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2. Classification and Diagnosis ofDiabetes: Standards of MedicalCare in Diabetesd2019Diabetes Care 2019;42(Suppl. 1):S13–S28 | https://doi.org/10.2337/dc19-S002

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes ADA’s current clinical practice recommendations and is intended to providethe components of diabetes care, general treatment goals and guidelines, and toolsto evaluate quality of care.Members of theADAProfessional Practice Committee, amultidisciplinary expert committee, are responsible for updating the Standards ofCare annually, or more frequently as warranted. For a detailed description of ADAstandards, statements, and reports, as well as the evidence-grading system forADA’s clinical practice recommendations, please refer to the Standards of CareIntroduction. Readers who wish to comment on the Standards of Care are invitedto 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 b-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 syndromes(such as neonatal diabetes and maturity-onset diabetes of the young [MODY]),diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), anddrug- or chemical-induced diabetes (such as with glucocorticoid use, in thetreatment of HIV/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 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 paradigms oftype 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 be more variable in adults, and they may not present with the

Suggested citation: American Diabetes Associa-tion. 2. Classification and diagnosis of diabetes:Standards of Medical Care in Diabetesd2019.Diabetes Care 2019;42(Suppl. 1):S13–S28

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American Diabetes Association

Diabetes Care Volume 42, Supplement 1, January 2019 S13

2.CLA

SSIFICATIO

NANDDIAGNOSIS

OFDIABETES

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classic symptoms seen in children. Oc-casionally, patients with type 2 diabetesmay present with DKA, particularly ethnicminorities (3). Although difficulties indistinguishing diabetes type may occur inall age-groups at onset, the true diag-nosis becomes more obvious overtime.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 themanypaths tob-cell demise or dysfunction (4).Characterization of the underlying

pathophysiology is more developed intype 1 diabetes than in type 2 diabetes. Itis now clear from studies of first-degreerelatives of patients with type 1 diabetesthat the persistent presence of two ormore autoantibodies is an almost certainpredictor of clinical hyperglycemia anddiabetes. The rate of progression is de-pendent 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 insulinsecretion, frequently in the setting ofinsulin resistance, appears to be thecommon denominator. Characterization

of 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 racialgroups. Type 2 diabetes is primarily as-sociated with insulin secretory defectsrelated to inflammation and metabolicstress among other contributors, includ-ing genetic factors. Future classificationschemes for diabetes will likely focuson the pathophysiology of the underly-ing b-cell dysfunction and the stage ofdisease as indicated by glucose status(normal, impaired, or diabetes) (4).

DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based onplasma glucose criteria, either the fastingplasma glucose (FPG) value or the 2-hplasma glucose (2-h PG) value during a75-g oral glucose tolerance test (OGTT),or A1C criteria (6) (Table 2.2).

Generally, FPG, 2-h PG during 75-gOGTT, and A1C are equally appropriatefor diagnostic testing. It should be notedthat the tests do not necessarily detectdiabetes in the same individuals. Theefficacy of interventions for primary pre-vention of type 2 diabetes (7,8) hasprimarily been demonstrated among in-dividuals who have impaired glucosetolerance (IGT) with or without elevatedfasting glucose, not for individuals withisolated impaired fasting glucose (IFG) orfor those with prediabetes defined byA1C 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 happen tohaveglucose testing, in individuals testedbased on diabetes risk assessment, andin symptomatic 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-h PGtests is imperfect, as is the concordancebetween A1C and either glucose-basedtest. Compared with FPG and A1C cutpoints, the 2-h PG value diagnoses morepeople with prediabetes and diabetes (9).

A1C

Recommendations

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

2.2 Marked discordance between mea-sured A1C and plasma glucoselevels should raise the possibilityof A1C assay interference due tohemoglobin variants (i.e., hemo-globinopathies) and consider-ation of using an assay withoutinterference or plasma blood glu-cose criteria to diagnose diabe-tes. B

2.3 In conditions associated with analtered relationship between A1Cand glycemia, such as sickle celldisease, pregnancy (second andthird trimesters and the postpar-tum period), glucose-6-phosphatedehydrogenase deficiency, HIV,hemodialysis, recent blood loss ortransfusion, or erythropoietin ther-apy, only plasma blood glucose cri-teria should be used to diagnosediabetes. B

The A1C test should be performed using amethod that is certified by the NGSP(www.ngsp.org) and standardized ortraceable to the Diabetes Control and

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

Stage 1 Stage 2 Stage 3

Characteristics c Autoimmunity c Autoimmunity c New-onset hyperglycemia

c Normoglycemia c Dysglycemia c Symptomatic

c Presymptomatic c Presymptomatic

Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptoms

c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria

c 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

S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 42, Supplement 1, January 2019

www.ngsp.org

Complications Trial (DCCT) referenceassay. Although point-of-care A1C assaysmay be NGSP certified or U.S. Food andDrug Administration approved for diag-nosis, proficiency testing is not alwaysmandated for performing 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 Section 6 “Glycemic Targets,”point-of-care A1C assays may be moregenerally applied for glucosemonitoring.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 duringstress and illness. However, these ad-vantages may be offset by the lowersensitivity of A1C at the designated cutpoint, greater cost, limited availability ofA1C testing in certain regions of the de-veloping world, and the imperfect corre-lation between A1C and average glucosein certain individuals. The A1C test, witha diagnostic threshold of $6.5% (48mmol/mol), diagnoses only 30% of thediabetes cases identified collectivelyusing A1C, FPG, or 2-h PG, accordingto National Health and Nutrition Exam-ination Survey (NHANES) data (10).When using A1C to diagnose diabetes,

it is important to recognize that A1C is anindirect measure of average blood glu-cose levels and to take other factors intoconsideration that may impact hemoglo-bin glycation independently of glycemiaincluding HIV treatment (11,12), age, race/ethnicity, pregnancy status, genetic back-ground, and anemia/hemoglobinopathies.

Age

The epidemiological studies that formedthe basis for recommending A1C to di-agnose diabetes included only adult pop-ulations (10). However, a recent ADA

clinical guidance concluded that A1C,FPG, or 2-h PG can be used to test forprediabetes or type 2 diabetes in chil-dren and adolescents. (see p. S20 SCREEN-ING AND TESTING FOR PREDIABETES AND TYPE 2

DIABETES IN CHILDREN AND ADOLESCENTS for ad-ditional information) (13).

Race/Ethnicity/Hemoglobinopathies

Hemoglobin variants can interfere withthe measurement of A1C, although mostassays in use in theU.S. are unaffected bythe most common variants. Marked dis-crepancies between measured A1C andplasma glucose levels should promptconsideration that the A1C assay maynot be reliable for that individual. Forpatients with a hemoglobin variant butnormal red blood cell turnover, such asthose with the sickle cell trait, an A1Cassay without interference from hemo-globin variants should be used. An up-dated list of A1C assays with interferencesis 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 (14). Another ge-neticvariant,X-linkedglucose-6-phosphatedehydrogenase G202A, carried by 11%of African Americans, was associatedwith a decrease in A1C of about 0.8%in homozygous men and 0.7% in homo-zygous women compared with thosewithout the variant (15).

Even in the absence of hemoglobinvariants, A1C levels may vary with race/ethnicity independently of glycemia(16–18). For example, African Americansmay have higher A1C levels than non-Hispanic whites with similar fasting andpostglucose load glucose levels (19), andA1C levels may be higher for a given meanglucose concentration when measuredwith continuous glucose monitoring (20).Though conflicting data exists, African

Americans may also have higher levels offructosamine and glycated albumin andlower levels of 1,5-anhydroglucitol, suggest-ing that their glycemic burden (particularlypostprandially) may be higher (21,22). Theassociation of A1C with risk for complica-tions appears to be similar in African Amer-icans and non-Hispanic whites (23,24).

Other Conditions Altering the Relationship

of A1C and Glycemia

In conditions associated with increasedred blood cell turnover, such as sickle celldisease, pregnancy (second and thirdtrimesters), glucose-6-phosphate dehy-drogenase deficiency (25,26), hemodialy-sis, recent blood loss or transfusion, orerythropoietin therapy, only plasma bloodglucose criteria should beused todiagnosediabetes (27). A1C is less reliable thanblood glucose measurement in other con-ditions such as postpartum (28–30), HIVtreated with certain drugs (11), and iron-deficient anemia (31).

Confirming the DiagnosisUnless there is a clear clinical diagnosis(e.g., patient in a hyperglycemic crisisor with classic symptoms of hyperglyce-mia and a random plasma glucose$200mg/dL [11.1mmol/L]), diagnosis requirestwo abnormal test results from thesame sample (32) or in two separatetest samples. If using two separate testsamples, it is recommended that thesecond test, which may either be a repeatof the initial test or a different test, beperformed without delay. For example, ifthe A1C is 7.0% (53 mmol/mol) and arepeat result is 6.8% (51 mmol/mol), thediagnosis 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 results

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 $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing theequivalent of 75-g anhydrous glucose dissolved in water.*

OR

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

OR

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

*In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples.

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from two different tests, then the testresult that is above the diagnostic cutpoint should be repeated, with consider-ation of the possibility of A1C assay in-terference. The diagnosis is made on thebasis of the confirmed test. For example,if a patient meets the diabetes criterionof the A1C (two results $6.5% [48mmol/mol]) but not FPG (,126 mg/dL[7.0 mmol/L]), that person should never-theless be considered to have diabetes.Since all the tests have preanalytic and

analytic variability, it is possible that anabnormal result (i.e., above the diagnosticthreshold), when repeated, will producea value below the diagnostic cut point.This scenario is likely for FPG and2-hPG ifthe glucose samples remain at room tem-peratureandarenot centrifugedpromptly.Because of the potential for preanalyticvariability, it is critical that samples forplasma glucose be spun and separatedimmediately after they are drawn. If pa-tients have test results near themarginsofthe diagnostic threshold, the health careprofessional should follow the patientclosely and repeat the test in 3–6 months.

TYPE 1 DIABETES

Recommendations

2.4 Plasma blood glucose rather thanA1C should be used to diagnosethe acute onset of type 1 diabetesin individuals with symptoms ofhyperglycemia. E

2.5 Screening for type 1 diabetes riskwith a panel of autoantibodies iscurrently recommended only inthe setting of a research trial or infirst-degree family members of aproband with type 1 diabetes. B

2.6 Persistence of two or more auto-antibodies predicts clinical diabe-tes andmay serve as an indicationfor intervention in the setting ofa clinical trial. B

DiagnosisIn a patient with classic symptoms, mea-surement of plasma glucose is sufficientto diagnose diabetes (symptoms of hy-perglycemia or hyperglycemic crisis plusa random plasma glucose $200 mg/dL[11.1 mmol/L]). In these cases, knowingthe plasma glucose level is critical be-cause, in addition to confirming thatsymptoms are due to diabetes, it will in-form management decisions. Some pro-viders may also want to know the A1C to

determine how long a patient has hadhyperglycemia. The criteria to diagnosediabetes are listed in Table 2.2.

Immune-Mediated DiabetesThis form, previously called “insulin-dependent diabetes” or “juvenile-onsetdiabetes,” accounts for 5–10%ofdiabetesand is due to cellular-mediated auto-immune destruction of the pancreaticb-cells. Autoimmune markers include isletcell autoantibodies and autoantibodies toGAD (GAD65), insulin, the tyrosine phos-phatases IA-2 and IA-2b, and ZnT8. Type 1diabetes is defined by the presence ofone or more of these autoimmunemarkers. The disease has strong HLAassociations, with linkage to the DQAand DQB genes. These HLA-DR/DQ allelescan be either predisposing 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 DKA as thefirst manifestation of the disease. Othershave modest fasting hyperglycemiathat can rapidly change to severe hyper-glycemia and/or DKA with infection orother stress. Adults may retain sufficientb-cell function to prevent DKA for manyyears; such individuals eventually be-come dependent on insulin for survivaland are at risk for DKA. At this latter stageof the disease, there is little or no insulinsecretion, as manifested by low or un-detectable levels of plasma C-peptide.Immune-mediated diabetes commonlyoccurs in childhood and adolescence,but it can occur at any age, even inthe 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 should not preclude the diagno-sis. People with type 1 diabetes are alsoprone to other autoimmune disorderssuch as Hashimoto thyroiditis, Graves dis-ease, Addison disease, celiac disease, vit-iligo, autoimmune hepatitis, myastheniagravis, and pernicious anemia (see Section4 “Comprehensive Medical Evaluationand Assessment of Comorbidities”).

Idiopathic Type 1 DiabetesSome forms of type 1 diabetes have noknown etiologies. These patients have

permanent insulinopenia and are proneto DKA, but have no evidence of b-cellautoimmunity. Although only a minorityof patients with type 1 diabetes fall intothis category, of those who do, most are ofAfrican or Asian ancestry. Individuals withthis form of diabetes suffer from episodicDKA and exhibit varying degrees of insulindeficiency between episodes. This formof diabetes is strongly inherited and isnot HLA associated. An absolute require-ment for insulin replacement therapy inaffected patients may be intermittent.

Screening for Type 1 Diabetes RiskThe incidence and prevalence of type 1diabetes is increasing (33). Patients withtype 1 diabetes often present with acutesymptoms of diabetes and markedlyelevated blood glucose levels, and ap-proximately one-third are diagnosedwith life-threatening DKA (2). Severalstudies indicate that measuring isletautoantibodies in relatives of thosewith type 1 diabetes may identify indi-viduals who are at risk for developingtype 1 diabetes (5). Such testing, coupledwith education about diabetes symp-toms and close follow-up, may enableearlier identification of type 1 diabetesonset. A study reported the risk of pro-gression to type 1 diabetes from the timeof seroconversion to autoantibody pos-itivity 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 (34). 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 sequence of events led toclinical disease in both “sporadic” andfamilial cases of type 1 diabetes. Indeed,the risk of type 1 diabetes increases asthe number of relevant autoantibodiesdetected increases (35–37).

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 clini-cal research study (www.diabetestrialnet.org). Widespread clinical testing of asymp-tomatic low-risk individuals is not currently


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recommended due to lack of approvedtherapeutic interventions. Individualswho test positive should be counseledabout the risk of developing diabetes,diabetes symptoms, and DKA preven-tion. Numerous clinical studies are be-ing conducted to test various methodsof preventing type 1 diabetes in thosewith evidence of autoimmunity (www.clinicaltrials.gov).

PREDIABETES AND TYPE2 DIABETES

Recommendations

2.7 Screening for prediabetes andtype 2 diabetes with an infor-mal assessment of risk factorsor validated tools should beconsidered in asymptomaticadults. B

2.8 Testing for prediabetes and/ortype 2 diabetes in asymptomaticpeople should be considered inadults of any age who are over-weightorobese (BMI$25kg/m2

or $23 kg/m2 in Asian Ameri-cans) and whohave oneormoreadditional risk factors for diabe-tes (Table 2.3). B

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

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

2.11 To test for prediabetes andtype 2 diabetes, fasting plasmaglucose, 2-h plasma glucoseduring 75-g oral glucose toler-ance test, and A1C are equallyappropriate. B

2.12 In patients with prediabetes andtype 2 diabetes, identify and, if

appropriate, treat other cardio-vascular disease risk factors. B

2.13 Risk-based screening for pre-diabetes and/or type 2 diabetesshould be considered after theonsetofpubertyorafter10yearsof age, whichever occurs earlier,in children and adolescents whoare overweight (BMI$85thper-centile) or obese (BMI $95thpercentile) and who have addi-tional risk factors for diabe-tes. (See Table 2.4 for evidencegrading of risk factors.)

Prediabetes“Prediabetes” is the term used for indi-vidualswhose glucose levels do notmeetthe criteria for diabetes but are too highto be considered normal (23,24). Pa-tients with prediabetes are defined bythe presence of IFG and/or IGT and/orA1C 5.7–6.4% (39–47 mmol/mol) (Table2.5). Prediabetes should not be viewedas a clinical entity in its own right butrather as an increased risk for diabetesand cardiovascular disease (CVD). Crite-ria for testing for diabetes or prediabe-tes in asymptomatic adults is outlinedin Table 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) (38,39) and IGT as 2-h PGduring 75-g OGTT levels between 140and 199 mg/dL (between 7.8 and 11.0mmol/L) (40). It should be noted that the

World Health Organization (WHO) andnumerous other diabetes organizationsdefine the IFG cutoff 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)had a substantially increased risk ofdiabetes (5-year incidence from 9 to25%). Those with an A1C range of6.0–6.5% (42–48 mmol/mol) had a5-year risk of developing diabetes be-tween 25 and 50% and a relative risk20 times higher compared with A1C of5.0% (31 mmol/mol) (41). In a commu-nity-based study of African Americanand non-Hispanic white adults withoutdiabetes, baseline A1C was a strongerpredictor of subsequent diabetes andcardiovascular events than fasting glu-cose (42). Other analyses suggest that A1Cof 5.7% (39 mmol/mol) or higher is asso-ciated with a diabetes risk similar to that ofthe high-risk participants in the DiabetesPreventionProgram (DPP) (43), andA1Catbaseline was a strong predictor of thedevelopment of glucose-defined diabe-tes during the DPP and its follow-up (44).

Hence, it is reasonable to consideran A1C range of 5.7–6.4% (39–47mmol/mol) as identifying individuals withprediabetes. Similar to those with IFGand/or IGT, individuals with A1C of 5.7–6.4% (39–47 mmol/mol) should be in-formed of their increased risk for diabetes

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 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, acanthosis nigricans)

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, with consideration of more frequent testing dependingon initial results and risk status.


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and CVD and counseled about effectivestrategies to lower their risks (see Section 3“Prevention or Delay of Type 2 Diabetes”).Similar to glucose measurements, the con-tinuum of risk is curvilinear, so as A1C rises,the diabetes risk rises disproportionately(41). Aggressive interventions and vig-ilant follow-up should be pursued forthose considered at very high risk (e.g.,those with A1C .6.0% [42 mmol/mol]).Table 2.5 summarizes the categories

of prediabetes and Table 2.3 the criteriafor prediabetes testing. The ADA dia-betes risk test is an additional optionfor assessment to determine the ap-propriateness of testing for diabetesor prediabetes in asymptomatic adults.(Fig. 2.1) (diabetes.org/socrisktest). Foradditional background regarding risk fac-tors and screening for prediabetes, see pp.S18–S20 (SCREENING AND TESTING FOR PREDIABETESAND TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS andSCREENING AND TESTING FOR PREDIABETES AND TYPE 2

DIABETES IN CHILDREN AND ADOLESCENTS).

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 deficiencyand have peripheral insulin resistance.At least initially, and often throughouttheir lifetime, these individuals may notneed insulin treatment to survive.There are various causes of type 2 di-

abetes. Although the specific etiologies

are not known, autoimmune destructionof b-cells does not occur and patients donot have any of the other known causesof diabetes. Most but not all patientswith type 2 diabetes are overweight orobese. Excess weight itself causes somedegree of insulin resistance. Patientswho are not obese 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 stressof another illness such as infection orwith the use of certain drugs (e.g.,corticosteroids, atypical antipsychotics,and sodium–glucose cotransporter 2 in-hibitors) (45,46). 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 glu-cose levels in these patients would beexpected to result in even higher insulinvalues had their b-cell function beennormal. Thus, insulin secretion is defec-tive in these patients and insufficientto compensate for insulin resistance.

Insulin resistance may improve withweight reduction and/or pharmacologictreatment of hyperglycemia but is sel-dom restored to normal.

The risk of developing type 2 diabetesincreases with age, obesity, and lack ofphysical activity. It occurs more fre-quently in women with prior GDM, inthose with hypertension or dyslipidemia,and in certain racial/ethnic subgroups(African American, American Indian,Hispanic/Latino, and Asian American). Itis often associated with a strong geneticpredisposition or family history in first-degree relatives, more so than type 1diabetes. However, the genetics of type 2diabetes is poorly understood. In adultswithout traditional risk factors fortype 2 diabetes and/or younger age, con-sider antibody testing to exclude thediagnosis of type 1 diabetes (i.e., GAD).

Screening and Testing forPrediabetes and Type 2 Diabetes inAsymptomatic AdultsScreening for prediabetes and type 2diabetes risk through an informal as-sessment of risk factors (Table 2.3) or withan assessment tool, such as the ADA risktest (Fig. 2.1) (diabetes.org/socrisktest),is recommended to guide providers onwhether performing a diagnostic test(Table 2.2) is appropriate. Prediabetesand type 2 diabetes meet criteria forconditions in which early detection isappropriate. Both conditions are com-mon and impose significant clinical andpublic health burdens. There is often along presymptomatic phase before thediagnosis of type 2 diabetes. Simple teststo detect preclinical disease are readilyavailable. The duration of glycemic bur-den is a strong predictor of adverse out-comes. There are effective interventionsthat prevent progression from prediabe-tes to diabetes (see Section 3 “Preventionor Delay of Type 2 Diabetes”) and re-duce the risk of diabetes complications

Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical settingTesting should be considered in youth* who are overweight ($85% percentile) or obese ($95 percentile) A and who have one or more additional

risk factors based on the strength of their association with diabetes:c Maternal history of diabetes or GDM during the child’s gestation Ac Family history of type 2 diabetes in first- or second-degree relative Ac Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) Ac Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarysyndrome, or small-for-gestational-age birth weight) B

*After the onset of puberty or after 10 years of age, whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, ormore frequently if BMI is increasing, is recommended.

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)

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


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(see Section 10 “Cardiovascular Diseaseand Risk Management” and Section 11“Microvascular Complications and FootCare”).Approximately one-quarter of people

with diabetes in the U.S. and nearly half

of Asian and Hispanic Americans withdiabetes are undiagnosed (38,39). Al-though screening of asymptomatic indi-viduals to identify those with prediabetesor diabetes might seem reasonable,rigorous clinical trials to prove the

effectiveness of such screening havenot been conducted and are unlikelyto occur.

A large European randomized con-trolled trial compared the impact ofscreening for diabetes and intensive

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


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multifactorial intervention with that ofscreening and routine care (47). 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 treatment com-pared with routine care, but the inci-dence of first CVD events or mortalitywas not significantly different betweenthe groups (40). 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 outcomes com-pared with no screening and later treat-ment after clinical diagnoses. Computersimulation modeling studies suggest thatmajor benefits are likely to accrue fromthe early diagnosis and treatment ofhyperglycemia and cardiovascular riskfactors in type 2 diabetes (48); more-over, screening, beginning at age 30or 45 years and independent of riskfactors, may be cost-effective (,$11,000per quality-adjusted life-year gained) (49).Additional considerations regarding

testing for type 2 diabetes and predia-betes in asymptomatic patients includethe following.

Age

Age is a major risk factor for diabetes.Testing should begin at no later than age45 years for all patients. Screening shouldbe considered in overweight or obeseadults of any age with one or more riskfactors 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 forthe Asian American population (50,51).The BMI cut points fall consistently be-tween 23 and 24 kg/m2 (sensitivity of 80%)for nearly all Asian American subgroups(with levels slightly lower for JapaneseAmericans). This makes a rounded cutpoint of 23 kg/m2 practical. An argumentcan be made to push the BMI cut pointto lower than 23 kg/m2 in favor of increasedsensitivity; however, this would lead toan unacceptably low specificity (13.1%).Data from the WHO also suggest that aBMI of $23 kg/m2 should be used todefine increased risk in Asian Americans

(52). The finding that one-third to one-half of diabetes in Asian Americans isundiagnosed suggests that testing isnot occurring at lower BMI thresholds(53,54).

Evidence also suggests that other pop-ulations may benefit from lower BMI cutpoints. For example, in a large multi-ethnic cohort study, for an equivalentincidence rate of diabetes, a BMI of30 kg/m2 in non-Hispanic whites wasequivalent to a BMI of 26 kg/m2 in Afri-can Americans (55).

Medications

Certain medications, such as glucocorti-coids, thiazide diuretics, some HIV med-ications, and atypical antipsychotics (56),are known to increase the risk of diabetesand should be considered when decidingwhether to screen.

Testing Interval

The appropriate interval between screen-ing tests is not known (57). The rationalefor the 3-year interval is that with thisinterval, the number of false-positivetests that require confirmatory testingwill be reduced and individuals withfalse-negative tests will be retestedbefore substantial time elapses andcomplications develop (57).

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,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 to reachthe groups most at risk and inappro-priately test those at very low risk oreven those who have already beendiagnosed (58).

Screening in Dental Practices

Because periodontal disease is associ-ated with diabetes, the utility of screen-ing in a dental setting and referral toprimary care as a means to improve thediagnosis of prediabetes and diabeteshas been explored (59–61), with onestudy estimating that 30% of patients$30 years of age seen in general dental

practices had dysglycemia (61). Furtherresearch is needed to demonstratethe feasibility, effectiveness, and cost-effectiveness 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 adoles-cents has increased dramatically, es-pecially in racial and ethnic minoritypopulations (33). See Table 2.4 for rec-ommendations on risk-based screeningfor type 2 diabetes or prediabetes inasymptomatic children and adolescentsin a clinical setting (13). See Tables 2.2and 2.5 for the criteria for the diagno-sis of diabetes and prediabetes, respec-tively,whichapply tochildren,adolescents,and adults. See Section 13 “Childrenand Adolescents” for additional infor-mation on type 2 diabetes in childrenand adolescents.

Some studies question the validity ofA1C in the pediatric population, espe-cially among certain ethnicities, and sug-gest OGTT or FPG as more suitablediagnostic tests (62). 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 (63). The ADA ac-knowledges the limited data supportingA1C for diagnosing type 2 diabetes inchildren and adolescents. Although A1Cis not recommended for diagnosis of di-abetes in children with cystic fibrosis orsymptoms suggestive of acute onset oftype 1 diabetes and only A1C assays with-out interference are appropriate for chil-dren with hemoglobinopathies, the ADAcontinues to recommend A1C for diagnosisof type 2 diabetes in this cohort (64,65).

GESTATIONAL DIABETESMELLITUS

Recommendations

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

2.15 Test for gestational diabetes mel-litus at 24–28 weeks of gestationin pregnant women not previ-ously known to have diabetes. A

2.16 Test women with gestational di-abetes mellitus for prediabetes


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or diabetes at 4–12 weeks post-partum, using the 75-g oral glu-cose tolerance test and clinicallyappropriate nonpregnancy diag-nostic criteria. B

2.17 Women with a history of gesta-tional diabetes mellitus shouldhave lifelong screening for thedevelopment of diabetes or pre-diabetes at least every 3 years. B

2.18 Women with a history of gesta-tional diabetes mellitus found tohave prediabetes should receiveintensive lifestyle interventions ormetformin to prevent diabetes. A

DefinitionFor many years, GDMwas defined as anydegree of glucose intolerance that wasfirst recognized during pregnancy (40),regardless of whether the conditionmay have predated the pregnancy orpersisted after the pregnancy. This def-inition facilitated a uniform strategy fordetection and classification of GDM, butit was limited by imprecision.The ongoing epidemic of obesity and

diabetes has led to more type 2 diabetesin women of childbearing age, with anincrease in the number of pregnantwomen with undiagnosed type 2 dia-betes (66). Because of the number ofpregnant women with undiagnosed type2 diabetes, it is reasonable to test womenwith risk factors for type 2 diabetes (67)

(Table 2.3) at their initial prenatalvisit, using standard diagnostic criteria(Table 2.2). Women diagnosed with di-abetes by standard diagnostic criteriain the first trimester should be classifiedas having preexisting pregestational di-abetes (type 2 diabetes or, very rarely,type 1 diabetes or monogenic diabe-tes). Women found to have prediabetesin the first trimester may be encour-aged to make lifestyle changes to reducetheir risk of developing type 2 diabetes,and perhaps GDM, though more studyis needed (68). GDM is diabetes that isfirst diagnosed in the second or thirdtrimester of pregnancy that is not clearlyeither preexisting type 1 or type 2 di-abetes (see Section 14 “Managementof Diabetes in Pregnancy”). The Inter-national Association of the Diabetesand Pregnancy Study Groups (IADPSG)GDM diagnostic criteria for the 75-gOGTT as well as the GDM screeningand diagnostic criteria used in the two-step approach were not derived fromdata in the first half of pregnancy, so thediagnosis of GDM in early pregnancy byeither FPG or OGTT values is not evidencebased (69).

Because GDM confers increased riskfor the development of type 2 diabetesafter delivery (70,71) and because effec-tive prevention interventions are avail-able (72,73), women diagnosed withGDM should receive lifelong screeningfor prediabetes and type 2 diabetes.

DiagnosisGDM carries risks for the mother, fetus,andneonate.Notall adverseoutcomesareof equal clinical importance. The Hyper-glycemia and Adverse Pregnancy Out-come (HAPO) study (74), 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 24–28 weeks of ges-tation, even within ranges previously con-sidered normal for pregnancy. For mostcomplications, there was no threshold forrisk. These results have led to careful re-consideration of the diagnostic criteria forGDM. GDM diagnosis (Table 2.6) can beaccomplished with either of two strategies:

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, leadingsomeexperts to debate, and disagree on,optimal strategies for the diagnosis ofGDM.

One-Step Strategy

The IADPSG defined diagnostic cut pointsfor GDM as the average fasting, 1-h, and2-h PG values during a 75-g OGTT in

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 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 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 diabetes.If theplasmaglucose levelmeasured1hafter the load is$130mg/dL,135mg/dL, or140mg/dL (7.2mmol/L, 7.5mmol/L, or 7.8mmol/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 if at least two* of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h during OGTT) aremet or

exceeded:

Carpenter-Coustan (86) or NDDG (87)

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)



NDDG, National Diabetes Data Group. *ACOG notes that one elevated value can be used for diagnosis (82).


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women at 24–28 weeks of gestationwho participated in the HAPO study atwhich odds for adverse outcomes reached1.75 times the estimated odds of theseoutcomes at the mean fasting, 1-h, and2-h PG levels of the study population.This one-step strategy was anticipatedto significantly increase the incidence ofGDM (from 5–6% to 15–20%), primarilybecause only one abnormal value, nottwo, became sufficient to make the di-agnosis (75). The anticipated increase inthe incidence of GDM could have a sub-stantial 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 beendiagnosed with GDM by the one-step ap-proach, as compared with those without,were at 3.4-fold higher risk of developingprediabetes and type 2 diabetes and hadchildren with a higher risk of obesity andincreased body fat, suggesting that thelarger group of women identified by theone-step approach would benefit fromincreased screening for diabetes andprediabetes that would accompany ahistory of GDM (76). Nevertheless, theADA recommends these diagnostic cri-teria with the intent of optimizing ges-tational outcomes because these criteriawere the only ones based on pregnancyoutcomes rather than end points suchas prediction of subsequent maternaldiabetes.The expected benefits to the off-

spring are inferred from interventiontrials that focused on women with lowerlevels of hyperglycemia than identifiedusing older GDM diagnostic criteria.Those trials found modest benefits includ-ing reduced rates of large-for-gestational-age births and preeclampsia (77,78). Itis important to note that 80–90% ofwomen being treated for mild GDM inthese two randomized controlled trialscould be managed with lifestyle therapyalone. The OGTT glucose cutoffs in thesetwo trials overlapped with the thresh-olds recommended by the IADPSG, andin one trial (78), the 2-h PG threshold(140 mg/dL [7.8 mmol/L]) was lowerthan the cutoff recommended by theIADPSG (153 mg/dL [8.5 mmol/L]). Norandomized controlled trials of identify-ing and treating GDM using the IADPSG

criteria versus older criteria have beenpublished to date. Data are also lackingon how the treatment of lower levelsof hyperglycemia affects a mother’s fu-ture risk for the development of type 2diabetes and her offspring’s risk forobesity, diabetes, and other meta-bolic disorders. Additional well-designedclinical studies are needed to deter-mine the optimal intensity of monitor-ing and treatment of women with GDMdiagnosed by the one-step strategy(79,80).

Two-Step Strategy

In 2013, the National Institutes of Health(NIH) convened a consensus develop-ment conference to consider diagnosticcriteria for diagnosing GDM (81). 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) followedby a 3-h 100-g OGTT for those whoscreened positive. The American Col-lege of 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 (82). 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) (83). The highercutoff yielded sensitivity of 70–88% andspecificity of 69–89%, while the lowercutoff was 88–99% sensitive and 66–77% specific. Data regarding a cutoffof 135 mg/dL are limited. As for otherscreening tests, choice of a cutoff isbased upon the trade-off between sen-sitivity and specificity. The use of A1C at24–28 weeks of gestation as a screeningtest for GDM does not function as wellas the GLT (84).

Key factors cited by the NIH panel intheir decision-making process were thelack of clinical trial data demonstratingthe benefits of the one-step strategyand the potential negative consequencesof identifying a large group of womenwith GDM, including medicalization ofpregnancy with increased health careutilization and costs. Moreover, screeningwith a 50-g GLT does not require fastingand is therefore easier to accomplishfor many women. Treatment of higher-threshold maternal hyperglycemia, as

identified by the two-step approach,reduces rates of neonatal macrosomia,large-for-gestational-age births (85), andshoulder dystocia, without increasingsmall-for-gestational-age births. ACOGcurrently supports the two-step ap-proach but notes that one elevatedvalue, as opposed to two, may beused for the diagnosis of GDM (82). Ifthis approach is implemented, the in-cidence of GDM by the two-step strat-egy will likely increase markedly.ACOG recommends either of two sets ofdiagnostic thresholds for the 3-h 100-gOGTT (86,87). Each is based on differentmathematical conversions of the originalrecommended thresholds, which usedwhole blood and nonenzymatic methodsfor glucose determination. A secondaryanalysis of data from a randomized clin-ical trial of identification and treatmentof mild GDM (88) demonstrated thattreatment was similarly beneficial inpatients meeting only the lower thresh-olds (86) and in those meeting only thehigher thresholds (87). If the two-stepapproach is used, it would appear advan-tageous to use the lower diagnosticthresholds as shown 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 (89). 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-stepstrategy”) have been adopted interna-tionally, further evidence has emerged tosupport improved pregnancy outcomeswith cost savings (90) and may be thepreferred approach. Data comparingpopulation-wide outcomes with one-step versus two-step approaches havebeen inconsistent to date (91,92). Inaddition, pregnancies complicated byGDM per the IADPSG criteria, but notrecognized as such, have comparable


outcomes to pregnancies diagnosed asGDM by the more stringent two-stepcriteria (93,94). There remains strongconsensus that establishing a uniformapproach to diagnosing GDM will benefitpatients, caregivers, and policy makers.Longer-term outcome studies are cur-rently underway.

CYSTIC FIBROSIS–RELATEDDIABETES

Recommendations

2.19 Annual screening for cysticfibrosis–related diabetes withan oral glucose tolerance testshould begin by age 10 yearsin all patients with cystic fibrosisnot previously diagnosed withcystic fibrosis–related diabe-tes. B

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

2.21 Patients with cystic fibrosis–related diabetes should betreated with insulin to attain in-dividualized glycemic goals. A

2.22 Beginning 5 years after the di-agnosis of cystic fibrosis–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%of adults (95). Diabetes in this popu-lation, compared with individuals withtype 1 or type 2 diabetes, is associatedwith worse nutritional status, moresevere inflammatory lung disease,and greater mortality. Insulin insuffi-ciency is the primary defect in CFRD.Genetically determined b-cell func-tion and insulin resistance associatedwith infection and inflammation mayalso contribute to the developmentof CFRD. Milder abnormalities of glu-cose tolerance are even more commonand occur at earlier ages than CFRD.Whether individuals with IGT should betreated with insulin replacement hasnot currently been determined. Al-though screening for diabetes beforethe age of 10 years can identify riskfor progression to CFRD in those withabnormal glucose tolerance, no benefithas been established with respect to

weight, height, BMI, or lung function.Continuous glucose monitoring orHOMA of b-cell function (96) may bemore sensitive than OGTT to detectrisk for progression to CFRD; how-ever, evidence linking these resultsto long-term outcomes is lacking, andthese tests are not recommended forscreening (97).

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 (98). There are limitedclinical trial dataon therapy forCFRD.Thelargest study compared three regimens:premeal insulin aspart, repaglinide, ororal placebo in cystic fibrosis patientswith diabetes or abnormal glucose tol-erance. Participants all had weight loss inthe year preceding treatment; however,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 sustainedby 6 months. The placebo group contin-ued to lose weight (99). Insulin remainsthe most widely used therapy for CFRD(100).

Additional resources for the clinicalmanagement of CFRD can be found inthe position statement “Clinical CareGuidelines for Cystic Fibrosis2RelatedDiabetes: A Position Statement of theAmerican Diabetes Association and a Clin-ical Practice Guideline of the Cystic FibrosisFoundation, Endorsed by the PediatricEndocrine Society” (101) and in the In-ternational Society for Pediatric and Ad-olescent Diabetes’s 2014 clinical practiceconsensus guidelines (102).

POSTTRANSPLANTATIONDIABETES MELLITUS

Recommendations

2.23 Patients should be screenedafter organ transplantation forhyperglycemia, with a formaldiagnosis of posttransplantationdiabetes mellitus being bestmade once a patient is stableon an immunosuppressive regi-men and in the absence of anacute infection. E

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

2.25 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. “New-onset diabetes after transplantation”(NODAT) is one such designation thatdescribes individuals who develop new-onset diabetes following transplant.NODAT excludes patients with pretrans-plant diabetes that was undiagnosedas well as posttransplant hyperglycemiathat resolves by the time of discharge(103). Another term, “posttransplan-tation diabetes mellitus” (PTDM) (103,104), describes the presence of diabetesin the posttransplant setting irrespec-tive of the timing of diabetes onset.

Hyperglycemia is very common dur-ing the early posttransplant period, with;90% of kidney allograft recipients ex-hibiting hyperglycemia in the first fewweeks following transplant (103–106).In most cases, such stress- or steroid-induced hyperglycemia resolves by thetime of discharge (106,107). 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 provider isto treat hyperglycemia appropriately re-gardless of the type of immunosuppres-sion (103). Risk factors for PTDM includeboth general diabetes risks (such as age,family history of diabetes, etc.) as well astransplant-specific factors, such as useof immunosuppressant agents (108).Whereas posttransplantation hypergly-cemia is an important risk factor forsubsequent PTDM, a formal diagnosisof PTDM is optimally made once thepatient is stable on maintenance immu-nosuppression and in the absence ofacute infection (106–108). The OGTT isconsidered the gold standard test forthe diagnosis of PTDM (103,104,109,110). 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 studies havereported on the short- and long-term


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use of antihyperglycemic agents in thesetting of PTDM (108,111,112). Moststudies have reported that transplantpatients with hyperglycemia and PTDMafter transplantation have higher ratesof rejection, infection, and rehospitali-zation (106,108,113).Insulin therapy is the agent of choice

for the management of hyperglycemiaand diabetes in the hospital setting. Af-ter discharge, patients with preexistingdiabetes could go back on their pre-transplant regimen if they were in goodcontrol before transplantation. Thosewith previously poor control or with per-sistent hyperglycemia should continue in-sulin with frequent home self-monitoringof blood glucose to determine wheninsulin dose reductions may be neededand when it may be appropriate to switchto noninsulin agents.No studies to date have established

which noninsulin agents are safest ormost efficacious in PTDM. The choiceof agent is usually made based on theside effect profile of the medication andpossible interactions with the patient’simmunosuppression regimen (108). Drug

dose 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 (114), but its safety hasnot been determined in other types oforgan transplant. Thiazolidinediones havebeen used successfully in patients withliver and kidney transplants, but sideeffects include fluid retention, heart fail-ure, and osteopenia (115,116). Dipeptidylpeptidase 4 inhibitors do not interact withimmunosuppressant drugs and havedemonstrated safety in small clinical trials(117,118). Well-designed interventiontrials examining the efficacy and safetyof these and other antihyperglycemicagents in patients with PTDM are needed.

MONOGENIC DIABETESSYNDROMES

Recommendations

2.26 All children diagnosed with di-abetes in the first 6 months of

life should have immediate ge-netic testing for neonatal diabe-tes. A

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

2.28 In both instances, consulta-tion with a center specializingin diabetes genetics is recom-mended to understand the sig-nificance of thesemutations andhow best to approach furtherevaluation, treatment, and ge-netic counseling. E

Monogenic defects that cause b-cell dys-function, such as neonatal diabetes andMODY, represent a small fraction ofpatients with diabetes (,5%). Table 2.7describes the most common causes of

Table 2.7—Most common causes of monogenic diabetes (119)

Gene Inheritance Clinical features

MODY

GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typicallydoes not require treatment; microvascular complications are rare; smallrise 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 renal disease (typically cystic); genitourinaryabnormalities; atrophy of the pancreas; hyperuricemia; gout

Neonatal diabetes

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

INS AD Permanent: IUGR; insulin requiring

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

6q24(PLAGL1, HYMA1)

AD for paternalduplications

Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6,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.


monogenic diabetes. For a comprehen-sive list of causes, see Genetic Diagnosisof Endocrine Disorders (119).

Neonatal Diabetes

Diabetes occurring under 6 months ofage is termed “neonatal” or “congenital”diabetes, and about 80–85% of cases canbe found to have an underlying mono-genic cause (120). Neonatal diabetesoccurs much less often after 6 monthsof age, whereas autoimmune type 1 di-abetes rarely occurs before 6 monthsof age. Neonatal diabetes can either betransient or permanent. Transient dia-betes is most often due to overexpres-sion of genes on chromosome 6q24, isrecurrent in about half of cases, and maybe treatable with medications other thaninsulin. Permanent neonatal diabetes ismost commonly due to autosomal dom-inant mutations in the genes encoding theKir6.2 subunit (KCNJ11) and SUR1 subunit(ABCC8) of theb-cell KATP channel. Correctdiagnosis has critical implications becausemost patients with KATP-related neonataldiabetes will exhibit improved glycemiccontrol when treated with high-dose oralsulfonylureas instead of insulin. Insulingene (INS) mutations are the second mostcommon cause of permanent neonataldiabetes, and, while intensive insulinmanagement is currently the preferredtreatment strategy, there are impor-tant genetic considerations, as most ofthe mutations that cause diabetes aredominantly inherited.

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 in anautosomal dominant pattern with ab-normalities in at least 13 genes on dif-ferent chromosomes identified to date.The most commonly reported formsareGCK-MODY (MODY2), HNF1A-MODY(MODY3), and HNF4A-MODY (MODY1).Clinically, patients with GCK-MODY

exhibit 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 are

considered 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.

Diagnosis of Monogenic Diabetes

A diagnosis of one of the three mostcommon forms of MODY, includingGCK-MODY, HNF1A-MODY, and HNF4A-MODY, allows for more cost-effectivetherapy (no therapy for GCK-MODY;sulfonylureas as first-line therapy forHNF1A-MODY and HNF4A-MODY). Ad-ditionally, diagnosis can lead to iden-tification of other affected familymembers.

A diagnosis of MODY should be con-sidered in individuals who have atypicaldiabetes and multiple family memberswith diabetes not characteristic of type 1or type 2 diabetes, although admittedly“atypical diabetes” is becoming increas-ingly difficult to precisely define in theabsence of a definitive set of tests foreither typeofdiabetes. Inmost cases, thepresence of autoantibodies for type 1diabetes precludes further testing formonogenic diabetes, but the presence ofautoantibodies in patients with mono-genic diabetes has been reported (121).Individuals inwhommonogenic diabetesis suspected should be referred to aspecialist for further evaluation if avail-able, and consultation is available fromseveral centers. Readily available com-mercial genetic testing following thecriteria listed below now enables acost-effective (122), often cost-saving,genetic diagnosis that is increasinglysupported by health insurance. A bio-marker screening pathway such as thecombination of urinary C-peptide/creatinine ratio and antibody screeningmay aid in determining who should getgenetic testing for MODY (123). It iscritical to correctly diagnose one ofthe monogenic forms of diabetes be-cause these patients may be incorrectlydiagnosed with type 1 or type 2 diabetes,leading to suboptimal, even potentiallyharmful, treatment regimens and delaysin diagnosing other family members(124). The correct diagnosis is especiallycritical for those with GCK-MODY mu-tations where multiple studies haveshown that no complications ensue in

the absence of glucose-lowering ther-apy (125). Genetic counseling is re-commended to ensure that affectedindividuals understand the patterns ofinheritance and the importance of acorrect diagnosis.

The diagnosis of monogenic diabetesshould be considered in children andadults diagnosed with diabetes in earlyadulthood with the following findings:

○ Diabetes diagnosed within the first6 months of life (with occasional casespresenting later, mostly INS andABCC8 mutations) (120,126)

○ Diabetes without typical features oftype 1 or type 2 diabetes (negativediabetes-associated autoantibodies,nonobese, lacking other metabolicfeatures 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), es-pecially if nonobese

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