2. Classification and Diagnosis ofDiabetes: Standards of MedicalCare in Diabetesd2020Diabetes Care 2020;43(Suppl. 1):S14–S31 | https://doi.org/10.2337/dc20-S002

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includestheADA’scurrentclinicalpracticerecommendationsandis intendedtoprovidethe components of diabetes care, general treatment goals and guidelines, and toolsto evaluate quality of care. Members of the ADA Professional Practice Committee(https://doi.org/10.2337/dc20-SPPC), a multidisciplinary expert committee, areresponsible for updating the Standards of Care annually, ormore frequently aswarranted.For a detailed description of ADA standards, statements, and reports, as well as theevidence-grading system for ADA’s clinical practice recommendations, please refer to theStandards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readerswhowish tocomment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

CLASSIFICATION

Diabetes can be classified into the following general categories:

1. Type1diabetes (due toautoimmuneb-cell destruction, usually leading toabsoluteinsulin deficiency)

2. Type 2 diabetes (due to a progressive loss of adequate b-cell insulin secretionfrequently on the background of insulin resistance)

3. Gestational diabetesmellitus (diabetes diagnosed in the second or third trimesterof pregnancy that was not clearly overt diabetes prior to gestation)

4. Specific typesofdiabetesdue toother causes, e.g.,monogenicdiabetes syndromes(such as neonatal diabetes andmaturity-onset diabetes of the young), diseases ofthe exocrine pancreas (such as cystic fibrosis and pancreatitis), 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) positionstatement “Diagnosis and Classification of Diabetes Mellitus” (1).

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinicalpresentation and disease progression may vary considerably. Classification isimportant for determining therapy, but some individuals cannot be clearly classifiedas having 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 age-groups. Children with type 1diabetes typically present with the hallmark symptoms of polyuria/polydipsia, andapproximately one-third present with diabetic ketoacidosis (DKA) (2). The onset oftype 1 diabetes may bemore variable in adults; they may not present with the classic

Suggested citation: American Diabetes Associa-tion. 2. Classification and diagnosis of diabetes:Standards of Medical Care in Diabetesd2020.Diabetes Care 2020;43(Suppl. 1):S14–S31

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American Diabetes Association

S14 Diabetes Care Volume 43, Supplement 1, January 2020

2.CLA

SSIFICATIONANDDIAGNOSISOFDIABETES

symptoms seen in children and may expe-rience temporary remission from the needfor insulin (3–5). Occasionally, patientswith type 2 diabetes may present withDKA (6), particularly ethnic minorities (7).It is important for the provider to realizethat classification of diabetes type is notalways straightforward at presentation andthat misdiagnosis is common (e.g., adultswith type 1 diabetes misdiagnosed as hav-ing type 2 diabetes; individuals with matu-rity-onset diabetes of the young [MODY]misdiagnosed as having type 1 diabetes,etc.). Although difficulties in distinguish-ing diabetes type may occur in all age-groups at onset, the diagnosis becomesmore obvious over time.In both type 1 and type 2 diabetes,

various genetic and environmental fac-tors can result in the progressive loss ofb-cell mass and/or function that mani-fests clinically as hyperglycemia. Oncehyperglycemia occurs, patients with allforms of diabetes are at risk for devel-oping the same chronic complications,although rates of progressionmay differ.The identification of individualized ther-apies for diabetes in the future will re-quire better characterization of the manypaths tob-cell demise or dysfunction (8).Characterization of the underlying path-

ophysiology is more developed in type 1diabetes than in type 2 diabetes. It is nowclear from studies of first-degree relativesof patients with type 1 diabetes that thepersistent presence of two or more isletautoantibodies is an almost certain pre-dictor of clinical hyperglycemia and diabe-tes.Therateofprogression isdependentonthe age at first detection of autoantibody,numberofautoantibodies, autoantibodyspecificity, and autoantibody 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) and

serve as a framework for future researchand regulatory decision-making (8,9). Thereis debate as to whether slowly progressiveautoimmune diabetes with an adult onsetshould be termed latent autoimmune di-abetes in adults (LADA) or whether theclinical priority is awareness that slow auto-immuneb-cell destructionmeans theremaybe long duration of marginal insulin secre-tory capacity. For the purpose of this clas-sification, all forms of diabetes mediated byautoimmuneb-cell destruction are includedunder the rubric of type 1 diabetes.

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 in-sulin resistance, appears to be thecommon denominator. Characterizationof subtypes of this heterogeneous dis-order have been developed and vali-dated in Scandinavian and NorthernEuropean populations but have notbeen confirmed in other ethnic and ra-cial groups. Type 2 diabetes is associatedwith insulin secretory defects relatedto inflammation and metabolic stressamong other contributors, includinggenetic factors. Future classificationschemes for diabetes will likely focuson the pathophysiology of the underly-ing b-cell dysfunction (8,10,11).

DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based onplasma glucose criteria, either the fast-ing plasma glucose (FPG) value or the2-h plasma glucose (2-h PG) value duringa 75-g oral glucose tolerance test (OGTT),or A1C criteria (12) (Table 2.2).

Generally, FPG, 2-h PG during 75-gOGTT, and A1C are equally appropriatefor diagnostic screening. It should benoted that the tests do not necessarilydetect diabetes in the same individuals.The efficacy of interventions for primaryprevention of type 2 diabetes (13,14) has

mainly been demonstrated among indi-viduals who have impaired glucose tol-erance (IGT) with or without elevatedfasting glucose, not for individuals withisolated impaired fasting glucose (IFG)or for those with prediabetes definedby A1C criteria.

The same tests may be used to screenfor and diagnose diabetes and to detectindividuals with prediabetes (Table 2.2and Table 2.5). Diabetes may be identi-fied anywhere along the spectrum ofclinical scenariosdin seemingly low-risk individuals who happen to have glu-cosetesting, in individuals testedbasedondiabetes risk assessment, and in symp-tomatic patients.

Fasting and 2-Hour Plasma GlucoseThe FPG and 2-h PG may be used todiagnose diabetes (Table 2.2). The con-cordance between the FPG and 2-hPG tests is imperfect, as is the concor-dance between A1C and either glucose-based test. Compared with FPG andA1C cut points, the 2-h PG value di-agnoses more people with prediabe-tes and diabetes (15).

A1C

Recommendations

2.1 To avoid misdiagnosis or misseddiagnosis, the A1C test should beperformed using amethod that iscertified by the NGSP and stan-dardized to the Diabetes Controland Complications Trial (DCCT)assay. B

2.2 Marked discordance betweenmeasured A1C and plasma glu-cose levels should raise the pos-sibility of A1C assay interferencedue to hemoglobin variants (i.e.,hemoglobinopathies) and con-sideration of using an assay with-out interference or plasma blood

Table 2.1—Staging of type 1 diabetes (8,9)

Stage 1 Stage 2 Stage 3

Characteristics 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

care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

glucose criteria to diagnose di-abetes. B

2.3 In conditions associated with analtered relationship between A1Cand glycemia, such as sickle celldisease, pregnancy (second andthird trimesters and the postpar-tumperiod), glucose-6-phosphatedehydrogenase deficiency, HIV,hemodialysis, recent blood lossor transfusion, or erythropoietintherapy, only plasma blood glu-cose criteria should be used todiagnose diabetes. B

The A1C test should be performed usinga method that is certified by the NGSP(www.ngsp.org) and standardized ortraceable to the Diabetes Control andComplications Trial (DCCT) reference as-say. Although point-of-care A1C assaysmay be NGSP certified or U.S. Food andDrug Administration approved for diag-nosis, proficiency testing is not alwaysmandated forperforming the test. There-fore, point-of-care assays approved fordiagnostic purposes should only be con-sidered in settings licensed to performmoderate-to-high complexity tests. Asdiscussed in Section6 “Glycemic Targets”(https://doi.org/10.2337/dc20-S006),point-of-care A1C assays may be moregenerally applied for assessment of gly-cemic control in the clinic.A1C has several advantages com-

pared with FPG and OGTT, includinggreater convenience (fasting not re-quired), greater preanalytical stability,and less day-to-day perturbations duringstress, diet, or illness. However, theseadvantages may be offset by the lowersensitivity of A1C at the designated

cut point, greater cost, limited availabil-ity of A1C testing in certain regions ofthe developingworld, and the imperfectcorrelation between A1C and averageglucose in certain individuals. The A1Ctest, with a diagnostic threshold of$6.5% (48 mmol/mol), diagnoses only30% of the diabetes cases identified col-lectively using A1C, FPG, or 2-h PG, ac-cording to National Health and NutritionExamination Survey (NHANES) data (16).

When using A1C to diagnose diabetes,it is important to recognize that A1C isan indirect measure of average bloodglucose levels and to take other factorsinto consideration that may impact he-moglobin glycation independently ofglycemia, such as hemodialysis, preg-nancy, HIV treatment (17,18), age, race/ethnicity, pregnancy status, genetic back-ground, and anemia/hemoglobinopathies.(See OTHER CONDITIONS ALTERING THE RELATION-

SHIP OF A1C AND GLYCEMIA below for moreinformation.)

Age

The epidemiological studies that formedthe basis for recommending A1C todiagnose diabetes included only adultpopulations (16). However, recent ADAclinical guidance concluded that A1C,FPG, or 2-h PG can be used to test forprediabetesor type2diabetes in childrenand adolescents (see SCREENING AND TESTING

FOR PREDIABETES AND TYPE 2 DIABETES IN CHILDREN

AND ADOLESCENTS below for additional in-formation) (19).

Race/Ethnicity/Hemoglobinopathies

Hemoglobin variants can interferewith the measurement of A1C, al-though most assays in use in theU.S. are unaffected by the most com-mon variants. Marked discrepancies

between measured A1C and plasma glu-cose levels should prompt considerationthat the A1C assaymay not be reliable forthat individual. For patients with a hemo-globin variant but normal red blood cellturnover, such as thosewith the sickle celltrait, an A1C assay without interferencefromhemoglobin variants shouldbeused.An updated list of A1C assays with inter-ferences is available at www.ngsp.org/interf.asp.

African Americans heterozygous forthe common hemoglobin variant HbSmay have, for any given level of meanglycemia, lower A1C by about 0.3% thanthose without the trait (20). Another ge-netic variant, X-linked glucose-6-phosphatedehydrogenase G202A, carried by 11% ofAfrican Americans, was associated with adecrease in A1C of about 0.8% in homo-zygous men and 0.7% in homozygouswomen compared with those withoutthe variant (21).

Even in the absence of hemoglobinvariants, A1C levels may vary with race/ethnicity independently of glycemia(22–24). For example, African Americansmay have higher A1C levels than non-Hispanic whites with similar fasting andpostglucose load glucose levels (25), andA1C levels may be higher for a givenmeanglucose concentration when measuredwith continuous glucosemonitoring (26).Though conflicting data exists, AfricanAmericans may also have higher levels offructosamine and glycated albumin andlower levels of 1,5-anhydroglucitol, sug-gesting that their glycemic burden (par-ticularly postprandially) may be higher(27,28). The association of A1C with riskfor complications appears to be similarin African Americans and non-Hispanicwhites (29,30).

Other Conditions Altering the Relationship

of A1C and Glycemia

In conditions associated with increasedred blood cell turnover, such as sicklecell disease, pregnancy (second andthird trimesters), glucose-6-phosphatedehydrogenase deficiency (31,32), he-modialysis, recent blood loss or trans-fusion, or erythropoietin therapy, onlyplasma blood glucose criteria should beused to diagnose diabetes (33). A1C isless reliable than blood glucose mea-surement in other conditions such asthe postpartum state (34–36), HIVtreated with certain drugs (17), andiron-deficient anemia (37).

Table 2.2—Criteria for the diagnosis of diabetes

FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*

OR

2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. 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).

DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucosetolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence ofunequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample orin two separate test samples.

S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

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 [11.1mmol/L]), diagnosis requirestwo abnormal test results from the samesample (38) or in two separate testsamples. If using two separate test sam-ples, it is recommended that the secondtest, which may either be a repeat of theinitial test or a different test, be per-formedwithoutdelay. For example, if theA1C is 7.0% (53 mmol/mol) and a repeatresult is 6.8% (51 mmol/mol), the di-agnosis of diabetes is confirmed. If twodifferent tests (such as A1C and FPG) areboth above the diagnostic thresholdwhen analyzed from the same sampleor in two different test samples, this alsoconfirms the diagnosis. On the otherhand, if a patient has discordant resultsfrom two different tests, then the testresult that is above the diagnostic cutpoint should be repeated, with consid-eration of the possibility of A1C assayinterference. The diagnosis is made onthe basis of the confirmed test. Forexample, if a patient meets the diabetescriterion of the A1C (two results$6.5%[48 mmol/mol]) but not FPG (,126mg/dL [7.0 mmol/L]), that person shouldnevertheless be considered to havediabetes.All the tests have preanalytic and

analytic variability, so it is possiblethat an abnormal result (i.e., abovethe diagnostic threshold), when re-peated, will produce a value belowthe diagnostic cut point. This scenariois likely for FPG and 2-h PG if the glucosesamples remain at room temperatureand are not centrifuged promptly. Be-cause of the potential for preanalyticvariability, it is critical that samples forplasma glucose be spun and separatedimmediately after they are drawn. Ifpatients have test results near the mar-gins of the diagnostic threshold, thehealth care professional should discusssigns and symptoms with the patient andrepeat the test in 3–6 months.

DiagnosisIn a patient with classic symptoms,measurement of plasma glucose is suf-ficient to diagnose diabetes (symptomsof hyperglycemia or hyperglycemic crisisplus a random plasma glucose $200mg/dL [11.1 mmol/L]). In these cases,

knowing the plasma glucose level iscritical because, in addition to confirm-ing that symptoms are due to diabetes,it will inform management decisions.Some providers may also want to knowthe A1C to determine how long a patienthas had hyperglycemia. The criteria todiagnose diabetes are listed in Table 2.2.

TYPE 1 DIABETES

Recommendations

2.4 Screening for type 1 diabetes riskwith a panel of islet autoanti-bodies is currently recommendedin the setting of a research trial orcan be offered as an option forfirst-degree family members of aproband with type 1 diabetes. B

2.5 Persistence of autoantibodies isa risk factor for clinical diabetesandmayserve as an indication forintervention in the setting ofa clinical trial. B

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. Autoimmune markers includeislet cell autoantibodies and autoanti-bodies to GAD (GAD65), insulin, thetyrosine phosphatases IA-2 and IA-2b,and zinc transporter 8 (ZnT8). Numer-ous clinical studies are being conductedto test various methods of preventingtype 1 diabetes in those with evidenceof islet autoimmunity (www.clinicaltrials.gov). Stage 1 of type 1 diabetes is definedby the presence of two or more of theseautoimmune markers. The disease hasstrong HLA associations, with linkage tothe DQA and DQB genes. These HLA-DR/DQ alleles can be either predisposing orprotective (Table 2.1). There are importantgenetic considerations, as most of the mu-tations that cause diabetes are dominantlyinherited. The importance of genetic testingis in the genetic counseling that follows.Some mutations are associated with otherconditions, which then may prompt addi-tional screenings.

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 DKA as the firstmanifestationof thedisease.Othershave

modest fasting hyperglycemia that canrapidly change to severe hyperglycemiaand/or DKA with infection or other stress.Adults may retain sufficient b-cell func-tion to prevent DKA for many years; suchindividuals may have remission or de-creased insulin needs formonthsor yearsand eventually become dependent oninsulin for survival and are at risk for DKA(3–5,39,40). At this latter stage of thedisease, there is little or no insulin se-cretion, asmanifested by loworundetect-able levels of plasma C-peptide. Immune-mediated diabetes is the most commonform of diabetes in childhood and ado-lescence, but it canoccur at any age, evenin the 8th and 9th decades of life.

Autoimmune destruction of b-cellshas multiple genetic predispositionsand is also related to environmentalfactors that are still poorly defined. Al-though patients are not typically obesewhen they present with type 1 diabetes,obesity is increasingly common in thegeneral population and there is evidencethat it may also be a risk factor for type 1diabetes. As such, obesity should notpreclude the diagnosis. People withtype 1 diabetes are also prone to otherautoimmune disorders such as Hashi-moto thyroiditis, Graves disease, celiacdisease, Addison disease, vitiligo, auto-immune hepatitis, myasthenia gravis,and pernicious anemia (see Section4 “Comprehensive Medical Evaluationand Assessment of Comorbidities,”https://doi.org/10.2337/dc20-S004).

Idiopathic Type 1 DiabetesSome forms of type 1 diabetes have noknown etiologies. These patients have per-manent insulinopeniaandareprone toDKAbut have no evidence of b-cell autoimmu-nity. However, only a minority of patientswith type 1 diabetes fall into this category.Individuals with autoantibody-negativetype 1 diabetes of African or Asian ancestrymay suffer from episodic DKA and exhibitvarying degrees of insulin deficiency be-tween episodes. This form of diabetes isstrongly inheritedandisnotHLAassociated.An absolute requirement for insulin re-placement therapy in affected patientsmay be intermittent. Future research isneeded to determine the cause of b-celldestruction in this rare clinical scenario.

Screening for Type 1 Diabetes RiskThe incidence and prevalence of type 1diabetes is increasing (41). Patients with

care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

type 1 diabetes often present with acutesymptoms of diabetes and markedlyelevated blood glucose levels, and ap-proximately one-third are diagnosedwith life-threatening DKA (2). Multiplestudies indicate that measuring isletautoantibodies in individuals geneticallyat risk for type 1 diabetes (e.g., relativesof those with type 1 diabetes or indi-viduals from the general populationwith type 1 diabetes–associated geneticfactors) identifies individuals who maydevelop type 1 diabetes (9). Such testing,coupled with education about diabetessymptoms and close follow-up, may en-able earlier identification of type 1 di-abetes onset. A study reported the risk ofprogression to type 1 diabetes from thetime of seroconversion to autoantibodypositivity in three pediatric cohorts fromFinland, Germany, and the U.S. Of the585 children who developed more thantwo autoantibodies, nearly 70% devel-oped type 1 diabetes within 10 years and84%within 15 years (42). These findingsare highly significant because while theGerman group was recruited from off-spring of parents with type 1 diabetes,the Finnish and American groups wererecruited from the general population.Remarkably, the findings in all threegroups were the same, suggesting thatthe same sequenceof events led to clinicaldisease in both “sporadic” and familialcases of type 1 diabetes. Indeed, the riskof type 1 diabetes increases as the numberof relevant autoantibodies detected in-creases (43–45). In The Environmental De-terminants of Diabetes in the Young(TEDDY) study, type 1 diabetes devel-oped in 21% of 363 subjects with at leastone autoantibody at 3 years of age (46).Although there is currently a lack of

accepted screening programs, one shouldconsider referring relatives of those withtype 1 diabetes for islet autoantibodytesting for risk assessment in the set-ting of a clinical research study (see www.diabetestrialnet.org). Widespread clini-cal testing of asymptomatic low-risk in-dividuals is not currently recommendeddue to lack of approved therapeutic inter-ventions. Individuals who test positiveshould be counseled about the risk ofdeveloping diabetes, diabetes symptoms,and DKA prevention. Numerous clinicalstudies are being conducted to test vari-ousmethods of preventing type 1 diabetesin those with evidence of autoimmunity(see www.clinicaltrials.gov).

PREDIABETES AND TYPE2 DIABETES

Recommendations

2.6 Screening for prediabetes andtype 2 diabetes with an informalassessment of risk factors or val-idated tools should be consid-ered in asymptomatic adults. B

2.7 Testing for prediabetes and/ortype 2 diabetes in asymptomaticpeople should be considered inadults of any age with over-weight or obesity (BMI $25kg/m2 or $23 kg/m2 in AsianAmericans) andwhohaveone ormore additional risk factors fordiabetes (Table 2.3). B

2.8 Testing for prediabetes and/ortype 2 diabetes should be con-sidered in women planningpregnancy with overweight orobesity and/or who have one ormore additional risk factor fordiabetes (Table 2.3). C

2.9 For all people, testing shouldbegin at age 45 years. B

2.10 If tests arenormal, repeat testingcarried out at a minimum of3-year intervals is reasonable. C

2.11 To test for prediabetes and type2 diabetes, fasting plasma glu-cose, 2-h plasma glucose during75-g oral glucose tolerance test,and A1C are equally appropriate(Table 2.2 and Table 2.5). B

2.12 In patientswithprediabetes andtype 2 diabetes, identify andtreat other cardiovascular dis-ease risk factors. B

2.13 Risk-based screening for predia-betes and/or type 2 diabetesshould be considered after theonsetofpubertyorafter10yearsof age, whichever occurs earlier,in children and adolescents withoverweight (BMI$85th percen-tile) or obesity (BMI$95th per-centile) and who have one ormore risk factor for diabetes.(See Table 2.4 for evidence grad-ing of risk factors.)

Prediabetes“Prediabetes” is the term used for indi-vidualswhose glucose levels do notmeetthe criteria for diabetes but are too hightobeconsiderednormal (29,30). Patientswith prediabetes are defined by thepresence of IFG and/or IGT and/or A1C5.7–6.4% (39–47 mmol/mol) (Table 2.5).Prediabetes should not be viewed as aclinical entity in its own right but ratheras an increased risk for diabetes andcardiovascular disease (CVD). Criteriafor testing for diabetes or prediabetesin asymptomatic adults is outlined inTable 2.3. Prediabetes is associatedwith obesity (especially abdominal orvisceral obesity), dyslipidemia with hightriglycerides and/or low HDL choles-terol, and hypertension.

Diagnosis

IFG is defined as FPG levels between100 and 125 mg/dL (between 5.6 and6.9 mmol/L) (47,56) and IGT as 2-h PGduring 75-g OGTT levels between 140and 199 mg/dL (between 7.8 and 11.0mmol/L) (48). It should be noted that the

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults

1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in AsianAmericans) adults who have one or more of the following risk factors:

c First-degree relative with diabetesc High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American,Pacific Islander)

c 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 associated with insulin resistance (e.g., severe obesity, acanthosisnigricans)

2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.

3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years.

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

5. If results are normal, testing should be repeated at a minimum of 3-year intervals, withconsideration of more frequent testing depending on initial results and risk status.

CVD, cardiovascular disease; GDM, gestational diabetes mellitus.

S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

World Health Organization (WHO) andnumerous other diabetes organizationsdefine the IFG cutoff at 110 mg/dL(6.1 mmol/L).As with the glucose measures, several

prospective 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 individuals from16 cohort studies with a follow-up in-terval averaging 5.6 years (range 2.8–12years), those with A1C between 5.5% and6.0% (between 37 and 42 mmol/mol)had a substantially increased risk of di-abetes (5-year incidence from 9% to25%). Those with an A1C range of 6.0–6.5% (42–48 mmol/mol) had a 5-yearrisk of developing diabetes between 25%and 50% and a relative risk 20 timeshigher compared with A1C of 5.0%(31 mmol/mol) (49). In a community-based study of African American andnon-Hispanic white adults without dia-betes, baseline A1C was a stronger pre-dictor of subsequent diabetes andcardiovascular events than fasting glucose(50). Other analyses suggest that A1C of5.7% (39mmol/mol) or higher is associatedwith a diabetes risk similar to that of

the high-risk participants in the DiabetesPrevention Program (DPP) (51), and A1Cat baseline was a strong predictor ofthe development of glucose-defined di-abetes during the DPP and its follow-up(52). Hence, it is reasonable to consideran A1C range of 5.7–6.4% (39–47 mmol/mol) as identifying individuals with pre-diabetes. Similar to thosewith IFGand/orIGT, individuals with A1C of 5.7–6.4%(39–47 mmol/mol) should be informedof their increased risk for diabetes andCVD and counseled about effective strat-egies to lower their risks (see Section3 “Prevention or Delay of Type 2 Di-abetes,” https://doi.org/10.2337/dc20-S003). Similar to glucose measurements,the continuum of risk is curvilinear, so asA1C rises, the diabetes risk rises dispro-portionately (49). 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 2.5 summarizes the categoriesof prediabetes and Table 2.3 the cri-teria for prediabetes testing. The ADAdiabetes risk test is an additional op-tion for assessment to determine theappropriateness of testing for diabetesor prediabetes in asymptomatic adults.

(Fig. 2.1) (diabetes.org/socrisktest). Foradditional background regarding risk fac-tors and screening for prediabetes, seeSCREENING AND TESTING FOR PREDIABETES AND

TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS andalso SCREENING AND TESTING FOR PREDIABETES

AND TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS

below.

Type 2 DiabetesType 2 diabetes, previously referred toas “noninsulin-dependent diabetes” or“adult-onset diabetes,” accounts for 90–95% of all diabetes. This form encom-passes individuals who have relative(rather than absolute) insulin deficiencyandhave peripheral insulin resistance. Atleast initially, and often throughout theirlifetime, these individuals may not needinsulin treatment to survive.

There are various causes of type 2diabetes. Although the specific etiologiesare not known, autoimmune destructionof b-cells does not occur and patients donot have any of the other known causesof diabetes. Most but not all patients withtype 2 diabetes have overweight or obe-sity. Excess weight itself causes somedegreeof insulin resistance.Patientswhodo not have obesity or overweight bytraditional weight criteria may have anincreased percentage of body fat distrib-uted predominantly in the abdominalregion.

DKA seldom occurs spontaneously intype 2 diabetes; when seen, it usuallyarises in association with the stress ofanother illness such as infection or withthe use of certain drugs (e.g., cortico-steroids, atypical antipsychotics, andsodium–glucose cotransporter 2 in-hibitors) (53,54). Type 2 diabetes fre-quently goes undiagnosed for manyyears because hyperglycemia developsgradually and, at earlier stages, is oftennot severe enough for the patient tonotice the classic diabetes symptoms.Nevertheless, even undiagnosed pa-tients are at increased risk of develop-ing macrovascular and microvascularcomplications.

Whereas patients with type 2 diabetesmay have insulin levels that appear nor-mal or elevated, the higher blood glucoselevels in thesepatientswouldbeexpectedto result in even higher insulin values hadtheir b-cell function been normal. Thus,insulin secretion is defective in thesepatients and insufficient to compensatefor insulin resistance. Insulin resistance

Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in asymptomaticchildren and adolescents in a clinical setting (163)

Testing should be considered in youth* who have overweight ($85th percentile) or obesity($95th percentile)A andwho have one ormore additional risk factors based on the strengthof their association with diabetes:

cMaternal history of diabetes or GDM during the child’s gestation A

c Family history of type 2 diabetes in first- or second-degree relative A

c Race/ethnicity (Native American, African American, Latino, Asian American, PacificIslander) A

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

GDM,gestational diabetesmellitus. *After theonset of puberty or after 10 years of age,whicheveroccurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, or morefrequently if BMI is increasing, is recommended. Reports of type 2 diabetes before age 10 yearsexist, and this can be considered with numerous risk factors.

Table 2.5—Criteria defining prediabetes*

FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG)

OR

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

OR

A1C 5.7–6.4% (39–47 mmol/mol)

FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT,oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is continuous,extending below the lower limit of the range and becoming disproportionately greater at thehigher end of the range.

care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

may improve with weight reductionand/or pharmacologic treatment of hy-perglycemia but is seldom restored tonormal.The risk of developing type 2 diabetes

increases with age, obesity, and lack ofphysical activity. It occurs more fre-quently in women with prior gestationaldiabetes mellitus (GDM), in those withhypertension or dyslipidemia, and incertain racial/ethnic subgroups (AfricanAmerican, American Indian, Hispanic/Latino, and Asian American). It is oftenassociated with a strong genetic predis-position or family history in first-degreerelatives, more so than type 1 diabetes.However, the genetics of type 2 diabetesis poorly understood. In adults withouttraditional risk factors for type 2 diabetesand/or younger age, consider islet auto-antibody testing (e.g., GAD65 autoanti-bodies) to exclude the diagnosis oftype 1 diabetes.

Screening and Testing for Prediabetesand Type 2 Diabetes in AsymptomaticAdultsScreening for prediabetes and type 2diabetes risk through an informal assess-ment of risk factors (Table 2.3) or withan assessment tool, such as the ADA risktest (Fig. 2.1) (online at diabetes.org/socrisktest), is recommended to guideproviders on whether performing a di-agnostic test (Table 2.2) is appropriate.Prediabetes and type 2 diabetes meetcriteria for conditions in which earlydetection 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 3 “Prevention or Delay of Type 2Diabetes,” https://doi.org/10.2337/dc20-S003) and reduce the risk of diabetescomplications (see Section 10 “Cardiovas-cular Disease and Risk Management,”https://doi.org/10.2337/dc20-S010, andSection 11 “Microvascular Complicationsand Foot Care,” https://doi.org/10.2337/dc20-S011).Approximately one-quarter of people

with diabetes in the U.S. and nearly halfof Asian and Hispanic Americans with

diabetes are undiagnosed (47,56). Al-though screening of asymptomatic indi-viduals to identify those with prediabetesor diabetes might seem reasonable, rig-orous clinical trials to prove the effective-ness of such screening have not beenconducted and are unlikely to occur.Based on a population estimate, diabe-tes in women of childbearing age isunderdiagnosed. Employing a probabi-listic model, Peterson et al. (57) dem-onstrated cost and health benefits ofpreconception screening.

A large European randomized con-trolled trial compared the impact ofscreening for diabetes and intensivemultifactorial intervention with that ofscreening and routine care (55). Generalpractice patients between the ages of40 and 69 years were screened for di-abetes and randomly assigned by prac-tice to intensive treatment of multiplerisk factors or routine diabetes care.After 5.3 years of follow-up, CVD riskfactors were modestly but significantlyimproved with intensive treatmentcompared with routine care, but theincidence of first CVD events or mortal-ity was not significantly different be-tween the groups (48). The excellentcare provided to patients in the routinecare group and the lack of an un-screened control arm limited the au-thors’ ability to determine whetherscreening and early treatment im-proved outcomes compared with noscreening and later treatment afterclinical diagnoses. Computer simula-tion modeling studies suggest thatmajor benefits are likely to accruefrom the early diagnosis and treat-ment of hyperglycemia and cardiovas-cular risk factors in type 2 diabetes(58); moreover, screening, beginning atage 30 or 45 years and independent ofrisk factors, may be cost-effective(,$11,000 per quality-adjusted life-year gained) (59).

Additional considerations regard-ing testing for type 2 diabetes andprediabetes in asymptomatic patientsinclude the following.

Age

Age is a major risk factor for diabetes.Testing should begin at no later thanage 45 years for all patients. Screeningshould be considered in adults of anyage with overweight or obesity and oneor more risk factors for diabetes.

BMI and Ethnicity

In general, BMI$25 kg/m2 is a risk factorfor diabetes. However, data suggest thatthe BMI cut point should be lower for theAsian American population (60,61). TheBMI cut points fall consistently between23 and 24 kg/m2 (sensitivity of 80%) fornearly all Asian American subgroups(with levels slightly lower for JapaneseAmericans). This makes a rounded cutpoint of 23 kg/m2 practical. An argumentcan bemade to push the BMI cut point tolower than 23 kg/m2 in favor of increasedsensitivity; however, this would lead toan unacceptably low specificity (13.1%).Data from the WHO also suggests that aBMI of $23 kg/m2 should be used todefine increased risk in Asian Americans(62). The finding that one-third to one-half of diabetes in Asian Americans isundiagnosed suggests that testing isnot occurring at lower BMI thresholds(63,64).

Evidence also suggests that other pop-ulations may benefit from lower BMI cutpoints. For example, in a large multieth-nic cohort study, for an equivalent in-cidence rate of diabetes, a BMI of 30kg/m2 in non-Hispanic whites was equiv-alent to a BMI of 26 kg/m2 in AfricanAmericans (65).

Medications

Certain medications, such as glucocor-ticoids, thiazide diuretics, some HIVmedications, and atypical antipsy-chotics (66), are known to increasethe risk of diabetes and should beconsidered when deciding whetherto screen.

Testing Interval

The appropriate interval betweenscreening tests is not known (67). Therationale for the 3-year interval isthat with this interval, the number offalse-positive tests that require confir-matory testing will be reduced andindividuals with false-negative testswill be retested before substantialtime elapses and complications de-velop (67).

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 generally not recom-mended because people with positivetests may not seek, or have access to,

S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

Figure 2.1—ADA risk test (diabetes.org/socrisktest).

care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

appropriate follow-up testing and care.However, in specific situations wherean adequate referral system is estab-lished beforehand for positive tests,community screening may be consid-ered. Community testing may also bepoorly targeted; i.e., it may fail toreach the groups most at risk and in-appropriately test those at very low riskor even those who have already beendiagnosed (68).

Screening in Dental Practices

Because periodontal disease is associatedwith diabetes, the utility of screening in adental setting and referral to primary careas a means to improve the diagnosis ofprediabetes and diabetes has beenexplored (69–71), with one study es-timating that 30% of patients $30years of age seen in general dentalpractices had dysglycemia (71). Furtherresearch is needed to demonstrate thefeasibility, effectiveness, and cost-effec-tiveness of screening in this setting.

Screening and Testing for Prediabetesand Type 2 Diabetes in Children andAdolescentsIn the last decade, the incidence andprevalence of type 2 diabetes in chil-dren and adolescents has increaseddramatically, especially in racial andethnic minority populations (41). SeeTable 2.4 for recommendations on risk-based screening for type 2 diabetes orprediabetes in asymptomatic childrenand adolescents in a clinical setting(19). See Table 2.2 and Table 2.5 forthe criteria for the diagnosis of diabetesand prediabetes, respectively, whichapply to children, adolescents, andadults. See Section 13 “Children andAdolescents” (https://doi.org/10.2337/dc20-S013) for additional informationon type 2 diabetes in children andadolescents.Some studies question the validity of

A1C in the pediatric population, espe-cially among certain ethnicities, and sug-gest OGTT or FPG as more suitablediagnostic tests (72). However, manyof these studies do not recognize thatdiabetes diagnostic criteria are based onlong-term health outcomes, and valida-tions are not currently available in thepediatric population (73). The ADA ac-knowledges the limited data supportingA1C for diagnosing type 2 diabetes inchildren and adolescents. Although A1Cis not recommended for diagnosis of

diabetes in childrenwith cystic fibrosis orsymptoms suggestive of acute onset oftype 1 diabetes and only A1C assayswithout interference are appropriatefor children with hemoglobinopathies,the ADA continues to recommend A1Cfor diagnosis of type 2 diabetes in thiscohort (74,75).

CYSTIC FIBROSIS–RELATEDDIABETES

Recommendations

2.14 Annual screening for cysticfibrosis–related diabetes (CFRD)with an oral glucose tolerancetest should begin by age 10 yearsin all patients with cystic fibrosisnot previously diagnosed withCFRD. B

2.15 A1C is not recommended as ascreening test for cysticfibrosis–related diabetes. B

2.16 Patients with cystic fibrosis–related diabetes should betreated with insulin to attainindividualized glycemic goals. A

2.17 Beginning 5 years after the di-agnosis of cysticfibrosis–relateddiabetes, annual monitoring forcomplications of diabetes is rec-ommended. E

Cystic fibrosis–related diabetes (CFRD)is the most common comorbidity inpeople with cystic fibrosis, occurring inabout 20% of adolescents and 40–50% ofadults (76). Diabetes in this population,compared with individuals with type 1 ortype 2 diabetes, is associated with worsenutritional status, more severe inflam-matory lung disease, and greater mor-tality. Insulin insufficiency is the primarydefect in CFRD. Genetically determinedb-cell function and insulin resistanceassociated with infection and inflamma-tion may also contribute to the devel-opment of CFRD. Milder abnormalitiesof glucose tolerance are even more com-mon and occur at earlier ages than CFRD.Whether individuals with IGT should betreated with insulin replacement has notcurrently been determined. Althoughscreening for diabetes before the ageof 10 years can identify risk for progres-sion to CFRD in those with abnormalglucose tolerance, no benefit has beenestablished with respect to weight,height, BMI, or lung function. OGTTis the recommended screening test;

however, recent publications suggestthat an A1C cut point lower than 5.4%(5.8% in a second study) would detectmore than 90% of cases and reducepatient screening burden (77,78). On-going studies are underway to validatethis approach. Regardless of age, weightloss or failure of expected weight gainis a risk for CFRD and should promptscreening (77,78). Continuous glucosemonitoring or HOMA of b-cell function(79)maybemore sensitive thanOGTT todetect risk for progression to CFRD;however, evidence linking these resultsto long-term outcomes is lacking, andthese tests are not recommended forscreening (80).

CFRD mortality has significantly de-creased over time, and the gap in mor-tality between cystic fibrosis patientswith and without diabetes has consid-erably narrowed (81). 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 hadweight loss in the year preceding treat-ment; however, in the insulin-treatedgroup, this pattern was reversed, andpatients gained 0.39 (60.21) BMI units(P 5 0.02). The repaglinide-treatedgroup had initial weight gain, but thiswas not sustained by 6 months. Theplacebo group continued to lose weight(81). Insulin remains the most widelyused therapy for CFRD (82).

Additional resources for the clinicalmanagement of CFRD can be found inthe position statement “Clinical CareGuidelines for Cystic Fibrosis–RelatedDiabetes: A Position Statement of theAmerican Diabetes Association and aClinical Practice Guideline of the CysticFibrosis Foundation, Endorsed by thePediatric Endocrine Society” (83) andin the International Society for Pedi-atric and Adolescent Diabetes’s 2014clinical practice consensus guidelines(84).

POSTTRANSPLANTATIONDIABETES MELLITUS

Recommendations

2.18 Patients should be screened af-ter organ transplantation forhyperglycemia, with a formaldiagnosis of posttransplantation

S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

diabetes mellitus being bestmade once a patient is stableon an immunosuppressive reg-imen and in the absence of anacute infection. E

2.19 The oral glucose tolerance testis the preferred test to makea diagnosis of posttransplanta-tion diabetes mellitus. B

2.20 Immunosuppressive regimensshown to provide the best out-comes for patient and graftsurvival should be used, irre-spective of posttransplantationdiabetes mellitus risk. E

Several terms are used in the literatureto describe the presence of diabetesfollowing organ transplantation (85).“New-onset diabetes after transplanta-tion” (NODAT) is one such designationthat describes individuals who developnew-onset diabetes following trans-plant. NODAT excludes patients withpretransplant diabetes that was undi-agnosed as well as posttransplant hy-perglycemia that resolves by the timeof discharge (86). Another term, “post-transplantation diabetes mellitus” (PTDM)(86,87), describes the presence of di-abetes in the posttransplant settingirrespective of the timing of diabetesonset.Hyperglycemia is very common during

the early posttransplant period, with;90% of kidney allograft recipients ex-hibiting hyperglycemia in the first fewweeks following transplant (86–89). Inmost cases, such stress- or steroid-induced hyperglycemia resolves by thetime of discharge (89,90). Althoughthe use of immunosuppressive therapiesis a major contributor to the develop-ment of PTDM, the risks of transplantrejection outweigh the risks of PTDMandthe role of the diabetes care provideris to treat hyperglycemia appropriatelyregardless of the type of immunosup-pression (86). Risk factors for PTDM in-clude both general diabetes risks (such asage, family history of diabetes, etc.) aswell as transplant-specific factors, suchas use of immunosuppressant agents(91). Whereas posttransplantation hy-perglycemia is an important risk factorfor subsequent PTDM, a formal diagnosisof PTDM is optimally made once thepatient is stable on maintenance immu-nosuppression and in the absence of

acute infection (89–91). The OGTT isconsidered the gold standard test forthe diagnosis of PTDM (86,87,92,93).However, screening patients usingfasting glucose and/or A1C can identifyhigh-risk patients requiring further as-sessment and may reduce the numberof overall OGTTs required.

Few randomized controlled studieshave reported on the short- and long-term use of antihyperglycemic agents inthe setting of PTDM (91,94,95). Moststudies have reported that transplantpatients with hyperglycemia and PTDMafter transplantation have higher rates ofrejection, infection, and rehospitalization(89,91,96).

Insulin therapy is the agent of choicefor the management of hyperglycemia,PTDM, and preexisting diabetes and di-abetes in the hospital setting. After dis-charge,patientswithpreexistingdiabetescould go back on their pretransplant reg-imen if they were in good control beforetransplantation. Thosewith previously poorcontrol or with persistent hyperglycemiashould continue insulin with frequenthome self-monitoring of blood glucose todetermine when insulin dose reduc-tions may be needed and when itmay be appropriate to switch to non-insulin agents.

No studies to date have establishedwhich noninsulin agents are safest ormost efficacious in PTDM. The choiceof agent is usually made based on the sideeffect profile of the medication andpossible interactions with the patient’simmunosuppression regimen (91). Drugdose adjustments may be required be-cause of decreases in the glomerularfiltration rate, a relatively common com-plication in transplant patients. A smallshort-term pilot study reported thatmetformin was safe to use in renal trans-plant recipients (97), but its safety hasnot been determined in other types oforgan transplant. Thiazolidinedioneshave been used successfully in patientswith liver andkidney transplants, but sideeffects include fluid retention, heart fail-ure, and osteopenia (98,99). Dipeptidylpeptidase 4 inhibitors do not interactwith immunosuppressant drugs and havedemonstrated safety in small clinical trials(100,101). Well-designed interventiontrials examining the efficacy and safetyof these and other antihyperglycemicagents in patients with PTDM areneeded.

MONOGENIC DIABETESSYNDROMES

Recommendations

2.21 All children diagnosed with di-abetes in the first 6 months oflife should have immediate ge-netic testing for neonatal dia-betes. A

2.22 Children and those diagnosedin early adulthood who havediabetes not characteristic oftype 1 or type 2 diabetes thatoccurs in successivegenerations(suggestive of an autosomaldominant pattern of inheri-tance) should have genetic test-ing for maturity-onset diabetesof the young. A

2.23 In both instances, consultationwith a center specializing in di-abetes genetics is recommen-dedtounderstandthesignificanceof these mutations and how bestto approach further evaluation,treatment, and genetic counsel-ing. E

Monogenic defects that cause b-celldysfunction, such as neonatal diabetesand MODY, represent a small fractionof patients with diabetes (,5%). Ta-ble 2.6 describes the most commoncauses ofmonogenic diabetes. For a com-prehensive list of causes, see GeneticDiagnosis of Endocrine Disorders(102).

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 under-lying monogenic cause (103). 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 withmedications other than insulin. Perma-nent neonatal diabetes ismost commonlydue to autosomal dominant mutations inthe genes encoding the Kir6.2 subunit(KCNJ11) and SUR1 subunit (ABCC8) ofthe b-cell KATP channel. Correct diagnosishas critical implications because most

care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

patients with KATP-related neonatal di-abetes will exhibit improved glycemiccontrol when treated with high-doseoral sulfonylureas instead of insulin.Insulin gene (INS) mutations are thesecond most common cause of perma-nent neonatal diabetes, and, whileintensive insulin management is cur-rently the preferred treatment strategy,there are important genetic counselingconsiderations, as most of the mutationsthat cause diabetes are dominantly in-herited.

Maturity-Onset Diabetes of the YoungMODY is frequently characterized byonset of hyperglycemia at an early age(classically before age 25 years, althoughdiagnosis may occur at older ages).MODY is characterized by impaired in-sulin secretion with minimal or no de-fects in insulin action (in the absence ofcoexistent obesity). It is inherited inan autosomal dominant pattern withabnormalities in at least 13 genes ondifferent chromosomes identified todate. The most commonly reportedforms are GCK-MODY (MODY2), HNF1A-

MODY (MODY3), and HNF4A-MODY(MODY1).

For individuals with MODY, the treat-ment implications are considerable andwarrant genetic testing (104,105). Clin-ically, patients with GCK-MODY exhibitmild, stable, fasting hyperglycemia anddo not require antihyperglycemic ther-apy except sometimes during pregnancy.Patients with HNF1A- or HNF4A-MODYusually respond well to low doses ofsulfonylureas, which are consideredfirst-line therapy. Mutations or deletionsin HNF1B are associated with renal cystsand uterine malformations (renal cystsand diabetes [RCAD] syndrome). Otherextremely rare formsofMODYhavebeenreported to involve other transcriptionfactor genes including PDX1 (IPF1) andNEUROD1.

Diagnosis of Monogenic DiabetesA diagnosis of one of the three mostcommon forms of MODY, including GCK-MODY, HNF1A-MODY, and HNF4A-MODY,allows for more cost-effective therapy(no therapy for GCK-MODY; sulfonylureasas first-line therapy for HNF1A-MODY and

HNF4A-MODY). Additionally, diagnosis canlead to identification of other affectedfamily members. Genetic screening is in-creasingly available and cost-effective(104,105).

A diagnosis of MODY should be con-sidered in individuals who have atypicaldiabetes and multiple family memberswith diabetes not characteristic of type1 or type 2 diabetes, although admit-tedly “atypical diabetes” is becomingincreasingly difficult to precisely definein the absence of a definitive set of testsfor either type of diabetes (104–110). Inmost cases, the presence of autoantibodiesfor type 1 diabetes precludes furthertesting for monogenic diabetes, butthe presence of autoantibodies in pa-tients withmonogenic diabetes has beenreported (111). Individuals in whommonogenic diabetes is suspected shouldbe referred to a specialist for furtherevaluation if available, and consultationis available from several centers. Readilyavailable commercial genetic testing fol-lowing the criteria listed below nowenables a cost-effective (112), often

Table 2.6—Most common causes of monogenic diabetes (102)

Gene Inheritance Clinical features

MODY

GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does notrequire treatment; microvascular complications are rare; 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 in adolescence or earlyadulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT(.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas

HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or earlyadulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive tosulfonylureas

HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinary abnormalities;atrophy of the pancreas; hyperuricemia; gout

Neonataldiabetes

KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures; responsive tosulfonylureas

INS AD Permanent: IUGR; insulin requiring

ABCC8 AD Permanent or transient: IUGR; rarely developmental delay; responsive to sulfonylureas

6q24 (PLAGL1,HYMA1)

AD for paternalduplications

Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, paternalduplication or maternal methylation defect; may be treatable with medications other thaninsulin

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

EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrineinsufficiency; insulin requiring

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

AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction; OGTT, oral glucose tolerance test; 2-h PG, 2-h plasmaglucose.

S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

cost-saving, genetic diagnosis that is in-creasingly supported by health insur-ance. A biomarker screening pathwaysuch as the combination of urinaryC-peptide/creatinine ratio and antibodyscreening may aid in determining whoshould get genetic testing for MODY(113). It is critical to correctly diagnoseone of the monogenic forms of diabetesbecause these patients may be incor-rectly diagnosed with type 1 or type 2diabetes, leading to suboptimal, evenpotentially harmful, treatment regimensand delays in diagnosing other familymembers (114). The correct diagnosis isespecially critical for those with GCK-MODYmutations where multiple studieshave shown that no complications ensuein the absence of glucose-lowering ther-apy (115). Genetic counseling is recom-mended to ensure that affectedindividuals understand the patterns ofinheritance and the importance of acorrect diagnosis.The diagnosis of monogenic diabetes

should be considered in children andadults diagnosed with diabetes inearly adulthood with the followingfindings:

c Diabetes diagnosed within the first6 months of life (with occasional casespresenting later, mostly INS andABCC8 mutations) (103,116)

c Diabetes without typical features oftype 1 or type 2 diabetes (negativediabetes-associatedautoantibodies,non-obese, lacking other metabolic featuresespecially with strong family history ofdiabetes)

c 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), es-pecially if nonobese

PANCREATIC DIABETES ORDIABETES IN THE CONTEXTOF DISEASE OF THEEXOCRINE PANCREAS

Pancreatic diabetes includes both struc-tural and functional loss of glucose-normalizing insulin secretion in the contextof exocrine pancreatic dysfunction andis commonly misdiagnosed as type 2diabetes. Hyperglycemia due to generalpancreatic dysfunction has been called“type 3c diabetes” and, more recently,diabetes in the context of disease ofthe exocrine pancreas has been termed

pancreoprivic diabetes (1). The diverse

set of etiologies includes pancreatitis

(acute and chronic), trauma or pancre-

atectomy, neoplasia, cystic fibrosis (ad-

dressed elsewhere in this chapter),

hemochromatosis, fibrocalculous pan-

creatopathy, rare genetic disorders

(117), and idiopathic forms (1). A distin-

guishing feature is concurrent pancreatic

exocrine insufficiency (according to the

monoclonal fecal elastase 1 test or direct

function tests), pathological pancreatic

imaging (endoscopic ultrasound, MRI,

computed tomography) and absence of

type 1 diabetes–associated autoimmu-

nity (118–122). There is loss of both

insulin andglucagon secretion and often

higher-than-expected insulin require-ments. Risk for microvascular complica-tions is similar to other formsof diabetes. Inthe context of pancreatectomy, islet auto-transplantationcanbedonetoretain insulinsecretion (123,124). In some cases, this canlead to insulin independence. In others,it may decrease insulin requirements(125).

GESTATIONAL DIABETES MELLITUS

Recommendations

2.24 Test for undiagnosed predia-betes and diabetes at the firstprenatal visit in those with riskfactors using standard diagnos-tic criteria. B

2.25 Test for gestational diabetesmellitus at 24–28 weeks of ges-tation in pregnant women notpreviously found to have diabe-tes. A

2.26 Test women with gestationaldiabetes mellitus for prediabe-tes or diabetes at 4–12 weekspostpartum, using the 75-g oralglucose tolerance test and clin-ically appropriate nonpregnancydiagnostic criteria. B

2.27 Women with a history of ges-tational diabetesmellitus shouldhave lifelong screening for thedevelopment of diabetes or pre-diabetes at least every 3 years. B

2.28 Women with a history of ges-tational diabetes mellitus foundto have prediabetes should re-ceive intensive lifestyle inter-ventions and/or metformin toprevent diabetes. A

DefinitionFor many years, GDM was defined asany degree of glucose intolerance thatwas first recognized during preg-nancy (49), regardless of the degreeof hyperglycemia. This definition facili-tated a uniform strategy for detectionand classification of GDM, but this defi-nition has serious limitations (126). First,the best available evidence reveals thatmany, perhaps most, cases of GDM rep-resent preexisting hyperglycemia that isdetected by routine screening in preg-nancy, as routine screening is not widelyperformed in nonpregnant women ofreproductive age. It is the severity ofhyperglycemia that is clinically importantwith regard to both short- and long-termmaternal and fetal risks. Universal pre-conception and/or first trimester screen-ing is hampered by lack of data andconsensus regarding both appropriatediagnostic thresholds and outcomes. Acompelling argument for further work inthis area is the fact that hyperglycemiathat would be diagnostic of diabetesoutside of pregnancy and is present atthe time of conception is associated withan increased risk of congenital malfor-mations that is not seen with lowerglucose levels (127,128).

The ongoing epidemic of obesity anddiabetes has led to more type 2 diabetesin women of reproductive age, with anincrease in the number of pregnantwomen with undiagnosed type 2 diabe-tes in early pregnancy (129–132). Be-cause of the number of pregnant womenwith undiagnosed type 2 diabetes, it isreasonable to test women with risk fac-tors for type 2 diabetes (133) (Table 2.3)at their initial prenatal visit, using stan-dard diagnostic criteria (Table 2.2).Women found to have diabetes by thestandard diagnostic criteria used outsideof pregnancy should be classified ashaving diabetes complicating pregnancy(most often type 2 diabetes, rarely type 1diabetes or monogenic diabetes) andmanaged accordingly. Women whomeet the lower glycemic criteria forGDM should be diagnosed with thatcondition and managed accordingly.Other women should be rescreenedfor GDM between 24 and 28 weeks ofgestation (see Section 14 “Managementof Diabetes in Pregnancy,” https://doi.org/10.2337/dc20-S014). The Interna-tional Association of the Diabetes andPregnancy Study Groups (IADPSG) GDM

care.diabetesjournals.org Classification and Diagnosis of Diabetes S25

diagnosticcriteria for the75-gOGTTaswellas the GDM screening and diagnostic cri-teria used in the two-step approach werenot derived from data in the first half ofpregnancy, so the diagnosis of GDM inearly pregnancy by either FPG or OGTTvalues is not evidence based (134) andfurther work is needed.GDM is often indicative of underly-

ing b-cell dysfunction (135), whichconfers marked increased risk for laterdevelopment of diabetes, generally butnot always type 2 diabetes, in the motherafter delivery (136,137). As effective pre-vention interventions are available(138,139), women diagnosed with GDMshould receive lifelong screening for pre-diabetes to allow interventions to reducediabetes risk and for type 2 diabetes toallow treatment at the earliest pos-sible time (140).

DiagnosisGDM carries risks for the mother, fetus,and neonate. The Hyperglycemia andAdverse Pregnancy Outcome (HAPO)study (141), a large-scale multinationalcohort study completed by more than23,000 pregnant women, demonstratedthat risk of adverse maternal, fetal, andneonatal outcomes continuously in-creased as a function of maternal glyce-mia at 24–28 weeks of gestation, evenwithin ranges previously considered

normal 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 2.7) can be ac-complished with either of two strate-gies:

1. The “one-step” 75-g OGTT derivedfrom the IADPSG criteria or

2. The older “two-step” approach with a50-g (nonfasting) screen followed bya 100-g OGTT for those who screenpositive, based on the work of Car-penter and Coustan’s interpretationof the older O’Sullivan (141a) criteria.

Different diagnostic criteria will iden-tify different degrees of maternal hyper-

glycemia andmaternal/fetal risk, leading

someexperts to debate, and disagree on,

optimal strategies for the diagnosis of

GDM.

One-Step Strategy

The IADPSG defined diagnostic cut pointsforGDMas the average fasting, 1-h, and2-h

PG values during a 75-g OGTT in women at

24–28 weeks of gestation who participated

in the HAPO study at which odds for ad-

verse outcomes reached 1.75 times the

estimated odds of these outcomes at the

mean fasting, 1-h, and2-hPG levels of the

study population. This one-step strategywas anticipated to significantly increasethe incidence of GDM (from 5–6% to 15–20%), primarily because only one abnor-mal value, not two, became sufficient tomake the diagnosis (142). Many regionalstudies have investigated the impact ofadopting IADPSG criteria on prevalenceand have seen a roughly one- to threefoldincrease (143). The anticipated increasein the incidence of GDM could have asubstantial impact on costs and medicalinfrastructure needs and has the poten-tial to “medicalize” pregnancies previ-ously categorized as normal. A recentfollow-up study of women participatingin a blinded study of pregnancy OGTTsfound that 11 years after their pregnan-cies, women who would have been di-agnosed with GDM by the one-stepapproach, as compared with thosewithout, were at 3.4-fold higher riskof developing prediabetes and type 2diabetes and had children with a higherrisk of obesity and increased body fat,suggesting that the larger group ofwomen identified by the one-step ap-proach would benefit from increasedscreening for diabetes and prediabetesthat would accompany a history of GDM(144). The ADA recommends the IADPSGdiagnostic criteria with the intent ofoptimizing gestational outcomes be-cause these criteria were the onlyones based on pregnancy outcomesrather than end points such as predictionof subsequent maternal diabetes.

Theexpectedbenefitsofusing IADPSGtothe offspring are inferred from interventiontrials that focused on women with lowerlevels of hyperglycemia than identifiedusing older GDM diagnostic criteria. Thosetrials found modest benefits including re-duced rates of large-for-gestational-agebirths and preeclampsia (145,146). It isimportant to note that 80–90% of womenbeing treated for mild GDM in these tworandomized controlled trials could beman-aged with lifestyle therapy alone. TheOGTT glucose cutoffs in these two trialsoverlapped with the thresholds recom-mended by the IADPSG, and in one trial(146), 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 treating versus nottreating GDM diagnosed by the IADPSGcriteria but not the Carpenter-Coustancriteria have been published to date.

Table 2.7—Screening for and diagnosis of GDMOne-step strategy

Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with 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 orexceeded:

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 strategy

Step 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 diabetes.

If the plasma glucose level measured 1 h after the load is$130, 135, or 140 mg/dL (7.2, 7.5, or7.8 mmol/L, respectively), 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 when at least two* of the following four plasma glucose levels(measured fasting and at 1, 2, and 3 h during OGTT) aremet or exceeded (Carpenter-Coustancriteria [154]):c Fasting: 95 mg/dL (5.3 mmol/L)c 1 h: 180 mg/dL (10.0 mmol/L)c 2 h: 155 mg/dL (8.6 mmol/L)c 3 h: 140 mg/dL (7.8 mmol/L)

GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance test.*American College of Obstetricians and Gynecologists notes that one elevated value can be usedfor diagnosis (150).

S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

Data are also lacking on how the treat-ment of lower levels of hyperglycemiaaffects a mother’s future risk for thedevelopment of type 2 diabetes and heroffspring’s risk for obesity, diabetes,and other metabolic disorders. Addi-tional well-designed clinical studies areneeded to determine the optimal in-tensity of monitoring and treatment ofwomen with GDM diagnosed by theone-step strategy (147,148).

Two-Step Strategy

In 2013, the National Institutes of Health(NIH) convened a consensus develop-ment conference to consider diagnosticcriteria for diagnosing GDM (149). The15-member panel had representativesfrom obstetrics and 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) followedby a 3-h 100-g OGTT for those whoscreenedpositive. TheAmericanCollegeof Obstetricians and Gynecologists(ACOG) recommends any of the com-monly used thresholds of 130, 135, or140 mg/dL for the 1-h 50-g GLT (150). Asystematic review for the U.S. PreventiveServices Task Force compared GLT cut-offs of 130 mg/dL (7.2 mmol/L) and140 mg/dL (7.8 mmol/L) (151). Thehigher cutoff yielded sensitivity of 70–88% and specificity of 69–89%, while thelower cutoff was 88–99% sensitive and66–77% specific. Data regarding a cutoffof 135 mg/dL are limited. As for otherscreening tests, choiceof a cutoff is basedupon the trade-off between sensitivityand specificity. The use of A1C at 24–28 weeks of gestation as a screening testfor GDM does not function as well as theGLT (152).Key factors cited by the NIH panel in

their decision-making process were thelack of clinical trial data demonstratingthe benefits of the one-step strategyand the potential negative consequen-ces of identifying a large group ofwomen with GDM, including medical-ization of pregnancy with increasedhealth care utilization and costs. More-over, screening with a 50-g GLT doesnot require fasting and is thereforeeasier to accomplish for many women.Treatment of higher-threshold mater-nal hyperglycemia, as identified bythe two-step approach, reduces rates

of neonatal macrosomia, large-for-gestational-age births (153), and shoulderdystocia, without increasing small-for-gestational-age births. ACOG currentlysupports the two-step approach butnotes that one elevated value, as op-posed to two, may be used for the di-agnosis of GDM (150). If this approachis implemented, the incidence of GDMby the two-step strategy will likely in-crease markedly. ACOG recommendseither of two sets of diagnostic thresh-olds for the 3-h 100-g OGTTdCarpenter-Coustan or National Diabetes DataGroup (154,155). Each is based on dif-ferent mathematical conversions of theoriginal recommended thresholds byO’Sullivan (141a), which used wholeblood and nonenzymatic methods forglucose determination. A secondaryanalysis of data from a randomizedclinical trial of identification and treat-ment of mild GDM (156) demonstratedthat treatment was similarly benefi-cial in patients meeting only the lowerthresholds per Carpenter-Coustan (154)and in those meeting only the higherthresholds per National Diabetes DataGroup (155). If the two-step approach isused, it would appear advantageous touse the Carpenter-Coustan lower diag-nostic thresholds as shown in step 2 inTable 2.7.

Future Considerations

The conflicting recommendations fromexpert groups underscore the fact thatthere aredata to support each strategy.Acost-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 (157). The decision of whichstrategy to implementmust therefore bemade based on the relative values placedon factors that have yet to be measured(e.g., willingness to change practicebased on correlation studies ratherthan intervention trial results, availableinfrastructure, and importance of costconsiderations).

As the IADPSG criteria (“one-stepstrategy”) have been adopted interna-tionally, further evidence has emergedto support improved pregnancy out-comes with cost savings (158) andIADPSGmay be the preferred approach.Data comparing population-wide out-comes with one-step versus two-step

approaches have been inconsistent todate (159,160). In addition, pregnanciescomplicated by GDM per the IADPSGcriteria, but not recognized as such,have outcomes comparable to preg-nancies with diagnosed GDM by themorestringent two-stepcriteria (161,162).There remains strong consensus thatestablishing a uniform approach to di-agnosing GDM will benefit patients,caregivers, and policy makers. Longer-term outcome studies are currentlyunderway.

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