Diabetes Care Volume 41, Supplement 1, January 2018 S13

2. Classification and Diagnosis of American Association Diabetes: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S13–S27 | https://doi.org/10.2337/dc18-S002 .CASFCTO N IGOI FDIABETES OF DIAGNOSIS AND CLASSIFICATION 2.

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduc- tion. Readers who wish to comment 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. (due to autoimmune b-cell destruction, usually leading to absolute deficiency) 2. (due to a progressive loss of b-cell insulin secretion frequently on the background of ) 3. mellitus (GDM) (diabetes diagnosed in the second or third trimester of 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 and maturity-onset diabetes of the young [MODY]), diseases of the exocrine (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treat- ment of HIV/AIDS, or after organ transplantation)

This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position state- ment “Diagnosis and 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 important fi for determining therapy, but some individuals cannot be clearly classi ed as having Suggested citation: American Diabetes Associa- type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 tion. 2. Classification and diagnosis of diabetes: diabetes occurring only in adults and type 1 diabetes only in children are no longer Standards of Medical Care in Diabetesd2018. accurate, as both diseases occur in both age-groups. Children with type 1 diabe- Diabetes Care 2018;41(Suppl. 1):S13–S27 tes typically present with the hallmark symptoms of /, and approx- © 2017 by the American Diabetes Association. imately one-third present with diabetic (DKA) (2). The onset of type 1 Readers may use this article as long as the work is properly cited, the use is educational and not diabetes may be more variable in adults, and they may not present with the classic for profit, and the work is not altered. More infor- symptoms seen in children. Occasionally, patients with type 2 diabetes may present mation is available at http://www.diabetesjournals with DKA, particularly ethnic minorities (3). Although difficulties in distinguishing .org/content/license. S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

diabetes type may occur in all age-groups defects related to inflammation and met- that compared with FPG and A1C cut at onset, the true diagnosis becomes abolic stress among other contributors, points, the 2-h PG value diagnoses more more obvious over time. including genetic factors. Future classi- people with diabetes. In both type 1 and type 2 diabetes, fication schemes for diabetes will likely various genetic and environmental fac- focus on the pathophysiology of the un- tors can result in the progressive loss of derlying b-cell dysfunction and the stage A1C b-cell mass and/or function that mani- of disease as indicated by status Recommendations fests clinically as . Once (normal, impaired, or diabetes) (4). c To avoid misdiagnosis or missed hyperglycemia occurs, patients with all diagnosis, the A1C test should be forms of diabetes are at risk for devel- DIAGNOSTIC TESTS FOR DIABETES performed using a method that is oping the same chronic complications, Diabetes may be diagnosed based on certified by the NGSP and standard- although rates of progression may differ. plasma glucose criteria, either the fasting ized to the Diabetes Control and fi The identi cation of individualized thera- plasma glucose (FPG) or the 2-h plasma Complications Trial (DCCT) assay. B pies for diabetes in the future will require glucose (2-h PG) value during a 75-g oral c Marked discordance between mea- better characterization of the many paths (OGTT), or A1C cri- sured A1C and plasma glucose b to -cell demise or dysfunction (4). teria (6) (Table 2.2). levels should raise the possibility Characterization of the underlying Generally, FPG, 2-h PG during 75-g of A1C assay interference due to pathophysiology is more developed in OGTT, and A1C are equally appropriate hemoglobin variants (i.e., hemoglo- type 1 diabetes than in type 2 diabetes. for diagnostic testing. It should be noted binopathies) and consideration of fi It is now clear from studies of rst-degree that the tests do not necessarily detect using an assay without interference relatives of patients with type 1 diabetes diabetes in the same individuals. The ef- or plasma blood glucose criteria to that the persistent presence of two or ficacy of interventions for primary pre- diagnose diabetes. B more autoantibodies is an almost certain vention of type 2 diabetes (7,8) has c In conditions associated with in- predictor of clinical hyperglycemia and primarily been demonstrated among in- creased turnover, diabetes. The rate of progression is de- dividuals who have impaired glucose tol- such as sickle cell disease, pregnancy fi pendent on the age at rst detection of erance (IGT) with or without elevated (secondandthirdtrimesters),hemo- antibody, number of antibodies, antibody fasting glucose, not for individuals with dialysis, recent blood loss or transfu- fi speci city, and antibody titer. Glucose isolated (IFG) sion, or erythropoietin therapy, only and A1C levels rise well before the clinical or for those with defined by plasma blood glucose criteria should onset of diabetes, making diagnosis A1C criteria. be used to diagnose diabetes. B feasible well before the onset of DKA. Three The same tests may be used to screen distinct stages of type 1 diabetes can be for and diagnose diabetes and to detect The A1C test should be performed using a fi fi identi ed (Table 2.1)andserveasa individuals with prediabetes. Diabetes method that is certi ed by the NGSP framework for future research and regu- may be identified anywhere along the (www.ngsp.org) and standardized or latory decision-making (4,5). spectrum of clinical scenarios: in seem- traceable to the Diabetes Control and b The paths to -cell demise and dys- ingly low-risk individuals who happen to Complications Trial (DCCT) reference as- fi function are less well de ned in type 2 have glucose testing, in individuals tested say. Although point-of-care A1C assays fi b fi fi diabetes, but de cient -cell insulin se- based on diabetes risk assessment, and in may be NGSP certi ed, pro ciency testing cretion, frequently in the setting of insulin symptomatic patients. is not mandated for performing the test, resistance, appears to be the common de- so use of point-of-care assays for diagnos- nominator. Characterization of subtypes Fasting and 2-Hour Plasma Glucose tic purposes is not recommended but of this heterogeneous disorder have been The FPG and 2-h PG may be used to di- may be considered in the future if pro- developed and validated in Scandinavian agnose diabetes (Table 2.2). The concor- ficiency testing is performed, documented, and Northern European populations but dance between the FPG and 2-h PG tests anddeemedacceptable. have not been confirmed in other ethnic is imperfect, as is the concordance be- The A1C has several advantages com- and racial groups. Type 2 diabetes is pri- tweenA1Candeitherglucose-based pared with the FPG and OGTT, including marily associated with insulin secretory test. Numerous studies have confirmed greater convenience (fasting not required),

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 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 care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

Confirming the Diagnosis 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.* Unless there is a clear clinical diagnosis OR (e.g., patient in a hyperglycemic crisis 2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the or with classic symptoms of hyperglyce- $ WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.* mia and a random plasma glucose 200 OR mg/dL [11.1 mmol/L]), a second test is fi A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is required for con rmation. It is recom- NGSP certified and standardized to the DCCT assay.* mended that the same test be repeated OR or a different test be performed without In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma delay using a new blood sample for con- glucose $200 mg/dL (11.1 mmol/L). firmation. For example, if the A1C is 7.0% (53 mmol/mol) and a repeat result is 6.8% *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. (51 mmol/mol), the diagnosis of diabetes is confirmed. If two different tests (such greater preanalytical stability, and less red blood cell turnover, such as those as A1C and FPG) are both above the di- day-to-day perturbations during stress with the sickle cell trait, an A1C assay with- agnostic threshold, this also confirms and illness. However, these advantages out interference from hemoglobin variants the diagnosis. On the other hand, if a pa- may be offset by the lower sensitivity of should be used. An updated list of A1C tient has discordant results from two A1C at the designated cut point, greater assays with interferences is available at different tests, then the test result that cost, limited availability of A1C testing in www.ngsp.org/interf.asp. is above the diagnostic cut point should certain regions of the developing world, African Americans heterozygous for the be repeated, with consideration of the and the imperfect correlation between common hemoglobin variant HbS may possibility of A1C assay interference. The A1C and average glucose in certain indi- have, for any given level of mean glycemia, diagnosis is made on the basis of the con- viduals. National Health and Nutrition lower A1C by about 0.3% than those with- firmed test. For example, if a patient meets Examination Survey (NHANES) data indi- out the trait (11). Another genetic variant, the diabetes criterion of the A1C (two cate that an A1C cut point of $6.5% X-linked glucose-6-phosphate dehydro- results $6.5% [48 mmol/mol]) but not (48 mmol/mol) identifies a prevalence genase G202A, carried by 11% of African FPG (,126 mg/dL [7.0 mmol/L]), that per- of undiagnosed diabetes that is one-third Americans, was associated with a decrease son should nevertheless be considered to of that using glucose criteria (9). in A1C of about 0.8% in hemizygous men have diabetes. When using A1C to diagnose diabetes, and 0.7% in homozygous women com- Since all the tests have preanalytic and it is important to recognize that A1C is pared with those without the variant (12). analytic variability, it is possible that an an indirect measure of average blood Even in the absence of hemoglobin abnormal result (i.e., above the diagnostic glucose levels and to take other factors variants, A1C levels may vary with race/ threshold), when repeated, will produce a into consideration that may impact he- ethnicity independently of glycemia value below the diagnostic cut point. This moglobin glycation independently of (13–15). For example, African Americans scenario is likely for FPG and 2-h PG if the glycemia including age, race/ethnicity, may have higher A1C levels than non- glucose samples remain at room temper- and anemia/hemoglobinopathies. Hispanic whites with similar fasting and ature and are not centrifuged promptly. postglucose load glucose levels (16), and Because of the potential for preanalytic Age A1C levels may be higher for a given mean variability, it is critical that samples for The epidemiological studies that formed glucose concentration when measured plasma glucose be spun and separated the basis for recommending A1C to diag- with continuous glucose monitoring immediately after they are drawn. If pa- nose diabetes included only adult popula- (17). Though conflicting data exists, African tients have test results near the margins tions. Therefore, it remains unclear whether Americans may also have higher levels of the diagnostic threshold, the health care A1C and the same A1C cut point should be of and glycated albumin professional should follow the patient – used to diagnose diabetes in children and and lower levels of 1,5-anhydroglucitol, closely and repeat the test in 3 6 months. adolescents (see p. S20 SCREENING AND TESTING suggesting that their glycemic burden FOR TYPE 2 DIABETES AND PREDIABETES IN CHILDREN (particularly postprandially) may be higher CATEGORIES OF INCREASED RISK AND ADOLESCENTS for additional information) (18,19). The association of A1C with risk FOR DIABETES (PREDIABETES) (9,10). for complications appears to be similar in Recommendations African Americans and non-Hispanic c Race/Ethnicity/Hemoglobinopathies Screening for prediabetes and risk Hemoglobin variants can interfere with whites (20,21). for future diabetes with an informal the measurement of A1C, although most assessment of risk factors or vali- Red Blood Cell Turnover dated tools should be considered assays in use in the U.S. are unaffected by In conditions associated with increased the most common variants. Marked dis- in asymptomatic adults. B red blood cell turnover, such as sickle c crepancies between measured A1C and Testing for prediabetes and risk for cell disease, pregnancy (second and third future diabetes in asymptomatic plasma glucose levels should prompt con- trimesters), hemodialysis, recent blood people should be considered in sideration that the A1C assay may not be loss or transfusion, or erythropoietin ther- adults of any age who are over- reliable for that individual. For patients apy, only plasma blood glucose criteria weight or obese (BMI $25 kg/m2 with a hemoglobin variant but normal should be used to diagnose diabetes (22). S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

or $23 kg/m2 in Asian Americans) Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults and who have one or more addi- 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian tional risk factors for diabetes (Table Americans) adults who have one or more of the following risk factors: 2.3). B c First-degree relative with diabetes c High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific c For all people, testing should begin Islander) at age 45 years. B c History of CVD c If tests are normal, repeat testing car- c Hypertension ($140/90 mmHg or on therapy for hypertension) riedoutataminimumof3-yearin- c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL tervalsisreasonable.C (2.82 mmol/L) c To test for prediabetes, fasting plasma c Women with polycystic ovary syndrome c glucose, 2-h plasma glucose during Physical inactivity c Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis 75-g oral glucose tolerance test, and nigricans) A1C are equally appropriate. B 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly. c In patients with prediabetes, identify 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. and, if appropriate, treat other car- 4. For all other patients, testing should begin at age 45 years. diovascular disease risk factors. B 5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with c Testing for prediabetes should be consideration of more frequent testing depending on initial results and risk status. considered in children and adoles- cents who are overweight or obese (BMI .85th percentile for age and review of 44,203 individuals from 16 co- interventions and vigilant follow-up should sex, weight for height .85th per- hort studies with a follow-up interval be pursued for those considered at very centile, or weight .120% of ideal averaging 5.6 years (range 2.8–12 years), high risk (e.g., those with A1C .6.0% for height) and who have additional those with A1C between 5.5 and 6.0% [42 mmol/mol]). risk factors for diabetes (Table 2.5). E (between 37 and 42 mmol/mol) had a Table 2.4 summarizes the categories of substantially increased risk of diabetes prediabetes and Table 2.3 the criteria for Description (5-year incidence from 9 to 25%). Those prediabetes testing. The ADA diabetes “Prediabetes” is the term used for individ- with an A1C range of 6.0–6.5% (42– risk test is an additional option for screen- uals whose glucose levels do not meet the 48 mmol/mol) had a 5-year risk of devel- ing (Fig. 2.1) (diabetes.org/socrisktest). criteria for diabetes but are too high to be oping diabetes between 25 and 50% For additional background regarding risk considered normal (23,24). Patients with and a relative risk 20 times higher com- factors and screening for prediabetes, see prediabetes are defined by the presence pared with A1C of 5.0% (31 mmol/mol) pp. S19–S20 (SCREENING AND TESTING FOR TYPE 2 of IFG and/or IGT and/or A1C 5.7–6.4% (26). In a community-based study of Afri- DIABETES AND PREDIABETES IN ASYMPTOMATIC ADULTS (39–47 mmol/mol) (Table 2.4). Prediabe- can American and non-Hispanic white and SCREENING AND TESTING FOR TYPE 2 DIABETES tes should not be viewed as a clinical adults without diabetes, baseline A1C AND PREDIABETES IN CHILDREN AND ADOLESCENTS). entity in its own right but rather as an was a stronger predictor of subsequent increased risk for diabetes and cardio- diabetes and cardiovascular events TYPE 1 DIABETES vascular disease (CVD). Criteria for testing than fasting glucose (27). Other analyses for diabetes or prediabetes in asymp- Recommendations suggest that A1C of 5.7% (39 mmol/mol) tomatic adults is outlined in Table 2.3. c Plasma blood glucose rather than or higher is associated with a diabetes risk Prediabetes is associated with obesity (es- A1C should be used to diagnose the similar to that of the high-risk participants pecially abdominal or visceral obesity), acute onset of type 1 diabetes in in- in the Diabetes Prevention Program (DPP) dyslipidemia with high triglycerides and/or dividuals with symptoms of hypergly- (28), and A1C at baseline was a strong low HDL cholesterol, and hypertension. cemia. E predictor of the development of glucose- c Screening for type 1 diabetes with a defined diabetes during the DPP and its Diagnosis panel of autoantibodies is currently IFG is defined as FPG levels between follow-up (29). recommended only in the setting 100 and 125 mg/dL (between 5.6 and Hence, it is reasonable to consider an A1C of a research trial or in first-degree 6.9 mmol/L) (24,25) and IGT as 2-h PG range of 5.7–6.4% (39–47 mmol/mol) as family members of a proband with during 75-g OGTT levels between 140 and identifying individuals with prediabe- type 1 diabetes. B 199 mg/dL (between 7.8 and 11.0 mmol/L) tes. Similar to those with IFG and/or c Persistence of two or more autoan- (23). It should be noted that the World IGT, individuals with A1C of 5.7–6.4% tibodies predicts clinical diabetes Health Organization (WHO) and numerous (39–47 mmol/mol) should be informed and may serve as an indication for other diabetes organizations define the IFG of their increased risk for diabetes and intervention in the setting of a clin- cutoff at 110 mg/dL (6.1 mmol/L). CVD and counseled about effective ical trial. B As with the glucose measures, several strategies to lower their risks (see Sec- prospective studies that used A1C to tion 5 “Prevention or Delay of Type 2 predict the progression to diabetes as Diabetes”). Similar to glucose measure- Diagnosis defined by A1C criteria demonstrated a ments, the continuum of risk is curvi- In a patient with classic symptoms, strong, continuous association between A1C linear, so as A1C rises, the diabetes risk measurement of plasma glucose is suf- and subsequent diabetes. In a systematic rises disproportionately (26). Aggressive ficient to diagnose diabetes (symptoms care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

Table 2.4—Categories of increased risk for diabetes (prediabetes)* cohorts from Finland, Germany, and the FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) U.S. Of the 585 children who developed OR more than two autoantibodies, nearly 2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) 70% developed type 1 diabetes within OR 10 years and 84% within 15 years (31). fi fi A1C 5.7–6.4% (39–47 mmol/mol) These ndings are highly signi cant be- cause while the German group was re- *For all three tests, risk is continuous, extending below the lower limit of the range and becoming cruited from offspring of parents with disproportionately greater at the higher end of the range. type 1 diabetes, the Finnish and American groups were recruited from the general of hyperglycemia or hyperglycemic crisis also related to environmental factors population. Remarkably, the findings plus a random plasma glucose $200 mg/ that are still poorly defined. Although pa- in all three groups were the same, sug- dL [11.1 mmol/L]). In these cases, know- tients are not typically obese when they gesting that the same sequence of events ing the plasma glucose level is critical be- present with type 1 diabetes, obesity led to clinical disease in both “sporadic” cause, in addition to confirming that should not preclude the diagnosis. Pa- and familial cases of type 1 diabetes. In- symptoms are due to diabetes, it will in- tients with type 1 diabetes are also prone deed, the risk of type 1 diabetes increases form management decisions. Some pro- to other autoimmune disorders such as as the number of relevant autoantibodies viders may also want to know the A1C to Hashimoto thyroiditis, Graves disease, detected increases (32–34). determine how long a patient has had Addison disease, celiac disease, vitiligo, Although there is currently a lack of hyperglycemia. The criteria to diagnose autoimmune hepatitis, myasthenia gravis, accepted screening programs, one should diabetes are listed in Table 2.2. and pernicious anemia (see Section 3 consider referring relatives of those with “Comprehensive Medical Evaluation and type 1 diabetes for antibody testing for Immune-Mediated Diabetes Assessment of Comorbidities”). risk assessment in the setting of a clinical This form, previously called “insulin- research study (www.diabetestrialnet dependent diabetes” or “juvenile-onset Idiopathic Type 1 Diabetes .org). Widespread clinical testing of asymp- diabetes,” accounts for 5–10% of diabetes Some forms of type 1 diabetes have no tomatic low-risk individuals is not currently and is due to cellular-mediated autoimmune known etiologies. These patients have recommended due to lack of approved destruction of the pancreatic b-cells. Auto- permanent insulinopenia and are prone therapeutic interventions. Individuals who immune markers include islet cell auto- to DKA, but have no evidence of b-cell test positive should be counseled about antibodies and autoantibodies to GAD autoimmunity. Although only a minority the risk of developing diabetes, diabetes (GAD65), insulin, the tyrosine phospha- of patients with type 1 diabetes fall into symptoms, and DKA prevention. Numer- tases IA-2 and IA-2b, and ZnT8. Type 1 this category, of those who do, most are ous clinical studies are being conducted diabetes is defined by the presence of of African or Asian ancestry. Individuals to test various methods of preventing one or more of these autoimmune markers. with this form of diabetes suffer from ep- type 1 diabetes in those with evidence of The disease has strong HLA associations, isodic DKA and exhibit varying degrees of autoimmunity (www.clinicaltrials.gov). with linkage to the DQA and DQB . insulin deficiency between episodes. This These HLA-DR/DQ alleles can be either form of diabetes is strongly inherited and TYPE 2 DIABETES predisposing or protective. is not HLA associated. An absolute re- The rate of b-cell destruction is quite quirement for insulin replacement therapy Recommendations c Screening for type 2 diabetes with variable, being rapid in some individuals in affected patients may be intermittent. an informal assessment of risk fac- (mainly and children) and slow in tors or validated tools should be others (mainly adults). Children and ado- Testing for Type 1 Diabetes Risk considered in asymptomatic adults. B lescents may present with DKA as the first The incidence and prevalence of type 1 c Testing for type 2 diabetes in asymp- manifestation of the disease. Others have diabetes is increasing (30). Patients with tomatic people should be consid- modest fasting hyperglycemia that can type 1 diabetes often present with acute ered in adults of any age who are rapidly change to severe hyperglycemia symptoms of diabetes and markedly overweight or obese (BMI $25 and/or DKA with infection or other stress. elevated blood glucose levels, and ap- kg/m2 or $23 kg/m2 in Asian Amer- Adults may retain sufficient b-cell function proximately one-third are diagnosed icans) and who have one or more to prevent DKA for many years; such in- with life-threatening DKA (2). Several additional risk factors for diabetes dividuals eventually become dependent studies indicate that measuring islet au- (Table 2.3). B on insulin for survival and are at risk for toantibodies in relatives of those with c For all people, testing should begin DKA. At this latter stage of the disease, type 1 diabetes may identify individuals at age 45 years. B there is little or no insulin secretion, as who are at risk for developing type 1 di- c If tests are normal, repeat testing manifested by low or undetectable levels abetes (5). Such testing, coupled with ed- carried out at a minimum of 3-year of plasma C-. Immune-mediated di- ucation about diabetes symptoms and intervalsisreasonable.C abetes commonly occurs in childhood and close follow-up, may enable earlier iden- c To test for type 2 diabetes, fasting adolescence, but it can occur at any age, tification of type 1 diabetes onset. A study plasma glucose, 2-h plasma glucose even in the 8th and 9th decades of life. reported the risk of progression to type 1 during 75-g oral glucose tolerance test, Autoimmune destruction of b-cells has diabetes from the time of seroconversion and A1C are equally appropriate. B multiple genetic predispositions and is to autoantibody positivity in three pediatric S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Figure 2.1—ADA risk test (diabetes.org/socrisktest). care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

36). Type 2 diabetes frequently goes un- assessment tool, such as the ADA risk c In patients with diabetes, identify diagnosed for many years because hy- test (Fig. 2.1) (diabetes.org/socrisktest), and treat other cardiovascular dis- perglycemia develops gradually and, is recommended to guide providers on ease risk factors. B at earlier stages, is often not severe whether performing a diagnostic test c Testing for type 2 diabetes should enough for the patient to notice the clas- (Table 2.2) is appropriate. Prediabetes be considered in children and ado- sic diabetes symptoms. Nevertheless, and type 2 diabetes meet criteria for con- lescents who are overweight or even undiagnosed patients are at in- ditions in which early detection is appro- obese (BMI .85th percentile for creased risk of developing macrovascular priate. Both conditions are common and age and sex, weight for height and microvascular complications. impose significant clinical and public .85th percentile,orweight .120% Whereas patients with type 2 diabetes health burdens. There is often a long pre- of ideal for height) and who have may have insulin levels that appear nor- symptomatic phase before the diagnosis additional risk factors for diabetes mal or elevated, the higher blood glucose of type 2 diabetes. Simple tests to detect (Table 2.5). E levels in these patients would be expected preclinical disease are readily available. to result in even higher insulin values had The duration of glycemic burden is a strong Description their b-cell function been normal. Thus, predictor of adverse outcomes. There are Type 2 diabetes, previously referred to insulin secretion is defective in these pa- effective interventions that prevent pro- as “noninsulin-dependent diabetes” or tients and insufficient to compensate for gression from prediabetes to diabetes (see “adult-onset diabetes,” accounts for 90– insulin resistance. Insulin resistance may Section 5 “Prevention or Delay of Type 2 95% of all diabetes. This form encom- improve with weight reduction and/or Diabetes”) and reduce the risk of diabetes passes individuals who have relative pharmacologic treatment of hyperglyce- complications (see Section 9 “Cardiovas- (rather than absolute) insulin deficiency mia but is seldom restored to normal. cular Disease and Risk Management” and and have peripheral insulin resistance. The risk of developing type 2 diabe- Section 10 “Microvascular Complications At least initially, and often throughout tes increases with age, obesity, and lack and Foot Care”). their lifetime, these individuals may not of physical activity. It occurs more fre- Approximately one-quarter of people need insulin treatment to survive. quently in women with prior GDM, in with diabetes in the U.S. and nearly half There are various causes of type 2 di- those with hypertension or dyslipidemia, of Asian and Hispanic Americans with di- abetes. Although the specific etiologies and in certain racial/ethnic subgroups abetes are undiagnosed (37,38). Although are not known, autoimmune destruction (African American, American Indian, screening of asymptomatic individuals to of b-cells does not occur and patients do Hispanic/Latino, and Asian American). It identify those with prediabetes or diabe- not have any of the other known causes is often associated with a strong genetic tes might seem reasonable, rigorous clin- of diabetes. Most but not all patients with predisposition or family history in first- ical trials to prove the effectiveness of type 2 diabetes are overweight or obese. degree relatives, more so than type 1 di- such screening have not been conducted Excess weight itself causes some degree abetes. However, the genetics of type 2 and are unlikely to occur. of insulin resistance. Patients who are not diabetes is poorly understood. In adults A large European randomized con- obese or overweight by traditional weight without traditional risk factors for type 2 trolled trial compared the impact of criteria may have an increased percent- diabetes and/or younger age, consider screening for diabetes and intensive age of body fat distributed predominantly antibody testing to exclude the diagnosis multifactorial intervention with that of in the abdominal region. of type 1 diabetes (i.e., GAD). screening and routine care (39). General DKA seldom occurs spontaneously in practice patients between the ages of type 2 diabetes; when seen, it usually Screening and Testing for Type 2 40 and 69 years were screened for diabe- arises in association with the stress of an- Diabetes and Prediabetes in tes and randomly assigned by practice to other illness such as infection or with the Asymptomatic Adults intensive treatment of multiple risk fac- use of certain drugs (e.g., corticosteroids, Screening for prediabetes and type 2 di- tors or routine diabetes care. After 5.3 atypical antipsychotics, and sodium– abetes through an informal assessment years of follow-up, CVD risk factors were glucose cotransporter 2 inhibitors) (35, of risk factors (Table 2.3)orwithan modestly but significantly improved with intensive treatment compared with rou- tine care, but the incidence of first CVD Table 2.5—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic events or mortality was not significantly children and adolescents in a clinical setting* different between the groups (39). The Criteria excellent care provided to patients in c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or the routine care group and the lack of weight .120% of ideal for height) A an unscreened control arm limited the Plus one or more additional risk factors based on the strength of their association with diabetes as authors’ ability to determine whether indicated by evidence grades: screening and early treatment improved c Maternal or GDM during the child’s gestation A outcomes compared with no screening fi c Family history of type 2 diabetes in rst- or second-degree relative A and later treatment after clinical diag- c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, noses. Computer simulation modeling hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B studies suggest that major benefits are likely to accrue from the early diagnosis *Persons aged ,18 years. and treatment of hyperglycemia and S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

cardiovascular risk factors in type 2 reduced and individuals with false-negative limited data supporting A1C for diag- diabetes (40); moreover, screening, be- tests will be retested before substantial time nosing type 2 diabetes in children and ginning at age 30 or 45 years and indepen- elapses and complications develop (47). adolescents. Although A1C is not recom- dent of risk factors, may be cost-effective mended for diagnosis of diabetes in chil- (,$11,000 per quality-adjusted life-year Community Screening dren with cystic fibrosis or symptoms Ideally, testing should be carried out gained) (41). suggestive of acute onset of type 1 diabe- within a health care setting because of Additional considerations regarding tes and only A1C assays without interfer- the need for follow-up and treatment. testing for type 2 diabetes and prediabe- ence are appropriate for children with Community screening outside a health tes in asymptomatic patients include the hemoglobinopathies, the ADA continues care setting is generally not recom- following. to recommend A1C for diagnosis of type 2 mended because people with positive diabetes in this cohort (54,55). Age tests may not seek, or have access to, Age is a major risk factor for diabetes. appropriate follow-up testing and care. Testing should begin at age 45 years for However, in specific situations where an GESTATIONAL DIABETES MELLITUS all patients. Screening should be consid- adequate referral system is established Recommendations ered in overweight or obese adults of beforehand for positive tests, community c Test for undiagnosed diabetes at any age with one or more risk factors for screening may be considered. Commu- the first prenatal visit in those diabetes. nity testing may also be poorly targeted; with risk factors, using standard di- i.e., it may fail to reach the groups most at BMI and Ethnicity agnostic criteria. B In general, BMI $25 kg/m2 is a risk factor risk and inappropriately test those at very c Test for gestational diabetes melli- for diabetes. However, data suggest that low risk or even those who have already tus at 24–28 weeks of gestation in the BMI cut point should be lower for been diagnosed (48). pregnant women not previously the Asian American population (42,43). Screening in Dental Practices known to have diabetes. A The BMI cut points fall consistently be- Because is associated c Test women with gestational diabe- tween 23 and 24 kg/m2 (sensitivity of with diabetes, the utility of screening in a tes mellitus for persistent diabetes 80%) for nearly all Asian American sub- dental setting and referral to primary care at 4–12 weeks postpartum, using groups (with levels slightly lower for Jap- as a means to improve the diagnosis of the oral glucose tolerance test and anese Americans). This makes a rounded prediabetes and diabetes has been ex- clinically appropriate nonpregnancy cut point of 23 kg/m2 practical. An argu- plored (49–51), with one study estimating diagnostic criteria. E ment can be made to push the BMI cut that 30% of patients $30 years of age c Women with a history of gesta- point to lower than 23 kg/m2 in favor of seen in general dental practices had dys- tional diabetes mellitus should increased sensitivity; however, this would glycemia (51). Further research is needed have lifelong screening for the de- lead to an unacceptably low specificity to demonstrate the feasibility, effective- velopment of diabetes or prediabe- (13.1%). Data from the WHO also suggest ness, and cost-effectiveness of screening tes at least every 3 years. B that a BMI of $23 kg/m2 should be used in this setting. c Women with a history of gesta- to define increased risk in Asian Ameri- tional diabetes mellitus found to cans (44). The finding that half of diabetes Screening and Testing for Type 2 have prediabetes should receive in- in Asian Americans is undiagnosed sug- Diabetes and Prediabetes in Children tensive lifestyle interventions or gests that testing is not occurring at lower and Adolescents metformin to prevent diabetes. A BMI thresholds (37,38). In the last decade, the incidence and prev- Evidence also suggests that other pop- alence of type 2 diabetes in adolescents Definition ulations may benefit from lower BMI cut has increased dramatically, especially in For many years, GDM was defined as any points. For example, in a large multiethnic racial and ethnic minority populations degree of glucose intolerance that was cohort study, for an equivalent incidence (30). See Table 2.5 for recommendations first recognized during pregnancy (23), re- rate of diabetes, a BMI of 30 kg/m2 in non- on risk-based screening for type 2 diabe- gardless of whether the condition may Hispanic whites was equivalent to a BMI tes or prediabetes in asymptomatic chil- have predated the pregnancy or persisted of 26 kg/m2 in African Americans (45). dren and adolescents in a clinical setting. See after the pregnancy. This definition facili- Section 12 “Children and Adolescents” for tated a uniform strategy for detection and Medications additional information on type 2 diabetes classification of GDM, but it was limited by Certain medications, such as glucocorti- in children and adolescents. imprecision. coids, thiazide diuretics, and atypical an- Some studies question the validity of The ongoing epidemic of obesity and tipsychotics (46), are known to increase A1C in the pediatric population, especially diabetes has led to more type 2 diabetes the risk of diabetes and should be consid- among certain ethnicities, and suggest inwomenofchildbearingage,withanin- ered when deciding whether to screen. OGTT or FPG as more suitable diagnos- crease in the number of pregnant women Testing Interval tic tests (52). However, many of these with undiagnosed type 2 diabetes (56). The appropriate interval between screen- studies do not recognize that diabetes di- Because of the number of pregnant ing tests is not known (47). The rationale agnostic criteria are based on long-term women with undiagnosed type 2 diabetes, for the 3-year interval is that with this in- health outcomes, and validations are not it is reasonable to test women with risk terval, the number of false-positive tests currently available in the pediatric popu- factors for type 2 diabetes (Table 2.3)at that require confirmatory testing will be lation (53). The ADA acknowledges the their initial prenatal visit, using standard care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

diagnostic criteria (Table 2.2). Women di- One-Step Strategy Two-Step Strategy agnosed with diabetes by standard diag- The IADPSG defined diagnostic cut points In 2013, the National Institutes of Health nostic criteria in the first trimester should for GDM as the average fasting, 1-h, and (NIH) convened a consensus develop- be classified as having preexisting preges- 2-hPGvaluesduringa75-gOGTTin ment conference to consider diagnostic tational diabetes (type 2 diabetes or, very women at 24–28 weeks of gestation criteria for diagnosing GDM (68). The rarely, type 1 diabetes or monogenic dia- who participated in the HAPO study at 15-member panel had representatives betes). GDM is diabetes that is first diag- which odds for adverse outcomes reached from obstetrics/gynecology, maternal- nosed in the second or third trimester of 1.75 times the estimated odds of these fetal medicine, pediatrics, diabetes re- pregnancy that is not clearly either preex- outcomes at the mean fasting, 1-h, and search, biostatistics, and other related isting type 1 or type 2 diabetes (see Section 2-h PG levels of the study population. fields. The panel recommended a two- 13 “Management of Diabetes in Preg- This one-step strategy was anticipated to step approach to screening that used a nancy”). The International Association of significantly increase the incidence of 1-h 50-g glucose load test (GLT) followed the Study Groups GDM (from 5–6% to 15–20%), primarily by a 3-h 100-g OGTT for those who screened (IADPSG) GDM diagnostic criteria for the because only one abnormal value, not positive. The American College of Ob- 75-g OGTT as well as the GDM screening two, became sufficient to make the di- stetriciansandGynecologists(ACOG)rec- and diagnostic criteria used in the two- agnosis (63). The anticipated increase in ommends any of the commonly used step approach were not derived from the incidence of GDM could have a sub- thresholds of 130, 135, or 140 mg/dL for data in the first half of pregnancy, so stantial impact on costs and medical in- the 1-h 50-g GLT (69). A systematic review the diagnosis of GDM in early pregnancy frastructure needs and has the potential for the U.S. Preventive Services Task Force by either FPG or OGTT values is not evi- to “medicalize” previously compared GLT cutoffs of 130 mg/dL dence based (57). categorized as normal. Nevertheless, (7.2 mmol/L) and 140 mg/dL (7.8 mmol/L) Because GDM confers increased risk the ADA recommends these diagnostic (70). The higher cutoff yielded sensitivity for the development of type 2 diabetes criteria with the intent of optimizing of 70–88% and specificity of 69–89%, after delivery (58,59) and because effec- gestational outcomesbecausethesecri- while the lower cutoff was 88–99% sensi- tive prevention interventions are avail- teria were the only ones based on preg- tive and 66–77% specific. Data regarding able (60,61), women diagnosed with nancy outcomes rather than end points a cutoff of 135 mg/dL are limited. As for GDM should receive lifelong screening such as prediction of subsequent mater- other screening tests, choice of a cutoff for prediabetes and type 2 diabetes. nal diabetes. is based upon the trade-off between sen- The expected benefits to the offspring sitivity and specificity. The use of A1C at are inferred from intervention trials that 24–28 weeks of gestation as a screening Diagnosis GDM carries risks for the mother and ne- focused on women with lower levels of test for GDM does not function as well as fi onate. Not all adverse outcomes are of hyperglycemia than identi ed using older the GLT (71). equal clinical importance. The Hypergly- GDM diagnostic criteria. Those trials Key factors cited by the NIH panel in fi cemia and Adverse Pregnancy Outcome found modest bene ts including reduced their decision-making process were the (HAPO) study (62), a large-scale multina- rates of large-for-gestational-age births lack of clinical trial data demonstrating tional cohort study completed by more and preeclampsia (64,65). It is important the benefits of the one-step strategy – than 23,000 pregnant women, demon- to note that 80 90% of women being and the potential negative consequences strated that risk of adverse maternal, fe- treated for mild GDM in two randomized of identifying a large group of women tal, and neonatal outcomes continuously controlled trials could be managed with with GDM, including medicalization of increased as a function of maternal glyce- lifestyle therapy alone. The OGTT glucose pregnancy with increased health care uti- mia at 24–28 weeks of gestation, even cutoffs in these two trials overlapped lization and costs. Moreover, screening within ranges previously considered nor- with the thresholds recommended by with a 50-g GLT does not require fasting mal for pregnancy. For most complications, theIADPSG,andinonetrial(65),the2-h and is therefore easier to accomplish for there was no threshold for risk. These re- PG threshold (140 mg/dL [7.8 mmol/L]) many women. Treatment of higher-threshold sults have led to careful reconsideration of was lower than the cutoff recommended maternal hyperglycemia, as identified by the the diagnostic criteria for GDM. GDM di- by the IADPSG (153 mg/dL [8.5 mmol/L]). two-step approach, reduces rates of neona- agnosis (Table 2.6) can be accomplished No randomized controlled trials of identi- tal macrosomia, large-for-gestational-age with either of two strategies: fying and treating GDM using the IADPSG births (72), and shoulder dystocia, without criteria versus older criteria have been increasing small-for-gestational-age births. 1. “One-step” 75-g OGTT or published to date. Data are also lacking ACOG currently supports the two-step ap- 2. “Two-step” approach with a 50-g (non- on how the treatment of lower levels of proach (69) but most recently noted that fasting) screen followed by a 100-g hyperglycemia affects a mother’s future one elevated value, as opposed to two, may OGTT for those who screen positive risk for the development of type 2 diabe- be used for the diagnosis of GDM. If this tes and her offspring’s risk for obesity, approach is implemented, the incidence of Different diagnostic criteria will identify diabetes, and other metabolic disorders. GDM by the two-step strategy will likely in- different degrees of maternal hypergly- Additional well-designed clinical studies crease markedly. ACOG recommends either cemia and maternal/fetal risk, leading are needed to determine the optimal in- of two sets of diagnostic thresholds for the some experts to debate, and disagree on, tensity of monitoring and treatment of 3-h 100-g OGTT (73,74). Each is based on optimal strategies for the diagnosis of women with GDM diagnosed by the different mathematical conversions of GDM. one-step strategy (66,67). the original recommended thresholds, S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Table 2.6—Screening for and diagnosis of GDM One-step strategy Perform 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 overt diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded: c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) c 2 h: 153 mg/dL (8.5 mmol/L) Two-step 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 overt diabetes. If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT. Step 2: The 100-g OGTT should be performed when the patient is fasting. The diagnosis of GDM is made if at least two* of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h during OGTT) are met or exceeded: Carpenter-Coustan (73) or NDDG (74) c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) NDDG, National Diabetes Data Group. *ACOG recently noted that alternatively one elevated value can be used for diagnosis.

which used whole blood and nonenzymatic outcomes with one-step versus two-step approach further evaluation, treat- methods for glucose determination. A re- approaches have been inconsistent to date ment, and genetic counseling. E cent secondary analysis of data from a ran- (78,79). In addition, pregnancies compli- domized clinical trial of identification and cated by GDM per the IADPSG criteria, but Monogenic defects that cause b-cell dys- treatment of mild GDM (75) demon- not recognized as such, have comparable function, such as neonatal diabetes and strated that treatment was similarly ben- outcomes to pregnancies diagnosed as MODY, represent a small fraction of pa- eficial in patients meeting only the lower GDM by the more stringent two-step crite- tients with diabetes (,5%). Table 2.7 thresholds (73) and in those meeting only ria (80,81). There remains strong consen- describes the most common causes of the higher thresholds (74). If the two-step sus that establishing a uniform approach monogenic diabetes. For a comprehen- approach is used, it would appear advan- to diagnosing GDM will benefitpatients, sive list of causes, see Genetic Diagnosis tageous to use the lower diagnostic thresh- caregivers, and policy makers. Longer- of Endocrine Disorders (82). olds as shown in step 2 in Table 2.6. term outcome studies are currently under way. Future Considerations Neonatal Diabetes The conflicting recommendations from MONOGENIC DIABETES Diabetes occurring under 6 months of age expert groups underscore the fact that SYNDROMES is termed “neonatal” or “congenital” di- there are data to support each strategy. abetes, and about 80–85% of cases can be Recommendations A cost-benefit estimation comparing the found to have an underlying monogenic c All children diagnosed with diabe- two strategies concluded that the one- cause (83). Neonatal diabetes occurs much tes in the first 6 months of life step approach is cost-effective only if less often after 6 months of age, whereas should have immediate genetic patients with GDM receive postdelivery autoimmune type 1 diabetes rarely occurs testing for neonatal diabetes. A counseling and care to prevent type 2 di- before 6 months of age. Neonatal diabetes c Children and adults, diagnosed in abetes (76). The decision of which strategy can either be transient or permanent. Tran- early adulthood, who have diabetes to implement must therefore be made sient diabetes is most often due to over- not characteristic of type 1 or type 2 basedontherelativevaluesplacedonfac- expression of genes on 6q24, diabetes that occurs in successive tors that have yet to be measured (e.g., is recurrent in about half of cases, and may generations (suggestive of an auto- willingness to change practice based on be treatable with medications other than somal dominant pattern of inheri- correlation studies rather than intervention insulin. Permanent neonatal diabetes is tance) should have genetic testing trial results, available infrastructure, and most commonly due to autosomal domi- for maturity-onset diabetes of the importance of cost considerations). nant in the genes encoding the young. A As the IADPSG criteria (“one-step strat- Kir6.2 subunit (KCNJ11) and SUR1 subunit c In both instances, consultation egy”) have been adopted internationally, (ABCC8)oftheb-cell K channel. Correct with a center specializing in diabe- ATP further evidence has emerged to support diagnosis has critical implications because tesgeneticsisrecommendedto improved pregnancy outcomes with cost most patients with K -related neonatal understand the significance of ATP savings (77) and may be the preferred ap- diabetes will exhibit improved glycemic these mutations and how best to proach. Data comparing population-wide control when treated with high-dose oral care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

Table 2.7—Most common causes of monogenic diabetes (82) Inheritance Clinical features MODY GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does not require 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 early adulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal ; sensitive to sulfonylureas HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout Neonatal diabetes KCNJ11 AD Permanentor transient: IUGR; possibledevelopmentaldelay and seizures; responsive to sulfonylureas INS AD Permanent: IUGR; insulin requiring ABCC8 AD Transient or permanent: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 (PLAGL1, HYMA1) AD for paternal duplications Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, paternal duplication or maternal defect; may be treatable with medications other than insulin GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine insufficiency; insulin requiring EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine insufficiency; 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.

sulfonylureas instead of insulin. Insulin gene (MODY2), HNF1A-MODY (MODY3), and therapy for GCK-MODY; sulfonylureas as (INS) mutations are the second most com- HNF4A-MODY (MODY1). first-line therapy for HNF1A-MODY and mon cause of permanent neonatal dia- Clinically, patients with GCK-MODY ex- HNF4A-MODY). Additionally, diagnosis betes, and, while treatment presently is hibit mild, stable, fasting hyperglycemia canleadtoidentification of other affected intensive insulin management, there are and do not require antihyperglycemic family members. important genetic considerations, as most therapy except sometimes during preg- A diagnosis of MODY should be consid- of the mutations that cause diabetes are nancy. Patients with HNF1A- or HNF4A- ered in individuals who have atypical di- dominantly inherited. MODY usually respond well to low doses abetes and multiple family members with of sulfonylureas, which are considered diabetes not characteristic of type 1 or Maturity-Onset Diabetes of the Young first-line therapy. Mutations or deletions in type 2 diabetes, although admittedly “atyp- MODY is frequently characterized by on- HNF1B are associated with renal cysts and ical diabetes” is becoming increasingly set of hyperglycemia at an early age (clas- uterine malformations (renal cysts and di- difficult to precisely define in the absence sically before age 25 years, although abetes [RCAD] syndrome). Other extremely of a definitive set of tests for either type diagnosis may occur at older ages). rare forms of MODY have been reported to of diabetes. In most cases, the presence of MODY is characterized by impaired insu- involve other factor genes in- autoantibodies for type 1 diabetes pre- lin secretion with minimal or no defects in cluding PDX1 (IPF1)andNEUROD1. cludes further testing for monogenic dia- insulin action (in the absence of coexis- betes, but the presence of autoantibodies tent obesity). It is inherited in an autoso- Diagnosis in patients with monogenic diabetes has mal dominant pattern with abnormalities A diagnosis of one of the three most com- been reported (84). Individuals in whom in at least 13 genes on different chromo- mon forms of MODY including GCK- monogenic diabetes is suspected should somes identified to date. The most com- MODY, HNF1A-MODY, and HNF4A-MODY be referred to a specialist for further eval- monly reported forms are GCK-MODY allows for more cost-effective therapy (no uation if available, and consultation is S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

available from several centers. Readily Insulin remains the most widely used c Patients with cystic fibrosis–related available commercial genetic testing fol- therapy for CFRD (94). diabetes should be treated with in- lowing the criteria listed below now Additional resources for the clinical sulin to attain individualized glyce- enables a cost-effective (85), often cost- management of CFRD can be found in mic goals. A saving, genetic diagnosis that is increas- the position statement “Clinical Care c Beginning 5 years after the diagnosis ingly supported by health insurance. A Guidelines for Cystic Fibrosis–Related Di- of cystic fibrosis–related diabetes, biomarker screening pathway such as the abetes: A Position Statement of the annual monitoring for complications combination of urinary C-peptide/creatinine American Diabetes Association and a Clin- of diabetes is recommended. E ratio and antibody screening may aid in ical Practice Guideline of the Cystic Fibro- determining who should get genetic sis Foundation, Endorsed by the Pediatric Cystic fibrosis–related diabetes (CFRD) is testing for MODY (86). It is critical to cor- Endocrine Society” (95) and in the Interna- the most common comorbidity in people rectly diagnose one of the monogenic tional Society for Pediatric and Adoles- with cystic fibrosis, occurring in about formsofdiabetesbecausethesepa- cent Diabetes’s 2014 clinical practice 20% of adolescents and 40–50% of adults. tients may be incorrectly diagnosed consensus guidelines (96). Diabetes in this population, compared with type 1 or type 2 diabetes, leading to with individuals with type 1 or type 2 di- suboptimal, even potentially harmful, treat- abetes, is associated with worse nutri- ment regimens and delays in diagnosing POSTTRANSPLANTATION tional status, more severe inflammatory other family members (87). The correct di- DIABETES MELLITUS lung disease, and greater mortality. Insu- agnosis is especially critical for those with Recommendations lin insufficiency is the primary defect in GCK-MODY mutations where multiple c Patients should be screened after CFRD. Genetically determined b-cell func- studies have shown that no complications organ transplantation for hypergly- tion and insulin resistance associated with ensue in the absence of glucose-lowering cemia, with a formal diagnosis of infection and inflammation may also con- therapy (88). Genetic counseling is rec- posttransplantation diabetes melli- ommended to ensure that affected individ- tribute to the development of CFRD. tus being best made once a patient uals understand the patterns of inheritance Milder abnormalities of glucose tolerance is stable on an immunosuppressive and the importance of a correct diagnosis. are even more common and occur at ear- regimen and in the absence of an The diagnosis of monogenic diabetes lier ages than CFRD. Whether individuals acute infection. E should be considered in children and with IGT should be treated with insulin c The oral glucose tolerance test is adults diagnosed with diabetes in early replacement has not currently been de- the preferred test to make a diag- adulthood with the following findings: termined. Although screening for diabe- nosis of posttransplantation diabe- tesbeforetheageof10yearscanidentify tes mellitus. B ○ Diabetes diagnosed within the first risk for progression to CFRD in those with c Immunosuppressive regimens shown 6 months of life (with occasional cases abnormal glucose tolerance, no benefit to provide the best outcomes for pa- presenting later, mostly INS and ABCC8 hasbeenestablishedwithrespectto tient and graft survival should be mutations) (83,89) weight, height, BMI, or lung function. used, irrespective of posttransplanta- ○ Diabetes without typical features of Continuous glucose monitoring or HOMA tion diabetes mellitus risk. E type 1 or type 2 diabetes (negative di- of b-cell function (90) may be more sen- abetes-associated autoantibodies, sitive than OGTT to detect risk for pro- Several terms are used in the literature to nonobese, lacking other metabolic fea- gression to CFRD; however, evidence describe the presence of diabetes follow- tures, especially with strong family linking these results to long-term out- ing organ transplantation. “New-onset di- history of diabetes) comes is lacking, and these tests are not abetes after transplantation” (NODAT) is ○ Stable, mild fasting hyperglycemia recommended for screening (91). one such designation that describes indi- (100–150 mg/dL [5.5–8.5 mmol/L]), CFRD mortality has significantly de- viduals who develop new-onset diabetes stable A1C between 5.6 and 7.6% (be- creased over time, and the gap in mortal- following transplant. NODAT excludes pa- tween 38 and 60 mmol/mol), espe- ity between cystic fibrosis patients with tients with pretransplant diabetes that cially if nonobese and without diabetes has considerably was undiagnosed as well as posttrans- narrowed (92). There are limited clinical plant hyperglycemia that resolves by the CYSTIC FIBROSIS–RELATED trial data on therapy for CFRD. The largest time of discharge (97). Another term, DIABETES study compared three regimens: premeal “posttransplantation diabetes mellitus” insulin aspart, repaglinide, or oral placebo (PTDM) (97,98), describes the presence Recommendations in cystic fibrosis patients with diabetes or of diabetes in the posttransplant setting c Annual screening for cystic fibrosis– abnormal glucose tolerance. Participants irrespective of the timing of diabetes onset. related diabetes with oral glucose all had weight loss in the year preced- Hyperglycemia is very common during tolerance test should begin by age ing treatment; however, in the insulin- the early posttransplant period, with 10 years in all patients with cystic fi- treated group, this pattern was reversed, ;90% of kidney allograft recipients ex- brosis not previously diagnosed with and patients gained 0.39 (6 0.21) BMI hibiting hyperglycemia in the first few cystic fibrosis–related diabetes. B units (P 5 0.02). The repaglinide-treated weeks following transplant (97–100). c A1C is not recommended as a group had initial weight gain, but this was In most cases, such stress- or steroid- screening test for cystic fibrosis– not sustained by 6 months. The placebo induced hyperglycemia resolves by the related diabetes. B group continued to lose weight (93). time of discharge (100,101). Although care.diabetesjournals.org Classification and Diagnosis of Diabetes S25

the use of immunosuppressive therapies metformin was safe to use in renal trans- transethnic genome-wide meta-analysis. PLoS is a major contributor to the development plant recipients (108), but its safety has Med 2017;14:e1002383 of PTDM, the risks of transplant rejection not been determined in other types of 13. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in outweigh the risks of PTDM and the role organ transplant. Thiazolidinediones hemoglobin A1c levels: a cross-sectional analysis of the diabetes care provider is to treat have been used successfully in patients of 2 studies. Ann Intern Med 2010;152:770–777 hyperglycemia appropriately regard- with liver and kidney transplants, but 14. Kumar PR, Bhansali A, Ravikiran M, et al. Util- less of the type of immunosuppression side effects include fluid retention, heart ity of in diagnosing type 2 (97). Risk factors for PTDM include both failure, and osteopenia (109,110). Dipep- diabetes mellitus: a community-based study. J Clin Endocrinol Metab 2010;95:2832–2835 general diabetes risks (such as age, fam- tidyl peptidase 4 inhibitors do not interact 15. Herman WH. Are there clinical implications of ily history of diabetes, etc.) as well as with immunosuppressant drugs and have racial differences in HbA1c? Yes, to not consider transplant-specific factors, such as use demonstrated safety in small clinical trials can do great harm! Diabetes Care 2016;39:1458– of immunosuppressant agents (102). (111,112). Well-designed intervention tri- 1461 Whereas posttransplantation hyperglyce- als examining the efficacy and safety of 16. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes Prevention Program Research Group. Differences mia is an important risk factor for subse- these and other antihyperglycemic agents in A1C by race and ethnicity among patients with quent PTDM, a formal diagnosis of PTDM in patients with PTDM are needed. impaired glucose tolerance in the Diabetes Pre- is optimally made once the patient is sta- vention Program. Diabetes Care 2007;30:2453– 2457 ble on maintenance immunosuppression References andintheabsenceofacuteinfection 17. Bergenstal RM, Gal RL, Connor CG, et al.; T1D 1. American Diabetes Association. Diagnosis and Exchange Racial Differences Study Group. Racial (100–102). The OGTT is considered the classification of diabetes mellitus. Diabetes Care differences in the relationship of glucose concen- gold standard test for the diagnosis of 2014;37(Suppl. 1):S81–S90 trations and hemoglobin A1c levels. Ann Intern PTDM (97,98,103,104). However, screen- 2.DabeleaD,RewersA,StaffordJM,etal.; Med 2017;167:95–102 ing patients using fasting glucose and/or SEARCH for Diabetes in Youth Study Group. Trends 18. Selvin E, Steffes MW, Ballantyne CM, in the prevalence of ketoacidosis at diabetes diag- A1C can identify high-risk patients requir- Hoogeveen RC, Coresh J, Brancati FL. Racial differ- nosis: the SEARCH for Diabetes in Youth Study. ences in glycemic markers: a cross-sectional anal- ing further assessment and may reduce Pediatrics 2014;133:e938–e945 ysis of community-based data. Ann Intern Med the number of overall OGTTs required. 3. Newton CA, Raskin P. in 2011;154:303–309 Few randomized controlled studies type 1 and type 2 diabetes mellitus: clinical and 19. Herman WH, Dungan KM, Wolffenbuttel have reported on the short- and long- biochemical differences. Arch Intern Med 2004; BHR, et al. Racial and ethnic differences in mean 164:1925–1931 plasma glucose, hemoglobin A1c, and 1,5- term use of antihyperglycemic agents in 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differen- anhydroglucitol in over 2000 patients with the setting of PTDM (102,105,106). Most tiation of diabetes by pathophysiology, natural his- type 2 diabetes. J Clin Endocrinol Metab 2009; studies have reported that transplant pa- tory, and prognosis. Diabetes 2017;66:241–255 94:1689–1694 tients with hyperglycemia and PTDM af- 5. Insel RA, Dunne JL, Atkinson MA, et al. Staging 20. Selvin E, Rawlings AM, Bergenstal RM, Coresh fi ter transplantation have higher rates of presymptomatic type 1 diabetes: a scienti c J, Brancati FL. No racial differences in the associ- statement of JDRF, the Endocrine Society, and ation of glycated hemoglobin with kidney disease rejection, infection, and rehospitalization the American Diabetes Association. Diabetes and cardiovascular outcomes. Diabetes Care (100,102,107). 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