum-marized in Table 2.5 (46).

GESTATIONAL DIABETESMELLITUS

Recommendations

c Test for undiagnosed diabetes atthe first prenatal visit in thosewith risk factors, using standarddiagnostic criteria. B

c Test for gestational diabetes mel-litus at 24–28 weeks of gestationin pregnant women not previouslyknown to have diabetes. A

c Test women with gestational dia-betes mellitus for persistent dia-betes at 4–12 weeks’ postpartum,using the oral glucose tolerancetest and clinically appropriatenonpregnancy diagnostic crite-ria. E

c Women with a history of gesta-tional diabetes mellitus should

have lifelong screening for the de-velopment of diabetes or predia-betes at least every 3 years. B

c Womenwith a history of gestationaldiabetes mellitus found to have pre-diabetes should receive intensivelifestyle interventions or metforminto prevent diabetes. A

DefinitionFor many years, GDM was defined asany degree of glucose intolerance thatwas first recognized during pregnancy(17), regardless of whether the condi-tion may have predated the pregnancyor persisted after the pregnancy. Thisdefinition facilitated a uniform strategyfor detection and classification of GDM,but it was limited by imprecision.

The ongoing epidemic of obesity anddiabetes has led to more type 2 diabetesin women of childbearing age, with anincrease in the number of pregnantwomen with undiagnosed type 2 diabe-tes (47). Because of the number of preg-nant women with undiagnosed type 2diabetes, it is reasonable to test womenwith risk factors for type 2 diabetes(Table 2.3) at their initial prenatal visit,using standard diagnostic criteria (Table2.2). Women diagnosed with diabetes inthe first trimester should be classified ashaving preexisting pregestational diabe-tes (type 2 diabetes or, very rarely,type 1 diabetes). GDM is diabetes thatis first diagnosed in the second or thirdtrimester of pregnancy that is not clearlyeither preexisting type 1 or type 2 dia-betes (see Section 13 “Management ofDiabetes in Pregnancy”). The Interna-tional Association of the Diabetes andPregnancy Study Groups (IADPSG)GDM diagnostic criteria for the 75-g

OGTT were not derived from data inthe first half of pregnancy, so the diag-nosis of GDM in early pregnancy by ei-ther FPG or OGTT values is not evidencebased (48).

DiagnosisGDM carries risks for the mother andneonate. Not all adverse outcomes areof equal clinical importance. The Hyper-glycemia and Adverse Pregnancy Out-come (HAPO) study (49), a large-scalemultinational cohort study completedby more than 23,000 pregnant women,demonstrated that risk of adverse ma-ternal, fetal, and neonatal outcomescontinuously increased as a function ofmaternal glycemia at 24–28weeks, evenwithin ranges previously considerednormal for pregnancy. For most compli-cations, there was no threshold for risk.These results have led to careful recon-sideration of the diagnostic criteria forGDM. GDM diagnosis (Table 2.6) canbe accomplished with either of twostrategies:

1. “One-step” 75-g OGTT or2. “Two-step” approach with a 50-g

(nonfasting) screen followed by a100-g OGTT for those who screenpositive

Different diagnostic criteria will identifydifferent degrees of maternal hypergly-cemia and maternal/fetal risk, leadingsome experts to debate, and disagreeon, optimal strategies for the diagnosisof GDM.

One-Step Strategy

In the 2011 Standards of Care (50), theADA for the first time recommendedthat all pregnant women not known tohave prior diabetes undergo a 75-g

Table 2.5—Testing for type 2 diabetes or prediabetes in asymptomatic children* (46)Criteria

cOverweight (BMI.85th percentile for age and sex, weight for height.85th percentile, orweight .120% of ideal for height)

Plus any two of the following risk factors:c Family history of type 2 diabetes in first- or second-degree relativec Race/ethnicity (Native American, African American, Latino, Asian American, PacificIslander)

c Signs of insulin resistance or conditions associated with insulin resistance (acanthosisnigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight)

c Maternal history of diabetes or GDM during the child’s gestation

Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age

Frequency: every 3 years

*Persons aged #18 years.

S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

OGTT at 24–28 weeks of gestation,based on a recommendation of theIADPSG (51). The IADPSG defined diag-nostic cut points for GDM as the averagefasting, 1-h, and 2-h plasma glucose val-ues in the HAPO study at which odds foradverse outcomes reached 1.75 timesthe estimated odds of these outcomesat themean fasting, 1-h, and 2-h PG levelsof the study population. This one-stepstrategy was anticipated to signifi-cantly increase the incidence of GDM(from 5–6% to 15–20%), primarily be-cause only one abnormal value, nottwo, became sufficient to make the di-agnosis. The ADA recognized that theanticipated increase in the incidence ofGDM would have a substantial impacton costs and medical infrastructureneeds and had the potential to “medi-calize” pregnancies previously catego-rized as normal. Nevertheless, the ADArecommended these changes in diag-nostic criteria with the intent of optimiz-ing gestational outcomes because thesecriteria were the only ones based onpregnancy outcomes rather than endpoints such as prediction of subsequentmaternal diabetes.The expected benefits to the offspring

are inferred from intervention trials thatfocused on women with lower levels ofhyperglycemia than identified using

older GDM diagnostic criteria. Those tri-als found modest benefits including re-duced rates of large-for-gestational-agebirths and preeclampsia (52,53). It is im-portant to note that 80–90% of womenbeing treated for mild GDM in two ran-domized controlled trials could be man-aged with lifestyle therapy alone. TheOGTT glucose cutoffs in these two trialsoverlapped with the thresholds recom-mended by the IADPSG, and in one trial(53), the 2-h PG threshold (140 mg/dL[7.8 mmol/L]) was lower than the cutoffrecommended by the IADPSG (153 mg/dL[8.5 mmol/L]). No randomized con-trolled trials of identifying and treatingGDM using the IADPSG criteria versusolder criteria have been published todate. Data are also lacking on how thetreatment of lower levels of hyperglyce-mia affects a mother’s future risk for thedevelopment of type 2 diabetes and heroffspring’s risk for obesity, diabetes, andother metabolic disorders. Additionalwell-designed clinical studies are neededto determine the optimal intensity ofmonitoring and treatment of womenwith GDM diagnosed by the one-stepstrategy.

Two-Step Strategy

In 2013, the National Institutes of Health(NIH) convened a consensus develop-ment conference to consider diagnostic

criteria for diagnosing GDM (54). The15-member panel had representativesfrom obstetrics/gynecology, maternal-fetal medicine, pediatrics, diabetes re-search, biostatistics, and other relatedfields. The panel recommended a two-step approach to screening that used a1-h 50-g glucose load test (GLT) fol-lowed by a 3-h 100-g OGTT for thosewho screened positive. Commonlyused cutoffs for the 1-h 50-g GLT include130, 135, and 140 mg/dL (7.2, 7.5, and7.8 mmol/L). The American College ofObstetricians and Gynecologists (ACOG)recommends either 135 or 140 mg/dL(45). A systematic review for the U.S. Pre-ventive Services Task Force comparedGLT cutoffs of 130 mg/dL (7.2 mmol/L)and 140 mg/dL (7.8 mmol/L) (55). Thehigher cutoff yielded sensitivity of70–88% and specificity of 69–89%,while the lower cutoff was 88–99%sensitive and 66–77% specific. Dataregarding a cutoff of 135 mg/dL are lim-ited. As for other screening tests, choiceof a cutoff is based upon the tradeoff be-tween sensitivity and specificity. The useof A1C at 24–28 weeks as a screening testfor GDM does not function as well as theGLT (56).

Key factors cited by the NIH panel intheir decision-making process werethe lack of clinical trial data demon-strating the benefits of the one-stepstrategy and the potential negative con-sequences of identifying a large group ofwomenwith GDM, includingmedicaliza-tion of pregnancy with increased healthcare utilization and costs. Moreover,screening with a 50-g GLT does not re-quire fasting and is therefore easier toaccomplish for many women. Treatmentof higher threshold maternal hypergly-cemia, as identified by the two-stepapproach, reduces rates of neonatalmacrosomia, large-for-gestational-agebirths (57), and shoulder dystocia, with-out increasing small-for-gestational-agebirths. ACOG updated its guidelines in2013 and supported the two-step ap-proach (58). The ACOG recommends ei-ther of two sets of diagnostic thresholdsfor the 3-h 100-g OGTT (59,60). Each isbased on different mathematical con-versions of the original recommendedthresholds, which used whole bloodand nonenzymatic methods for glucosedetermination. A recent secondary anal-ysis of data from a randomized clinicaltrial of identification and treatment of

Table 2.6—Screening for and diagnosis of GDMOne-step strategyPerform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and

2 h, at 24228 weeks of 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 of GDM is made when any of the following plasma glucose values are met or

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)

Two-step strategyStep 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28

weeks of gestation in women not previously diagnosed with overt diabetes.If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or

140 mg/dL* (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT.Step 2: The 100-g OGTT should be performed when the patient is fasting.The diagnosis of GDM is made if at least two of the following four plasma glucose levels

(measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded:

Carpenter/Coustan (59) or NDDG (60)

c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L)c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L)c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L)c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L)

NDDG, National Diabetes Data Group. *The ACOG recommends either 135 mg/dL (7.5 mmol/L)or 140 mg/dL (7.8 mmol/L). A systematic review determined that a cutoff of 130 mg/dL(7.2 mmol/L) was more sensitive but less specific than 140 mg/dL (7.8 mmol/L) (55).

care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

mild GDM (61) demonstrated that treat-ment was similarly beneficial in patientsmeeting only the lower thresholds (59)and in those meeting only the higherthresholds (60). If the two-step approachis used, it would appear advantageous touse the lower diagnostic thresholds asshown in Step 2 in Table 2.6.

Future Considerations

The conflicting recommendations fromexpert groups underscore the fact thatthere are data to support each strategy.A cost-benefit estimation comparing thetwo strategies concluded that the one-step approach is cost-effective only ifpatients with GDM receive postdeliverycounseling and care to prevent type 2diabetes (62). The decision of whichstrategy to implement must thereforebe made based on the relative valuesplaced on factors that have yet to bemeasured (e.g., willingness to changepractice based on correlation studiesrather than intervention trial results,available infrastructure, and importanceof cost considerations).As the IADPSG criteria (“one-step strat-

egy”) have been adopted internationally,further evidence has emerged to supportimproved pregnancy outcomes with costsavings (63) and may be the preferred ap-proach. Data comparing population-wideoutcomes with one-step versus two-stepapproaches have been inconsistent todate (64,65). In addition, pregnancies com-plicated by GDM per the IADPSG criteria,but not recognized as such, have compa-rable outcomes to pregnancies diag-nosed as GDM by the more stringenttwo-step criteria (66,67). There remainsstrong consensus that establishing a uni-form approach to diagnosing GDM willbenefit patients, caregivers, and policy-makers. Longer-term outcome studiesare currently under way.

MONOGENIC DIABETESSYNDROMES

Recommendations

c All children diagnosed with diabe-tes in the first 6 months of lifeshould have immediate genetictesting for neonatal diabetes. A

c Children and adults, diagnosed inearly adulthood, who have diabe-tes not characteristic of type 1 ortype 2 diabetes that occurs in suc-cessive generations (suggestive ofan autosomal dominant pattern of

inheritance) should have genetictesting for maturity-onset diabe-tes of the young. A

c In both instances, consultationwith a center specializing in diabetesgenetics is recommended to under-stand the significance of these mu-tations and how best to approachfurther evaluation, treatment, andgenetic counseling. E

Monogenic defects that cause b-celldysfunction, such as neonatal diabetesand MODY, represent a small fraction ofpatients with diabetes (,5%). Table 2.7describes the most common causes ofmonogenic diabetes. For a comprehen-sive list of causes, see Genetic Diagnosisof Endocrine Disorders (68).

Neonatal DiabetesDiabetes occurring under 6 months ofage is termed “neonatal” or “congeni-tal” diabetes, and about 80–85% ofcases can be found to have an underly-ing monogenic cause (69). Neonataldiabetes occurs much less often after6 months of age, whereas autoimmunetype 1 diabetes rarely occurs before6 months of age. Neonatal diabetescan either be transient or permanent.Transient diabetes is most often due tooverexpression of genes on chromo-some 6q24, is recurrent in about halfof cases, and may be treatable with med-ications other than insulin. Permanentneonatal diabetes is most commonlydue to autosomal dominant mutationsin the genes encoding the Kir6.2 subunit(KCNJ11) and SUR1 subunit (ABCC8) ofthe b-cell KATP channel. Correct diagnosishas critical implications because most pa-tients with KATP-related neonatal diabeteswill exhibit improved glycemic controlwhen treated with high-dose oral sulfo-nylureas instead of insulin. Insulin gene(INS) mutations are the second mostcommon cause of permanent neonataldiabetes, and, while treatment presentlyis intensive insulin management, thereare important genetic considerations asmost of the mutations that cause diabe-tes are dominantly inherited.

Maturity-Onset Diabetes of the YoungMODY is frequently characterized byonset of hyperglycemia at an earlyage (classically before age 25 years, al-though diagnosis may occur at older

ages). MODY is characterized by impairedinsulin secretion with minimal or no de-fects in insulin action (in the absence ofcoexistent obesity). It is inherited in an au-tosomal dominant pattern with abnormal-ities in at least 13 genes on differentchromosomes identified to date. Themost commonly reported forms are GCK-MODY (MODY2), HNF1A-MODY (MODY3),and HNF4A-MODY (MODY1).

Clinically, patients with GCK-MODYexhibit mild, stable, fasting hyperglyce-mia and do not require antihyperglyce-mic therapy except sometimes duringpregnancy. Patients with HNF1A- orHNF4A-MODY usually respond well tolow doses of sulfonylureas, which areconsidered first-line therapy. Mutationsor deletions in HNF1B are associatedwith renal cysts and uterine malforma-tions (renal cysts and diabetes [RCAD]syndrome). Other extremely rare formsof MODY have been reported to involveother transcription factor genes includ-ing PDX1 (IPF1) and NEUROD1.

DiagnosisA diagnosis of one of the three mostcommon forms of MODY including GCK-MODY, HNF1A-MODY, and HNF4A-MODYallows for more cost-effective therapy (notherapy for GCK-MODY; sulfonylureas asfirst-line therapy for HNF1A-MODY andHNF4A-MODY). Additionally, diagnosiscan lead to identification of other affectedfamily members.

A diagnosis of MODY should be con-sidered in individuals who have atypicaldiabetes and multiple family memberswith diabetes not characteristic oftype 1 or type 2 diabetes, although ad-mittedly “atypical diabetes” is becomingincreasingly difficult to precisely definein the absence of a definitive set of testsfor either type of diabetes. In mostcases, the presence of autoantibodiesfor type 1 diabetes precludes furthertesting for monogenic diabetes, but thepresence of autoantibodies in patientswith monogenic diabetes has been re-ported (70). Individuals in whom mono-genic diabetes is suspected should bereferred to a specialist for further eva-luation if available, and consultation isavailable from several centers. Readilyavailable commercial genetic testingfollowing the criteria listed below nowenables a cost-effective (71), oftencost-saving, genetic diagnosis that is in-creasingly supported by health insurance. It

S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

is critical to correctly diagnose one of themonogenic forms of diabetes becausethese patients may be incorrectly diag-nosed with type 1 or type 2 diabetes, lead-ing to suboptimal, evenpotentially harmful,treatment regimens and delays in diagnos-ing other family members (72). The infor-mation is especially critical for GCK-MODYmutations where multiple studies haveshown that no complications ensue inthe absence of glucose-lowering therapy(73). Genetic counseling is recommen-ded to ensure that affected individualsunderstand the patterns of inheritanceand the importanceof a correct diagnosis.The diagnosis of monogenic diabetes

should be considered in children andadults diagnosed with diabetes in earlyadulthood with the following findings:

○ Diabetes diagnosed within the first6 months of life (with occasionalcases presenting later, mostly INSand ABCC8 mutations) (69,74)

○ Diabetes without typical features oftype 1 or type 2 diabetes (negativediabetes–associated autoantibodies;nonobese, lacking other metabolic

features, especially with strong familyhistory of diabetes)

○ Stable, mild fasting hyperglycemia(100–150 mg/dL [5.5–8.5 mmol/L]),stable A1C between 5.6 and 7.6%(between 38 and 60 mmol/mol), espe-cially if nonobese

CYSTIC FIBROSIS–RELATEDDIABETES

Recommendations

c Annual screening for cystic fibrosis–related diabetes with oral glucosetolerance test should begin by age10 years in all patients with cystic fi-brosis not previously diagnosed withcystic fibrosis–related diabetes. B

c A1C as a screening test for cysticfibrosis–related diabetes is notrecommended. B

c Patients with cystic fibrosis–relateddiabetes should be treated with in-sulin to attain individualized glyce-mic goals. A

c Beginning 5 years after the diagnosisof cystic fibrosis–related diabetes,annual monitoring for complicationsof diabetes is recommended. E

Cystic fibrosis–related diabetes (CFRD) isthe most common comorbidity in peoplewith cystic fibrosis, occurring in about 20%of adolescents and 40–50% of adults. Di-abetes in this population, compared withindividuals with type 1 or type 2 diabetes,is associated with worse nutritional status,more severe inflammatory lung disease,and greater mortality. Insulin insufficiencyis the primary defect in CFRD. Geneticallydetermined b-cell function and insulin re-sistance associated with infection and in-flammation may also contribute to thedevelopment of CFRD. Milder abnormali-ties of glucose tolerance are even morecommon and occur at earlier ages thanCFRD.Whether individualswith IGT shouldbe treatedwith insulin replacementhasnotcurrently been determined. Althoughscreening for diabetes before the age of10 years can identify risk for progressionto CFRD in those with abnormal glucosetolerance, no benefit has been establishedwith respect to weight, height, BMI, orlung function. Continuous glucosemonitor-ing may be more sensitive than OGTT todetect risk for progression to CFRD; how-ever, evidence linking continuous glucose

Table 2.7—Most common causes of monogenic diabetes (68)

Gene Inheritance Clinical features

MODYGCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose;

typically does not require treatment; microvascular complications arerare; small rise in 2-h PG level on OGTT (,54 mg/dL [3 mmol/L])

HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation inadolescence or early adulthood; lowered renal threshold for glucosuria;large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive tosulfonylureas

HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation inadolescence or early adulthood; may have large birth weight andtransient neonatal hypoglycemia; sensitive to sulfonylureas

HNF1B AD HNF1B-MODY:developmental renaldisease (typicallycystic); genitourinaryabnormalities; atrophy of the pancreas; hyperuricemia; gout

Neonatal diabetesKCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures;

responsive to sulfonylureasINS AD Permanent: IUGR; insulin requiring

ABCC8 AD Transient or permanent: IUGR; rarely developmental delay; responsive tosulfonylureas

6q24(PLAGL1, HYMA1)

AD for paternalduplications

Transient: IUGR;macroglossia;umbilical hernia;mechanisms includeUPD6,paternal duplication or maternal methylation defect; may be treatablewith medications other than insulin

GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreaticexocrine insufficiency; insulin requiring

EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreaticexocrine insufficiency; insulin requiring

FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy, enteropathyX-linked (IPEX) syndrome: autoimmune diabetes; autoimmune thyroiddisease; exfoliative dermatitis; insulin requiring

AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction.

care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

monitoring results to long-term outcomesis lacking, and its use is not recommendedfor screening (75).CFRD mortality has significantly de-

creased over time, and the gap in mor-tality between cystic fibrosis patientswith and without diabetes has consider-ably narrowed (76). There are limitedclinical trial data on therapy for CFRD.The largest study compared three regi-mens: premeal insulin aspart, repagli-nide, or oral placebo in cystic fibrosispatients with diabetes or abnormal glu-cose tolerance. Participants all had weightloss in the year preceding treatment; how-ever, in the insulin-treated group, this pat-tern was reversed, and patients gained0.39 (6 0.21) BMI units (P 5 0.02). Therepaglinide-treated group had initialweight gain, but this was not sustainedby6months. Theplacebogroup continuedto lose weight (77). Insulin remains themost widely used therapy for CFRD (78).Recommendations for the clinical

management of CFRD can be found inthe ADA position statement “ClinicalCareGuidelines for Cystic Fibrosis–RelatedDiabetes: A Position Statement of theAmerican Diabetes Association and aClinical Practice Guideline of the CysticFibrosis Foundation, Endorsed by thePediatric Endocrine Society” (79).

POSTTRANSPLANTATIONDIABETES MELLITUS

Recommendations

c Patients should be screened afterorgan transplantation for hyper-glycemia, with a formal diagnosisof posttransplantation diabetesmellitus being best made once apatient is stable on an immuno-suppressive regimen and in the ab-sence of an acute infection. E

c The oral glucose tolerance test isthe preferred test to make a diag-nosis of posttransplantation dia-betes mellitus. B

c Immunosuppressive regimensshown toprovide thebest outcomesfor patient and graft survival shouldbe used, irrespective of posttrans-plantation diabetes mellitus risk. E

Several terms are used in the literatureto describe the presence of diabetes fol-lowing organ transplantation. “New-onset diabetes after transplantation”(NODAT) is one such designation that

describes individuals who developnew-onset diabetes following trans-plant. NODAT excludes patients withpretransplant diabetes that was undiag-nosed as well as posttransplant hyper-glycemia that resolves by the time ofdischarge (80). Another term, “posttrans-plantation diabetes mellitus” (PTDM)(80), describes the presence of diabetesin the posttransplant setting irrespectiveof the timing of diabetes onset.

Hyperglycemia is very common dur-ing the early posttransplant period,with;90% of kidney allograft recipientsexhibiting hyperglycemia in the firstfew weeks following transplant (80,81).In most cases, such stress or steroid-induced hyperglycemia resolves by thetime of discharge. Risk factors for PTDMinclude both general diabetes risks (suchas age, family history of diabetes, etc.)as well as transplant-specific factors,such as use of immunosuppressantagents. Whereas posttransplantationhyperglycemia is an important risk factorfor subsequent PTDM, a formal diagnosisof PTDM is optimally made once the pa-tient is stable on maintenance immuno-suppression and in the absence of acuteinfection.

The OGTT is considered the gold stan-dard test for the diagnosis of PTDM(80,82–84). However, screening patientsusing fasting glucose and/or A1C canidentify high-risk patients requiring fur-ther assessment and may reduce thenumber of overall OGTTs required (85).There is currently a lack of clinical dataexamining the use of antidiabetes agentsin the setting of PTDM to inform specificrecommendations for use in this popula-tion. Although the use of immunosup-pressive therapies is a major contributorto the development of PTDM, the risks oftransplant rejection outweigh the risks ofPTDM and the role of the diabetes careprovider is to treat hyperglycemia appro-priately regardless of the type of immuno-suppression (80).

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