2. Classification and Diagnosis of Diabetes

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Diabetes Care Volume 40, Supplement 1, January 2017 S11

2. Classification and Diagnosis American Diabetes Association of Diabetes Diabetes Care 2017;40(Suppl. 1):S11–S24 | DOI: 10.2337/dc17-S005

CLASSIFICATION Diabetes can be classiﬁed into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to ab- DIABETES OF DIAGNOSIS AND CLASSIFICATION 2. solute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. 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 drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position statement “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 for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, patients with type 2 diabetes may present with diabetic ketoacidosis (DKA), particularly ethnic minorities (2). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with DKA (3). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in children. Although difficulties in distin- guishing diabetes type may occur in all age-groups at onset, the true diagnosis becomes more obvious over time. In October 2015, the ADA, JDRF, the European Association for the Study of Di- abetes, and the American Association of Clinical Endocrinologists convened the Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Re- search Symposium (4). The goals of the symposium were to discuss the genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, to determine appropriate therapeutic approaches based on disease pathophysiology and stage, and to define research gaps hindering a personalized approach to treatment. The experts agreed that in both type 1 and type 2 diabetes, various genetic b and environmental factors can result in the progressive loss of -cell mass and/or Suggested citation: American Diabetes Associa- function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, tion. Classification and diagnosis of diabetes. patients with all forms of diabetes are at risk for developing the same complications, Sec. 2. In Standards of Medical Care in Diabetesd although rates of progression may differ. They concluded that the identification of 2017. Diabetes Care 2017;40(Suppl. 1):S11–S24 individualized therapies for diabetes in the future will require better characteriza- © 2017 by the American Diabetes Association. tion of the many paths to b-cell demise or dysfunction. Readers may use this article as long as the work is properly cited, the use is educational and not Characterization of the underlying pathophysiology is much more developed in for profit, and the work is not altered. More infor- type 1 diabetes than in type 2 diabetes. It is now clear from studies of first-degree mation is available at http://www.diabetesjournals relatives of patients with type 1 diabetes that the persistent presence of two or .org/content/license. S12 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

more autoantibodies is an almost cer- interventions for primary prevention of advantages may be offset by the lower tain predictor of clinical hyperglycemia type 2 diabetes (7,8) has primarily been sensitivity of A1C at the designated cut and diabetes. The rate of progression is demonstrated among individuals with point, greater cost, limited availability dependent on the age at first detection impaired glucose tolerance (IGT), not of A1C testing in certain regions of the of antibody, number of antibodies, anti- for individuals with isolated impaired developing world, and the imperfect body specificity, and antibody titer. Glu- fasting glucose (IFG) or for those with correlation between A1C and average cose and A1C levels rise well before the prediabetes defined by A1C criteria. glucose in certain individuals. National clinical onset of diabetes, making diag- The same tests may be used to screen Health and Nutrition Examination Survey nosis feasible well before the onset of for and diagnose diabetes and to detect (NHANES) data indicate that an A1C cut DKA. Three distinct stages of type 1 di- individuals with prediabetes. Diabetes point of $6.5% (48 mmol/mol) identifies abetes can be identified (Table 2.1) and maybeidentified anywhere along the one-third fewer cases of undiagnosed di- serve as a framework for future research spectrum of clinical scenarios: in seem- abetes than a fasting glucose cut point and regulatory decision making (4,5). ingly low-risk individuals who happen of $126 mg/dL (7.0 mmol/L) (9). The paths to b-cell demise and dys- to have glucose testing, in individuals When using A1C to diagnose diabetes, function are less well definedintype2 tested based on diabetes risk assess- it is important to recognize that A1C is diabetes, but deficient b-cell insulin se- ment, and in symptomatic patients. an indirect measure of average blood glu- cretion frequently in the setting of insu- cose levels and to take other factors into lin resistance appears to be the common Fasting and 2-Hour Plasma Glucose The FPG and 2-h PG may be used to di- considerationthatmayimpact hemoglobin denominator. Characterization of sub- agnose diabetes (Table 2.2). The concor- glycation independently of glycemia in- types of this heterogeneous disorder dance between the FPG and 2-h PG tests cluding age, race/ethnicity, and anemia/ have been developed and validated in is imperfect, as is the concordance be- hemoglobinopathies. Scandinavian and Northern European tween A1C and either glucose-based Age populations, but have not been con- test. Numerous studies have confirmed The epidemiological studies that formed firmed in other ethnic and racial groups. that,comparedwithFPGandA1Ccut the basis for recommending A1C to di- Type 2 diabetes is primarily associated points, the 2-h PG value diagnoses agnose diabetes included only adult pop- with insulin secretory defects related more people with diabetes. ulations. Therefore, it remains unclear if to inflammation and metabolic stress among other contributors including A1C and the same A1C cut point should A1C be used to diagnose diabetes in children genetic factors. Future classification The A1C test should be performed and adolescents (9,10). schemes for diabetes will likely focus using a method that is certified by the on the pathophysiology of the under- NGSP (www.ngsp.org) and standardized Race/Ethnicity lying b-cell dysfunction and the stage or traceable to the Diabetes Control and A1C levels may vary with race/ethnicity of disease as indicated by glucose status Complications Trial (DCCT) reference as- independently of glycemia (11,12). For (normal, impaired, or diabetes) (4). say. Although point-of-care A1C assays example, African Americans may have may be NGSP certified, proficiency test- higher A1C levels than non-Hispanic DIAGNOSTIC TESTS FOR DIABETES ing is not mandated for performing the whites despite similar fasting and post- Diabetes may be diagnosed based on test, so use of point-of-care assays for glucose load glucose levels (13). Though plasma glucose criteria, either the fast- diagnostic purposes is not recommen- thereissomeconflicting data, African ing plasma glucose (FPG) or the 2-h ded but may be considered in the future Americans may also have higher levels plasma glucose (2-h PG) value after a if proficiency testing is performed and of fructosamine and glycated albumin 75-g oral glucose tolerance test (OGTT) documented. and lower levels of 1,5-anhydroglucitol, or A1C criteria (1,6) (Table 2.2). The A1C has several advantages com- suggesting that their glycemic burden FPG, 2-h PG after 75-g OGTT, and A1C pared with the FPG and OGTT, including (particularly postprandially) may be are equally appropriate for diagnostic greater convenience (fasting not re- higher (14,15). The association of A1C testing. It should be noted that the tests quired), greater preanalytical stability, with risk for complications appears to do not necessarily detect diabetes in and less day-to-day perturbations dur- be similar in African Americans and the same individuals. The efficacy of ing stress and illness. However, these non-Hispanic whites (16).

Table 2.1—Staging of type 1 diabetes (4,5) Stage 1 Stage 2 Stage 3 Stage 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 care.diabetesjournals.org Classiﬁcation and Diagnosis of Diabetes S13

Table 2.2—Criteria for the diagnosis of diabetes c To test for prediabetes, fasting FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* plasma glucose, 2-h plasma glucose OR after 75-g oral glucose tolerance 2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described test, and A1C are equally appropri- by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose ate. B dissolved in water.* c In patients with prediabetes, OR identify and, if appropriate, treat $ A1C 6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that other cardiovascular disease risk is NGSP certified and standardized to the DCCT assay.* factors. B OR c Testing for prediabetes should be In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma considered in children and ado- glucose $200 mg/dL (11.1 mmol/L). lescents who are overweight or *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. obeseandwhohavetwoormore additional risk factors for diabetes. E Hemoglobinopathies/Red Blood Cell FPG (,126 mg/dL [7.0 mmol/L]), that Turnover person should nevertheless be consid- Interpreting A1C levels in the presence ered to have diabetes. Description of certain hemoglobinopathies may be Sinceallthetestshavepreanalytic In 1997 and 2003, the Expert Committee fi problematic. For patients with an abnor- and analytic variability, it is possible on the Diagnosis and Classi cation of mal hemoglobin but normal red blood that an abnormal result (i.e., above the Diabetes Mellitus (17,18) recognized a cell turnover, such as those with the diagnostic threshold), when repeated, group of individuals whose glucose lev- sickle cell trait, an A1C assay without will produce a value below the diagnos- els did not meet the criteria for diabetes interference from abnormal hemoglo- tic cut point. This scenario is likely for but were too high to be considered nor- “ ” bins should be used. An updated list of FPG and 2-h PG if the glucose samples mal. Prediabetes is the term used for interferences is available at www.ngsp remain at room temperature and are individuals with IFG and/or IGT and/or – – .org/interf.asp. not centrifuged promptly. Because of A1C 5.7 6.4% (39 47 mmol/mol). Pre- In conditions associated with in- the potential for preanalytic variability, diabetes should not be viewed as a clin- creased red blood cell turnover, such it is critical that samples for plasma glu- ical entity in its own right but rather as as pregnancy (second and third trimes- cose be spun and separated immedi- an increased risk for diabetes (Table 2.3) ters), hemodialysis, recent blood loss or ately after they are drawn. If patients and cardiovascular disease (CVD). transfusion, or erythropoietin therapy, have test results near the margins of Prediabetes is associated with obe- only blood glucose criteria should be the diagnostic threshold, the health sity (especially abdominal or visceral used to diagnose diabetes. care professional should follow the pa- obesity), dyslipidemia with high triglyc- tient closely and repeat the test in erides and/or low HDL cholesterol, and fi Con rming the Diagnosis 3–6months. hypertension. Unless there is a clear clinical diagnosis (e.g., patient in a hyperglycemic crisis or CATEGORIES OF INCREASED RISK Diagnosis with classic symptoms of hyperglycemia FOR DIABETES (PREDIABETES) The Expert Committee on the Diagnosis and a random plasma glucose $200 and Classification of Diabetes Mellitus Recommendations mg/dL [11.1 mmol/L]), a second test is re- (17,18) defined IFG as FPG levels be- c Screening for prediabetes and risk quired for confirmation. It is recom- tween 100 and 125 mg/dL (between for future diabetes with an infor- mended that the same test be repeated 5.6 and 6.9 mmol/L) and IGT as 2-h PG mal assessment of risk factors or without delay using a new blood sample after 75-g OGTT levels between 140 and validated tools should be consid- for confirmation because there will be a 199 mg/dL (between 7.8 and 11.0 mmol/L). ered in asymptomatic adults. B greater likelihood of concurrence. For ex- It should be noted that the World Health c Testing for prediabetes and risk ample, if the A1C is 7.0% (53 mmol/mol) Organization (WHO) and numerous other for future diabetes in asymptom- and a repeat result is 6.8% (51 mmol/mol), diabetes organizations define the IFG atic people should be considered the diagnosis of diabetes is confirmed. If cutoff at 110 mg/dL (6.1 mmol/L). in adults of any age who are over- two different tests (such as A1C and FPG) As with the glucose measures, several weight or obese (BMI $25 kg/m2 are both above the diagnostic threshold, prospective studies that used A1C to or $23 kg/m2 in Asian Ameri- this also confirms the diagnosis. On the predict the progression to diabetes as cans) and who have one or more other hand, if a patient has discordant defined by A1C criteria demonstrated a additional risk factors for diabe- results from two different tests, then the strong, continuous association between tes. B test result that is above the diagnostic cut A1C and subsequent diabetes. In a sys- c For all people, testing should be- point should be repeated. The diagnosis tematic review of 44,203 individuals gin at age 45 years. B is made on the basis of the confirmed from 16 cohort studies with a follow-up c If tests are normal, repeat testing test. For example, if a patient meets interval averaging 5.6 years (range 2.8– carried out at a minimum of 3-year the diabetes criterion of the A1C (two 12 years), those with A1C between 5.5 intervals is reasonable. C results $6.5% [48 mmol/mol]) but not and 6.0% (between 37 and 42 mmol/mol) S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults andmayserveasanindicationfor 2 2 1. Testing should be considered in overweight or obese (BMI $25 kg/m or $23 kg/m in Asian intervention in the setting of a clini- Americans) adults who have one or more of the following risk factors: cal trial. Outcomes may include re- c A1C $5.7% (39 mmol/mol), IGT, or IFG on previous testing c first-degree relative with diabetes version of autoantibody status, c high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, prevention of glycemic progression Pacific Islander) within the normal or prediabetes c women who were diagnosed with GDM range, prevention of clinical diabe- c history of CVD tes, or preservation of residual $ c hypertension ( 140/90 mmHg or on therapy for hypertension) C-peptide secretion. A 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 syndrome Diagnosis c physical inactivity In a patient with classic symptoms, mea- c other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis surement of blood glucose is sufficient nigricans). to diagnose diabetes (symptoms of hy- 2. For all patients, testing should begin at age 45 years. perglycemia or hyperglycemic crisis 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with plus a random plasma glucose $200 consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status. mg/dL [11.1 mmol/L]). In these cases, knowing the blood glucose level is critical because, in addition to confirming that symptoms are due to diabetes, it had a substantially increased risk of diabe- Table 2.4 summarizes the categories will inform management decisions. tes (5-year incidence from 9 to 25%). An of prediabetes and Table 2.3 the criteria Some providers may also want to know A1C range of 6.0–6.5% (42–48 mmol/mol) for prediabetes testing. The ADA diabe- the A1C to determine how long a patient had a 5-year risk of developing diabetes tes risk test is an additional option for has had hyperglycemia. between25and50%andarelativerisk screening (Fig. 2.1). For recommenda- 20 times higher compared with A1C of tions regarding risk factors and screen- Immune-Mediated Diabetes 5.0% (31 mmol/mol) (19). In a community- ing for prediabetes, see pp. S17–S18 This form, previously called “insulin- based study of African American and (“Screening and Testing for Type 2 Di- dependent diabetes” or “juvenile-onset non-Hispanic white adults without diabe- abetes and Prediabetes in Asymptom- diabetes,” accounts for 5–10% of diabetes, baseline A1C was a stronger predictor atic Adults” and “Screening and Testing tes and is due to cellular-mediated au- of subsequent diabetes and cardiovascu- for Type 2 Diabetes and Prediabetes in toimmune destruction of the pancreatic lar events than fasting glucose (20). Children and Adolescents”). b-cells. Autoimmune markers include is- Other analyses suggest that A1C of let cell autoantibodies and autoanti- 5.7% (39 mmol/mol) or higher is associ- bodies to GAD (GAD65), insulin, the ated with a diabetes risk similar to that TYPE 1 DIABETES tyrosine phosphatases IA-2 and IA-2b, and ZnT8. Type 1 diabetes is defined of the high-risk participants in the Di- Recommendations by the presence of one or more of these abetes Prevention Program (DPP) (21), c Blood glucose rather than A1C should autoimmune markers. The disease has and A1C at baseline was a strong pre- be used to diagnose the acute onset strong HLA associations, with linkage dictor of the development of glucose- of type 1 diabetes in individuals with fi to the DQA and DQB genes. These de ned diabetes during the DPP and its symptoms of hyperglycemia. E HLA-DR/DQ alleles can be either predis- follow-up (22). c Screening for type 1 diabetes with a posing or protective. Hence, it is reasonable to consider an panel of autoantibodies is currently – – Therateofb-cell destruction is quite A1C range of 5.7 6.4% (39 47 mmol/mol) recommended only in the setting variable, being rapid in some individuals as identifying individuals with prediabe- of a research trial or in first-degree (mainly infants and children) and slow in tes. Similar to those with IFG and/or IGT, family members of a proband with – – others (mainly adults). Children and ado- individuals with A1C of 5.7 6.4% (39 type 1 diabetes. B lescents may present with ketoacidosis as 47 mmol/mol) should be informed of c Persistence of two or more autoan- the first manifestation of the disease. their increased risk for diabetes and tibodies predicts clinical diabetes CVD and counseled about effective strat- Others have modest fasting hyperglycemia egies to lower their risks (see Section “ 5 Prevention or Delay of Type 2 Diabe- Table 2.4—Categories of increased risk for diabetes (prediabetes)* tes”). Similar to glucose measurements, FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) the continuum of risk is curvilinear, so as OR A1C rises, the diabetes risk rises dispro- 2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) portionately (19). Aggressive interven- OR tions and vigilant follow-up should be A1C 5.726.4% (39247 mmol/mol) pursued for those considered at very high risk (e.g., those with A1C .6.0% *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range. [42 mmol/mol]). care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

Figure 2.1—ADA risk test. that can rapidly change to severe hyper- ketoacidosis for many years; such indi- disease, there is little or no insulin secre- glycemia and/or ketoacidosis with infec- viduals eventually become dependent tion, as manifested by low or undetectable tion or other stress. Adults may retain on insulin for survival and are at risk for levels of plasma C-peptide. Immune-mediated sufﬁcient b-cellfunctiontoprevent ketoacidosis. At this latter stage of the diabetes commonly occurs in childhood S16 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

and adolescence, but it can occur at any 70% developed type 1 diabetes within c Testing for type 2 diabetes should age, even in the 8th and 9th decades of life. 10 years and 84% within 15 years (24). be considered in children and ado- Autoimmune destruction of b-cells These findings are highly significant lescents who are overweight or has multiple genetic predispositions because, while the German group was obese and who have two or more ad- and is also related to environmental fac- recruited from offspring of parents with ditional risk factors for diabetes. E tors that are still poorly defined. Al- type 1 diabetes, the Finnish and American though patients are not typically obese groups were recruited from the general when they present with type 1 diabetes, population. Remarkably, the findings in Description obesity should not preclude the diag- all three groups were the same, suggesting Type 2 diabetes, previously referred to nosis. Patients with type 1 diabetes are that the same sequence of events led to as “noninsulin-dependent diabetes” or also prone to other autoimmune disor- clinical disease in both “sporadic” and fa- “adult-onset diabetes,” accounts for ders such as Hashimoto thyroiditis, milial cases of type 1 diabetes. Indeed, the 90–95% of all diabetes. This form en- Graves disease, Addison disease, celiac risk of type 1 diabetes increases as the compasses individuals who have relative disease, vitiligo, autoimmune hepatitis, number of relevant autoantibodies de- (rather than absolute) insulin deficiency myasthenia gravis, and pernicious ane- tected increases (25–27). and have peripheral insulin resistance. At mia (see Section 3 “Comprehensive Although there is currently a lack of least initially, and often throughout their Medical Evaluation and Assessment of accepted screening programs, one should lifetime, these individuals may not need Comorbidities”). consider referring relatives of those with insulin treatment to survive. type 1 diabetes for antibody testing for There are various causes of type 2 di- Idiopathic Type 1 Diabetes risk assessment in the setting of a clinical abetes. Although the specific etiologies Some forms of type 1 diabetes have no research study (http://www.diabetestrialnet are not known, autoimmune destruc- known etiologies. These patients have .org). Widespread clinical testing of tion of b-cells does not occur, and pa- permanent insulinopenia and are prone asymptomatic low-risk individuals is not tients do not have any of the other to ketoacidosis, but have no evidence of currently recommended due to lack of known causes of diabetes. Most, but b-cell autoimmunity. Although only a approved therapeutic interventions. In- not all, patients with type 2 diabetes minority of patients with type 1 diabetes dividuals who test positive will be coun- are overweight or obese. Excess weight fall into this category, of those who do, seled about the risk of developing itself causes some degree of insulin re- most are of African or Asian ancestry. diabetes, diabetes symptoms, and DKA sistance. Patients who are not obese or Individuals with this form of diabetes prevention. Numerous clinical studies overweight by traditional weight criteria suffer from episodic ketoacidosis and are being conducted to test various may have an increased percentage of exhibit varying degrees of insulin defi- methods of preventing type 1 diabetes body fat distributed predominantly in ciency between episodes. This form of in those with evidence of autoimmunity the abdominal region. diabetes is strongly inherited and is not (www.clinicaltrials.gov). Ketoacidosis seldom occurs sponta- HLA associated. An absolute requirement neously in type 2 diabetes; when seen, for insulin replacement therapy in affected TYPE 2 DIABETES it usually arises in association with the patients may be intermittent. stress of another illness such as infec- Recommendations tion. Type 2 diabetes frequently goes c Screening for type 2 diabetes with undiagnosed for many years because Testing for Type 1 Diabetes Risk an informal assessment of risk fac- The incidence and prevalence of type 1 hyperglycemia develops gradually and, tors or validated tools should be con- diabetes is increasing (23). Patients with at earlier stages, is often not severe sideredinasymptomaticadults.B type 1 diabetes often present with acute enough for the patient to notice the c Testing for type 2 diabetes in asymp- symptoms of diabetes and markedly el- classic diabetes symptoms. Neverthe- tomatic people should be considered evated blood glucose levels, and ap- less, even undiagnosed patients are at in adults of any age who are over- proximately one-third are diagnosed increased risk of developing macrovas- weight or obese (BMI $25 kg/m2 with life-threatening ketoacidosis (3). cular and microvascular complications. or $23 kg/m2 in Asian Americans) Several studies indicate that measuring Whereas patients with type 2 diabe- and who have one or more additional islet autoantibodies in relatives of those tes may have insulin levels that appear risk factors for diabetes. B with type 1 diabetes may identify indi- normal or elevated, the higher blood c For all people, testing should be- viduals who are at risk for developing glucose levels in these patients would gin at age 45 years. B type 1 diabetes (5). Such testing, cou- be expected to result in even higher in- c If tests are normal, repeat testing pled with education about diabetes sulin values had their b-cell function carried out at a minimum of 3-year symptoms and close follow-up, may en- been normal. Thus, insulin secretion is intervals is reasonable. C able earlier identification of type 1 di- defective in these patients and insuffi- c To test for type 2 diabetes, fasting abetes onset. A study reported the risk cient to compensate for insulin resis- plasma glucose, 2-h plasma glucose of progression to type 1 diabetes from tance. Insulin resistance may improve with after 75-g oral glucose tolerance test, the time of seroconversion to autoanti- weight reduction and/or pharmacological and A1C are equally appropriate. B body positivity in three pediatric co- treatment of hyperglycemia but is seldom c In patients with diabetes, identify and horts from Finland, Germany, and the restored to normal. treat other cardiovascular disease U.S. Of the 585 children who developed The risk of developing type 2 diabetes risk factors. B more than two autoantibodies, nearly increases with age, obesity, and lack of care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

physical activity. It occurs more fre- 40 and 69 years were screened for di- numerous false positives. An argument quently in women with prior GDM, in abetes and randomly assigned by prac- can be made to push the BMI cut point those with hypertension or dyslipide- tice to intensive treatment of multiple to lower than 23 kg/m2 in favor of in- mia, and in certain racial/ethnic sub- risk factors or routine diabetes care. Af- creased sensitivity; however, this would groups (African American, American ter 5.3 years of follow-up, CVD risk fac- lead to an unacceptably low specificity Indian, Hispanic/Latino, and Asian American). tors were modestly but significantly (13.1%). Data from the WHO also suggest It is often associated with a strong improved with intensive treatment that a BMI of $23 kg/m2 should be used genetic predisposition, more so than compared with routine care, but the in- to define increased risk in Asian Ameri- type 1 diabetes. However, the genetics cidence of first CVD events or mortality cans (34). The finding that half of diabe- of type 2 diabetes is poorly understood. was not significantly different between tes in Asian Americans is undiagnosed In adults without traditional risk factors the groups (29). The excellent care pro- suggests that testing is not occurring at for type 2 diabetes and/or younger age, vided to patients in the routine care lower BMI thresholds (28). consider antibody testing for type 1 di- group and the lack of an unscreened Evidence also suggests that other abetes (i.e., GAD). control arm limited the authors’ ability populations may benefitfromlower to determine whether screening and BMI cut points. For example, in a large Screening and Testing for Type 2 early treatment improved outcomes multiethnic cohort study, for an equiva- Diabetes and Prediabetes in compared with no screening and later lent incidence rate of diabetes, a BMI of Asymptomatic Adults treatment after clinical diagnoses. Com- 30 kg/m2 in non-Hispanic whites was Screening for prediabetes and type 2 di- puter simulation modeling studies sug- equivalent to a BMI of 26 kg/m2 in Afri- abetes through an informal assessment gest that major benefits are likely to can Americans (35). of risk factors (Table 2.3)orwithanas- accrue from the early diagnosis and treat- Medications sessment tool, such as the ADA risk test ment of hyperglycemia and cardiovas- Certain medications, such as glucocorti- (Fig. 2.1), is recommended to guide pro- cular risk factors in type 2 diabetes coids, thiazide diuretics, and atypical an- viders on whether performing a diag- (30); moreover, screening, beginning tipsychotics (36), are known to increase nostic test (Table 2.2) is appropriate. at age 30 or 45 years and independent the risk of diabetes and should be consid- Prediabetes and type 2 diabetes meet of risk factors, may be cost-effective ered when deciding whether to screen. criteria for conditions in which early de- (,$11,000 per quality-adjusted life-year tection is appropriate. Both conditions gained) (31). Testing Interval fi are common and impose signi cant clin- Additional considerations regarding The appropriate interval between ical and public health burdens. There is testing for type 2 diabetes and predia- screening tests is not known (37). The often a long presymptomatic phase be- betes in asymptomatic patients include rationale for the 3-year interval is that fore the diagnosis of type 2 diabetes. the following. with this interval, the number of false- Simple tests to detect preclinical disease positive tests that require confirmatory Age are readily available. The duration of testing will be reduced and individuals Screening recommendations for diabe- glycemic burden is a strong predictor with false-negative tests will be retested tes in asymptomatic adults are listed in of adverse outcomes. There are effec- before substantial time elapses and Table 2.3. Age is a major risk factor for tive interventions that prevent progres- complications develop (37). sion from prediabetes to diabetes (see diabetes. Testing should begin at age Community Screening Section 5 “Prevention or Delay of Type 2 45 years for all patients. Screening Ideally, testing should be carried out Diabetes”) and reduce the risk of diabe- should be considered in overweight or within a health care setting because of tes complications (see Section 9 “Cardio- obese adults of any age with one or the need for follow-up and treatment. vascular Disease and Risk Management” more risk factors for diabetes. Community screening outside a health and Section 10 “Microvascular Complica- BMI and Ethnicity care setting is not recommended be- tions and Foot Care”). In general, BMI $25 kg/m2 is a risk fac- cause people with positive tests may Approximately one-quarter of people tor for diabetes. Data and recommenda- not seek, or have access to, appropriate with diabetes in the U.S. and nearly half tions from the ADA position statement follow-up testing and care. Community of Asian and Hispanic Americans with “BMI Cut Points to Identify At-Risk testing may also be poorly targeted; i.e., diabetes are undiagnosed (28). Although Asian Americans for Type 2 Diabetes it may fail to reach the groups most at screening of asymptomatic individuals to Screening” (32,33) suggest that the identify those with prediabetes or diabetes BMI cut point should be lower for the risk and inappropriately test those at might seem reasonable, rigorous clinical Asian American population. The BMI cut very low risk or even those who have trials to prove the effectiveness of such points fall consistently between 23 and already been diagnosed (38). screening have not been conducted and 24 kg/m2 (sensitivity of 80%) for nearly Screening in Dental Practices are unlikely to occur. all Asian American subgroups (with levels Because periodontal disease is associ- A large European randomized con- slightly lower for Japanese Americans). ated with diabetes, the utility of chair- trolled trial compared the impact of This makes a rounded cut point of side screening and referral to primary screening for diabetes and intensive 23 kg/m2 practical. In determining a sin- care as a means to improve the diagno- multifactorial intervention with that of gle BMI cut point, it is important to bal- sis of prediabetes and diabetes has been screening and routine care (29). General ance sensitivity and specificity so as to explored (39–41), with one study esti- practice patients between the ages of provide a valuable screening tool without mating that 30% of patients $30 years S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

of age seen in general dental practices Table 2.5—Testing for type 2 diabetes or prediabetes in asymptomatic children* (46) had dysglycemia (41). Further research Criteria is needed to demonstrate the feasibility, c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or effectiveness, and cost-effectiveness of weight .120% of ideal for height) screening in this setting. Plus any two of the following risk factors: c Family history of type 2 diabetes in first- or second-degree relative Screening and Testing for Type 2 c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Diabetes and Prediabetes in Children Islander) and Adolescents c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis In the last decade, the incidence and nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for- prevalence of type 2 diabetes in ado- gestational-age birth weight) ’ lescents has increased dramatically, c Maternal history of diabetes or GDM during the child s gestation especially in racial and ethnic minority Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age populations (23). Recent studies ques- Frequency: every 3 years tion the validity of A1C in the pediatric *Persons aged #18 years. population, especially among certain ethnicities, and suggest OGTT or FPG OGTT were not derived from data in as more suitable diagnostic tests (42). have lifelong screening for the de- the first half of pregnancy, so the diag- However, many of these studies do not velopment of diabetes or predia- nosis of GDM in early pregnancy by ei- recognize that diabetes diagnostic crite- betes at least every 3 years. B ther FPG or OGTT values is not evidence ria are based on long-term health out- c Women with a history of gestational based (48). comes, and validations are not currently diabetes mellitus found to have pre- available in the pediatric population diabetes should receive intensive Diagnosis (43). The ADA acknowledges the limited lifestyle interventions or metformin GDM carries risks for the mother and data supporting A1C for diagnosing to prevent diabetes. A neonate. Not all adverse outcomes are type 2 diabetes in children and adoles- of equal clinical importance. The Hyper- cents. Although A1C is not recom- fi glycemia and Adverse Pregnancy Out- mended for diagnosis of diabetes in De nition For many years, GDM was defined as come (HAPO) study (49), a large-scale children with cystic fibrosis or symptoms any degree of glucose intolerance that multinational cohort study completed suggestive of acute onset of type 1 di- was first recognized during pregnancy by more than 23,000 pregnant women, abetes and only A1C assays without (17), regardless of whether the condi- demonstrated that risk of adverse ma- interference are appropriate for children tion may have predated the pregnancy ternal, fetal, and neonatal outcomes with hemoglobinopathies, the ADA con- or persisted after the pregnancy. This continuously increased as a function of tinues to recommend A1C for diagnosis definition facilitated a uniform strategy maternal glycemia at 24–28 weeks, even of type 2 diabetes in this cohort (44,45). for detection and classification of GDM, within ranges previously considered The modified recommendations of the but it was limited by imprecision. normal for pregnancy. For most compli- ADA consensus report “Type 2 Diabetes The ongoing epidemic of obesity and cations, there was no threshold for risk. in Children and Adolescents” are sum- diabetes has led to more type 2 diabetes These results have led to careful recon- marized in Table 2.5 (46). in women of childbearing age, with an sideration of the diagnostic criteria for GESTATIONAL DIABETES increase in the number of pregnant GDM. GDM diagnosis (Table 2.6)can MELLITUS women with undiagnosed type 2 diabe- be accomplished with either of two tes (47). Because of the number of preg- strategies: Recommendations nant women with undiagnosed type 2 c Test for undiagnosed diabetes at diabetes, it is reasonable to test women 1. “One-step” 75-g OGTT or the first prenatal visit in those with risk factors for type 2 diabetes 2. “Two-step” approach with a 50-g with risk factors, using standard (Table 2.3) at their initial prenatal visit, (nonfasting) screen followed by a diagnostic criteria. B using standard diagnostic criteria (Table 100-g OGTT for those who screen c Test for gestational diabetes mel- 2.2). Women diagnosed with diabetes in positive litus at 24–28 weeks of gestation the first trimester should be classified as in pregnant women not previously having preexisting pregestational diabe- Different diagnostic criteria will identify known to have diabetes. A tes (type 2 diabetes or, very rarely, different degrees of maternal hypergly- c Test women with gestational dia- type 1 diabetes). GDM is diabetes that cemia and maternal/fetal risk, leading betes mellitus for persistent dia- is first diagnosed in the second or third some experts to debate, and disagree betes at 4–12 weeks’ postpartum, trimester of pregnancy that is not clearly on, optimal strategies for the diagnosis using the oral glucose tolerance either preexisting type 1 or type 2 dia- of GDM. test and clinically appropriate betes (see Section 13 “Management of One-Step Strategy nonpregnancy diagnostic crite- Diabetes in Pregnancy”). The Interna- In the 2011 Standards of Care (50), the ria. E tional Association of the Diabetes and ADA for the first time recommended c Women with a history of gesta- Pregnancy Study Groups (IADPSG) that all pregnant women not known to tional diabetes mellitus should GDM diagnostic criteria for the 75-g have prior diabetes undergo a 75-g care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Table 2.6—Screening for and diagnosis of GDM criteria for diagnosing GDM (54). The One-step strategy 15-member panel had representatives Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and from obstetrics/gynecology, maternal- 2h,at24228 weeks of gestation in women not previously diagnosed with overt diabetes. fetal medicine, pediatrics, diabetes re- The OGTT should be performed in the morning after an overnight fast of at least 8 h. search, biostatistics, and other related The diagnosis of GDM is made when any of the following plasma glucose values are met or fields. The panel recommended a two- exceeded: step approach to screening that used a c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) 1-h 50-g glucose load test (GLT) fol- c 2 h: 153 mg/dL (8.5 mmol/L) lowedbya3-h100-gOGTTforthose Two-step strategy who screened positive. Commonly Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 used cutoffs for the 1-h 50-g GLT include weeks of gestation in women not previously diagnosed with overt diabetes. 130, 135, and 140 mg/dL (7.2, 7.5, and If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 7.8 mmol/L). The American College of 140 mg/dL* (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT. Obstetricians and Gynecologists (ACOG) Step 2: The 100-g OGTT should be performed when the patient is fasting. recommends either 135 or 140 mg/dL The diagnosis of GDM is made if at least two of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded: (45). A systematic review for the U.S. Pre- ventive Services Task Force compared Carpenter/Coustan (59) or NDDG (60) GLT cutoffs of 130 mg/dL (7.2 mmol/L) c Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) and 140 mg/dL (7.8 mmol/L) (55). The c 1 h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) higher cutoff yielded sensitivity of c 2 h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) – fi – c 3 h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) 70 88% and speci city of 69 89%, while the lower cutoff was 88–99% NDDG, National Diabetes Data Group. *The ACOG recommends either 135 mg/dL (7.5 mmol/L) – fi or 140 mg/dL (7.8 mmol/L). A systematic review determined that a cutoff of 130 mg/dL sensitive and 66 77% speci c. Data (7.2 mmol/L) was more sensitive but less specific than 140 mg/dL (7.8 mmol/L) (55). regarding a cutoff of 135 mg/dL are limited. As for other screening tests, choice of a cutoff is based upon the tradeoff between sensitivity and specificity. The use – OGTT at 24 28 weeks of gestation, older GDM diagnostic criteria. Those tri- of A1C at 24–28 weeks as a screening test fi based on a recommendation of the als found modest bene ts including re- for GDM does not function as well as the fi IADPSG (51). The IADPSG de ned diag- duced rates of large-for-gestational-age GLT (56). nostic cut points for GDM as the average births and preeclampsia (52,53). It is im- Key factors cited by the NIH panel in – fasting, 1-h, and 2-h plasma glucose val- portant to note that 80 90% of women their decision-making process were ues in the HAPO study at which odds for being treated for mild GDM in two ran- the lack of clinical trial data demon- adverse outcomes reached 1.75 times domized controlled trials could be man- strating the benefits of the one-step the estimated odds of these outcomes aged with lifestyle therapy alone. The strategy and the potential negative con- at the mean fasting, 1-h, and 2-h PG levels OGTT glucose cutoffs in these two trials sequences of identifying a large group of of the study population. This one-step overlapped with the thresholds recom- women with GDM, including medicaliza- strategy was anticipated to signifi- mended by the IADPSG, and in one trial tion of pregnancy with increased health cantly increase the incidence of GDM (53), the 2-h PG threshold (140 mg/dL care utilization and costs. Moreover, (from 5–6% to 15–20%), primarily be- [7.8 mmol/L]) was lower than the cutoff screening with a 50-g GLT does not re- cause only one abnormal value, not recommended by the IADPSG (153 mg/dL quire fasting and is therefore easier to two, became sufficient to make the di- [8.5 mmol/L]). No randomized con- accomplish for many women. Treatment agnosis. The ADA recognized that the trolled trials of identifying and treating of higher threshold maternal hypergly- anticipated increase in the incidence of GDM using the IADPSG criteria versus cemia, as identified by the two-step GDM would have a substantial impact older criteria have been published to approach, reduces rates of neonatal on costs and medical infrastructure date. Data are also lacking on how the macrosomia, large-for-gestational-age needs and had the potential to “medi- treatment of lower levels of hyperglyce- births (57), and shoulder dystocia, with- ’ calize” pregnancies previously catego- mia affects a mother s future risk for the out increasing small-for-gestational-age rized as normal. Nevertheless, the ADA development of type 2 diabetes and her births. ACOG updated its guidelines in ’ recommended these changes in diag- offspring s risk for obesity, diabetes, and 2013 and supported the two-step ap- nostic criteria with the intent of optimiz- other metabolic disorders. Additional proach (58). The ACOG recommends ei- ing gestational outcomes because these well-designed clinical studies are needed ther of two sets of diagnostic thresholds criteria were the only ones based on to determine the optimal intensity of for the 3-h 100-g OGTT (59,60). Each is pregnancy outcomes rather than end monitoring and treatment of women based on different mathematical con- points such as prediction of subsequent with GDM diagnosed by the one-step versions of the original recommended maternal diabetes. strategy. thresholds, which used whole blood The expected benefits to the offspring Two-Step Strategy and nonenzymatic methods for glucose are inferred from intervention trials that In 2013, the National Institutes of Health determination. A recent secondary anal- focused on women with lower levels of (NIH) convened a consensus develop- ysis of data from a randomized clinical hyperglycemia than identified using ment conference to consider diagnostic trial of identification and treatment of S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

mild GDM (61) demonstrated that treat- ages). MODY is characterized by impaired inheritance) should have genetic ment was similarly beneficial in patients insulin secretion with minimal or no de- testing for maturity-onset diabe- meeting only the lower thresholds (59) fects in insulin action (in the absence of tes of the young. A and in those meeting only the higher coexistent obesity). It is inherited in an au- c In both instances, consultation thresholds (60). If the two-step approach tosomal dominant pattern with abnormal- with a center specializing in diabetes is used, it would appear advantageous to ities in at least 13 genes on different genetics is recommended to under- use the lower diagnostic thresholds as chromosomes identified to date. The stand the significance of these mu- shown in Step 2 in Table 2.6. most commonly reported forms are GCK- tations and how best to approach MODY (MODY2), HNF1A-MODY (MODY3), Future Considerations further evaluation, treatment, and and HNF4A-MODY (MODY1). The conflicting recommendations from genetic counseling. E expert groups underscore the fact that Clinically, patients with GCK-MODY there are data to support each strategy. exhibit mild, stable, fasting hyperglyce- A cost-benefit estimation comparing the Monogenic defects that cause b-cell mia and do not require antihyperglyce- two strategies concluded that the one- dysfunction, such as neonatal diabetes mic therapy except sometimes during step approach is cost-effective only if and MODY, represent a small fraction of pregnancy. Patients with HNF1A- or patients with GDM receive postdelivery patients with diabetes (,5%). Table 2.7 HNF4A-MODY usually respond well to counseling and care to prevent type 2 describes the most common causes of low doses of sulfonylureas, which are fi diabetes (62). The decision of which monogenic diabetes. For a comprehen- considered rst-line therapy. Mutations strategy to implementmusttherefore sive list of causes, see Genetic Diagnosis or deletions in HNF1B are associated be made based on the relative values of Endocrine Disorders (68). with renal cysts and uterine malforma- placed on factors that have yet to be tions (renal cysts and diabetes [RCAD] measured (e.g., willingness to change Neonatal Diabetes syndrome). Other extremely rare forms practice based on correlation studies Diabetes occurring under 6 months of of MODY have been reported to involve rather than intervention trial results, age is termed “neonatal” or “congeni- other transcription factor genes includ- available infrastructure, and importance tal” diabetes, and about 80–85% of ing PDX1 (IPF1)andNEUROD1. of cost considerations). cases can be found to have an underly- As the IADPSG criteria (“one-step strating monogenic cause (69). Neonatal Diagnosis egy”) have been adopted internationally, diabetes occurs much less often after A diagnosis of one of the three most further evidence has emerged to support 6 months of age, whereas autoimmune common forms of MODY including GCK- improved pregnancy outcomes with cost type 1 diabetes rarely occurs before MODY, HNF1A-MODY, and HNF4A-MODY savings (63) and may be the preferred ap- 6 months of age. Neonatal diabetes allows for more cost-effective therapy (no proach. Data comparing population-wide can either be transient or permanent. therapy for GCK-MODY; sulfonylureas as fi outcomes with one-step versus two-step Transient diabetes is most often due to rst-line therapy for HNF1A-MODY and approaches have been inconsistent to overexpression of genes on chromo- HNF4A-MODY). Additionally, diagnosis fi date (64,65). In addition, pregnancies com- some 6q24, is recurrent in about half canleadtoidenti cation of other affected plicated by GDM per the IADPSG criteria, of cases, and may be treatable with med- family members. but not recognized as such, have compa- ications other than insulin. Permanent A diagnosis of MODY should be con- rable outcomes to pregnancies diag- neonatal diabetes is most commonly sidered in individuals who have atypical nosed as GDM by the more stringent due to autosomal dominant mutations diabetes and multiple family members two-step criteria (66,67). There remains in the genes encoding the Kir6.2 subunit with diabetes not characteristic of strong consensus that establishing a uni- (KCNJ11) and SUR1 subunit (ABCC8)of type 1 or type 2 diabetes, although ad- b mittedly “atypical diabetes” is becoming form approach to diagnosing GDM will the -cell KATP channel. Correct diagnosis fi fi benefit patients, caregivers, and policy- has critical implications because most pa- increasingly dif cult to precisely de ne in the absence of a definitive set of tests makers. Longer-term outcome studies tients with KATP-related neonatal diabetes are currently under way. will exhibit improved glycemic control for either type of diabetes. In most when treated with high-dose oral sulfo- cases, the presence of autoantibodies MONOGENIC DIABETES nylureas instead of insulin. Insulin gene for type 1 diabetes precludes further SYNDROMES (INS) mutations are the second most testing for monogenic diabetes, but the common cause of permanent neonatal presence of autoantibodies in patients Recommendations diabetes, and, while treatment presently with monogenic diabetes has been re- c All children diagnosed with diabe- ported (70). Individuals in whom mono- tes in the first 6 months of life is intensive insulin management, there genic diabetes is suspected should be should have immediate genetic are important genetic considerations as referred to a specialist for further eva- testing for neonatal diabetes. A most of the mutations that cause diabetes are dominantly inherited. luation if available, and consultation is c Children and adults, diagnosed in available from several centers. Readily early adulthood, who have diabe- available commercial genetic testing tes not characteristic of type 1 or Maturity-Onset Diabetes of the Young MODY is frequently characterized by following the criteria listed below now type 2 diabetes that occurs in suc- onset of hyperglycemia at an early enables a cost-effective (71), often cessive generations (suggestive of age (classically before age 25 years, al- cost-saving, genetic diagnosis that is in- an autosomal dominant pattern of though diagnosis may occur at older creasingly supported by health insurance. It care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

Table 2.7—Most common causes of monogenic diabetes (68) Gene 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 sulfonylureas HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive to sulfonylureas HNF1B AD HNF1B-MODY:developmentalrenaldisease(typicallycystic);genitourinary abnormalities; 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 Transient or permanent: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 AD for paternal Transient:IUGR;macroglossia;umbilical hernia;mechanismsincludeUPD6, (PLAGL1, HYMA1) duplications paternal duplication or maternal methylation 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. is critical to correctly diagnose one of the features, especially with strong family Cystic fibrosis–related diabetes (CFRD) is monogenic forms of diabetes because history of diabetes) the most common comorbidity in people these patients may be incorrectly diag- ○ Stable, mild fasting hyperglycemia with cystic fibrosis, occurring in about 20% nosed with type 1 or type 2 diabetes, lead- (100–150 mg/dL [5.5–8.5 mmol/L]), of adolescents and 40–50% of adults. Di- ing to suboptimal, even potentially harmful, stable A1C between 5.6 and 7.6% abetes in this population, compared with treatment regimens and delays in diagnos- (between 38 and 60 mmol/mol), espe- individuals with type 1 or type 2 diabetes, ing other family members (72). The infor- cially if nonobese is associated with worse nutritional status, mation is especially critical for GCK-MODY more severe inflammatory lung disease, CYSTIC FIBROSIS–RELATED mutations where multiple studies have and greater mortality. Insulin insufficiency DIABETES shown that no complications ensue in is the primary defect in CFRD. Genetically b the absence of glucose-lowering therapy Recommendations determined -cell function and insulin re- fi – (73). Genetic counseling is recommen- c Annual screening for cystic brosis sistance associated with infection and in- fl ded to ensure that affected individuals related diabetes with oral glucose ammation may also contribute to the understand the patterns of inheritance tolerance test should begin by age development of CFRD. Milder abnormali- 10 years in all patients with cystic fi- and the importance of a correct diagnosis. ties of glucose tolerance are even more brosis not previously diagnosed with The diagnosis of monogenic diabetes common and occur at earlier ages than cystic fibrosis–related diabetes. B should be considered in children and CFRD. Whether individuals with IGT should c A1C as a screening test for cystic adults diagnosed with diabetes in early be treated with insulin replacement has not fibrosis–related diabetes is not adulthood with the following findings: currently been determined. Although recommended. B screening for diabetes before the age of c Patients with cystic fibrosis–related ○ Diabetes diagnosed within the first 10 years can identify risk for progression diabetes should be treated with in- 6 months of life (with occasional to CFRD in those with abnormal glucose sulin to attain individualized glyce- cases presenting later, mostly INS tolerance, no benefit has been established mic goals. A and ABCC8 mutations) (69,74) with respect to weight, height, BMI, or c Beginning 5 years after the diagnosis ○ Diabetes without typical features of lung function. Continuous glucose monitor- of cystic fibrosis–related diabetes, type 1 or type 2 diabetes (negative ing may be more sensitive than OGTT to annual monitoring for complications diabetes–associated autoantibodies; detect risk for progression to CFRD; how- of diabetes is recommended. E nonobese, lacking other metabolic ever, evidence linking continuous glucose S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

monitoring results to long-term outcomes describes individuals who develop diabetes diagnosis: the Search for Diabetes in is lacking, and its use is not recommended new-onset diabetes following trans- Youth Study. Pediatrics 2014;133:e938–e945 for screening (75). plant. NODAT excludes patients with 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differen- fi tiation of diabetes by pathophysiology, natural his- CFRD mortality has signi cantly de- pretransplant diabetes that was undiag- tory, and prognosis. Diabetes. 15 December 2016 creased over time, and the gap in mor- nosed as well as posttransplant hyper- [Epub ahead of print]. DOI: 10.2337/db16-0806 tality between cystic fibrosis patients glycemia that resolves by the time of 5. Insel RA, Dunne JL, Atkinson MA, et al. Stag- with and without diabetes has consider- discharge (80). Another term, “posttrans- ing presymptomatic type 1 diabetes: a scientific ably narrowed (76). There are limited plantation diabetes mellitus” (PTDM) statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes clinical trial data on therapy for CFRD. (80), describes the presence of diabetes Care 2015;38:1964–1974 The largest study compared three regi- in the posttransplant setting irrespective 6. International Expert Committee. Interna- mens: premeal insulin aspart, repagli- of the timing of diabetes onset. tional Expert Committee report on the role of nide, or oral placebo in cystic fibrosis Hyperglycemia is very common dur- the A1C assay in the diagnosis of diabetes. – patients with diabetes or abnormal glu- ing the early posttransplant period, Diabetes Care 2009;32:1327 1334 7. Knowler WC, Barrett-Connor E, Fowler SE, cose tolerance. Participants all had weight with ;90% of kidney allograft recipients et al.; Diabetes Prevention Program Research loss in the year preceding treatment; how- exhibiting hyperglycemia in the first Group. Reduction in the incidence of type 2 di- ever, in the insulin-treated group, this pat- few weeks following transplant (80,81). abetes with lifestyle intervention or metformin. tern was reversed, and patients gained In most cases, such stress or steroid- N Engl J Med 2002;346:393–403 ¨ 0.39 (6 0.21) BMI units (P 5 0.02). The induced hyperglycemia resolves by the 8. Tuomilehto J, Lindstrom J, Eriksson JG, et al.; Finnish Diabetes Prevention Study Group. Pre- repaglinide-treated group had initial time of discharge. Risk factors for PTDM vention of type 2 diabetes mellitus by changes in weight gain, but this was not sustained include both general diabetes risks (such lifestyle among subjects with impaired glucose by 6 months. The placebo group continued as age, family history of diabetes, etc.) tolerance. N Engl J Med 2001;344:1343–1350 to lose weight (77). Insulin remains the as well as transplant-specificfactors, 9. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prev- alence of diabetes and high risk for diabetes most widely used therapy for CFRD (78). such as use of immunosuppressant using A1C criteria in the U.S. population in Recommendations for the clinical agents. Whereas posttransplantation 1988–2006. Diabetes Care 2010;33:562–568 management of CFRD can be found in hyperglycemia is an important risk factor 10. Nowicka P, Santoro N, Liu H, et al. Utility of the ADA position statement “Clinical for subsequent PTDM, a formal diagnosis hemoglobin A1c for diagnosing prediabetes and Care Guidelines for Cystic Fibrosis–Related of PTDM is optimally made once the pa- diabetes in obese children and adolescents. Di- abetes Care 2011;34:1306–1311 Diabetes: A Position Statement of the tient is stable on maintenance immuno- 11. Ziemer DC, Kolm P, Weintraub WS, et al. American Diabetes Association and a suppression and in the absence of acute Glucose-independent, black-white differences in Clinical Practice Guideline of the Cystic infection. hemoglobin A1c levels: a cross-sectional analysis Fibrosis Foundation, Endorsed by the The OGTT is considered the gold stan- of 2 studies. Ann Intern Med 2010;152:770–777 Pediatric Endocrine Society” (79). dard test for the diagnosis of PTDM 12. Kumar PR, Bhansali A, Ravikiran M, et al. Utility – of glycated hemoglobin in diagnosing type 2 diabe- (80,82 84). However, screening patients tes mellitus: a community-based study. J Clin Endo- POSTTRANSPLANTATION using fasting glucose and/or A1C can crinol Metab 2010;95:2832–2835 DIABETES MELLITUS identify high-risk patients requiring fur- 13. Herman WH, Ma Y, Uwaifo G, et al.; Diabe- ther assessment and may reduce the tes Prevention Program Research Group. Differ- Recommendations number of overall OGTTs required (85). ences in A1C by race and ethnicity among c Patients should be screened after patients with impaired glucose tolerance in There is currently a lack of clinical data organ transplantation for hyper- the Diabetes Prevention Program. Diabetes glycemia, with a formal diagnosis examining the use of antidiabetes agents Care 2007;30:2453–2457 fi of posttransplantation diabetes in the setting of PTDM to inform speci c 14. Carson AP, Munter P, Selvin E, et al. Do glycemic marker levels vary by race? Differing mellitus being best made once a recommendations for use in this population. Although the use of immunosup- results from a cross-sectional analysis of individ- patient is stable on an immuno- uals with and without diagnosed diabetes. BMJ pressive therapies is a major contributor suppressive regimen and in the ab- Open Diabetes Res Care 2016;4:e000213 sence of an acute infection. E to the development of PTDM, the risks of 15. Herman WH, Dungan KM, Wolffenbuttel BH, transplant rejection outweigh the risks of et al. Racial and ethnic differences in mean plasma c The oral glucose tolerance test is glucose, hemoglobin A1c, and 1,5-anhydroglucitol the preferred test to make a diag- PTDM and the role of the diabetes care provider is to treat hyperglycemia appro- in over 2000 patients with type 2 diabetes. J Clin nosis of posttransplantation dia- Endocrinol Metab 2009;94:1689–1694 priately regardless of the type of immuno- betes mellitus. B 16. Selvin E, Rawlings AM, Bergenstal RM, suppression (80). c Immunosuppressive regimens Coresh J, Brancati FL. No racial differences in shown to provide the best outcomes the association of glycated hemoglobin with kidney disease and cardiovascular outcomes. for patient and graft survival should References Diabetes Care 2013;36:2995–3001 be used, irrespective of posttrans- 1. American Diabetes Association. Diagnosis 17. Expert Committee on the Diagnosis and plantation diabetes mellitus risk. E and classification of diabetes mellitus. Diabetes Classification of Diabetes Mellitus. Report of Care 2014;37(Suppl. 1):S81–S90 the Expert Committee on the Diagnosis and 2. Newton CA, Raskin P. Diabetic ketoacidosis Classification of Diabetes Mellitus. Diabetes Several terms are used in the literature in type 1 and type 2 diabetes mellitus: clinical Care 1997;20:1183–1197 to describe the presence of diabetes fol- and biochemical differences. Arch Intern Med 18. Genuth S, Alberti KG, Bennett P, et al.; Expert – fi “ 2004;164:1925 1931 Committee on the Diagnosis and Classi cation of lowing organ transplantation. New- 3. Dabelea D, Rewers A, Stafford JM, et al.; Diabetes Mellitus. Follow-up report on the diagno- onset diabetes after transplantation” SEARCH for Diabetes in Youth Study Group. sis of diabetes mellitus. Diabetes Care 2003;26: (NODAT) is one such designation that Trends in the prevalence of ketoacidosis at 3160–3167 care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

19. Zhang X, Gregg EW, Williamson DF, et al. 33. Hsu WC, Araneta MRG, Kanaya AM, Chiang and adverse pregnancy outcomes. N Engl J Med A1C level and future risk of diabetes: a system- JL, Fujimoto W. BMI cut points to identify at-risk 2008;358:1991–2002 atic review. Diabetes Care 2010;33:1665–1673 Asian Americans for type 2 diabetes screening. 50. American Diabetes Association. Standards 20. Selvin E, Steffes MW, Zhu H, et al. Glycated Diabetes Care 2015;38:150–158 of medical care in diabetesd2011.Diabetes hemoglobin, diabetes, and cardiovascular risk in 34. WHO Expert Consultation. Appropriate Care 2011;34(Suppl. 1):S11–S61 nondiabetic adults. N Engl J Med 2010;362:800– body-mass index for Asian populations and its 51. Metzger BE, Gabbe SG, Persson B, et al.; 811 implications for policy and intervention strate- International Association of Diabetes and Preg- 21. Ackermann RT, Cheng YJ, Williamson DF, gies. Lancet 2004;363:157–163 nancy Study Groups Consensus Panel. Interna- Gregg EW. Identifying adults at high risk for di- 35. Chiu M, Austin PC, Manuel DG, Shah BR, Tu tional Association of Diabetes and Pregnancy abetes and cardiovascular disease using hemo- JV. Deriving ethnic-specific BMI cutoff points for Study Groups recommendations on the diagno- globin A1c National Health and Nutrition assessing diabetes risk. Diabetes Care 2011;34: sis and classification of hyperglycemia in preg- Examination Survey 2005–2006. Am J Prev 1741–1748 nancy. Diabetes Care 2010;33:676–682 Med 2011;40:11–17 36. Erickson SC, Le L, Zakharyan A, et al. New- 52. Landon MB, Spong CY, Thom E, et al.; Eunice 22. Diabetes Prevention Program Research onset treatment-dependent diabetes mellitus Kennedy Shriver National Institute of Child Group. HbA1c as a predictor of diabetes and and hyperlipidemia associated with atypical an- Health and Human Development Maternal- as an outcome in the diabetes prevention pro- tipsychotic use in older adults without schizo- Fetal Medicine Units Network. A multicenter, ran- gram: a randomized clinical trial. Diabetes Care phrenia or bipolar disorder. J Am Geriatr Soc domized trial of treatment for mild gestational 2015;38:51–58 2012;60:474–479 diabetes. N Engl J Med 2009;361:1339–1348 23. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; 37. Johnson SL, Tabaei BP, Herman WH. The 53. Crowther CA, Hiller JE, Moss JR, McPhee AJ, SEARCH for Diabetes in Youth Study. Prevalence efficacy and cost of alternative strategies for Jeffries WS, Robinson JS; Australian Carbohy- of type 1 and type 2 diabetes among children systematic screening for type 2 diabetes in the drate Intolerance Study in Pregnant Women and adolescents from 2001 to 2009. JAMA 2014; U.S. population 45-74 years of age. Diabetes (ACHOIS) Trial Group. Effect of treatment of 311:1778–1786 Care 2005;28:307–311 gestational diabetes mellitus on pregnancy out- 24. Ziegler AG, Rewers M, Simell O, et al. Sero- 38. Tabaei BP, Burke R, Constance A, et al. comes. N Engl J Med 2005;352:2477–2486 conversion to multiple islet autoantibodies and Community-based screening for diabetes in 54. Vandorsten JP, Dodson WC, Espeland MA, risk of progression to diabetes in children. JAMA Michigan. Diabetes Care 2003;26:668–670 et al. NIH consensus development conference: 2013;309:2473–2479 39. Lalla E, Kunzel C, Burkett S, Cheng B, diagnosing gestational diabetes mellitus. NIH 25. Sosenko JM, Skyler JS, Palmer JP, et al.; Lamster IB. Identification of unrecognized dia- Consens State Sci Statements 2013;29:1–31 Type 1 Diabetes TrialNet Study Group; Diabetes betes and pre-diabetes in a dental setting. 55. Donovan L, Hartling L, Muise M, Guthrie A, Prevention Trial–Type 1 Study Group. The pre- J Dent Res 2011;90:855–860 Vandermeer B, Dryden DM. Screening tests for diction of type 1 diabetes by multiple autoanti- 40. Lalla E, Cheng B, Kunzel C, Burkett S, gestational diabetes: a systematic review for body levels and their incorporation into an Lamster IB. Dental findings and identification the U.S. Preventive Services Task Force. Ann In- autoantibody risk score in relatives of type 1 of undiagnosed hyperglycemia. J Dent Res tern Med 2013;159:115–122 diabetic patients. Diabetes Care 2013;36: 2013;92:888–892 56. Khalafallah A, Phuah E, Al-Barazan AM, 2615–2620 41. Herman WH, Taylor GW, Jacobson JJ, Burke et al. Glycosylated haemoglobin for screening 26. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY R, Brown MB. Screening for prediabetes and and diagnosis of gestational diabetes mellitus. Study Group. Predictors of progression from the type 2 diabetes in dental offices. J Public Health BMJ Open 2016;6:e011059 appearance of islet autoantibodies to early Dent 2015;75:175–182 57. Horvath K, Koch K, Jeitler K, et al. Effects of childhood diabetes: The Environmental Deter- 42. Buse JB, Kaufman FR, Linder B, Hirst K, El treatment in women with gestational diabetes minants of Diabetes in the Young (TEDDY). Di- Ghormli L, Willi S; HEALTHY Study Group. Diabetes mellitus: systematic review and meta-analysis. abetes Care 2015;38:808–813 screening with hemoglobin A1c versus fasting BMJ 2010;340:c1395 27. Orban T, Sosenko JM, Cuthbertson D, et al.; plasma glucose in a multiethnic middle-school co- 58. Committee on Practice BulletinsdObstetrics. Diabetes Prevention Trial–Type 1 Study Group. hort. Diabetes Care 2013;36:429–435 Practice Bulletin No. 137: gestational diabetes mel- Pancreatic islet autoantibodies as predictors 43. Kapadia C, Zeitler P; Drugs and Therapeutics litus. Obstet Gynecol 2013;122:406–416 of type 1 diabetes in the Diabetes Prevention Committee of the Pediatric Endocrine Society. 59. Carpenter MW, Coustan DR. Criteria for Trial–Type 1. Diabetes Care 2009;32:2269–2274 Hemoglobin A1c measurement for the diagnosis screening tests for gestational diabetes. Am J 28. Menke A, Casagrande S, Geiss L, Cowie CC. of type 2 diabetes in children. Int J Pediatr En- Obstet Gynecol 1982;144:768–773 Prevalence of and trends in diabetes among docrinol 2012;2012:31 60. National Diabetes Data Group. Classifica- adults in the United States, 1988–2012. JAMA 44. Kester LM, Hey H, Hannon TS. Using hemo- tion and diagnosis of diabetes mellitus and 2015;314:1021–1029 globin A1c for prediabetes and diabetes diagno- other categories of glucose intolerance. Diabe- 29. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. sis in adolescents: can adult recommendations tes 1979;28:1039–1057 Effect of early intensive multifactorial therapy be upheld for pediatric use? J Adolesc Health 61. Harper LM, Mele L, Landon MB, et al.; Eu- on 5-year cardiovascular outcomes in individu- 2012;50:321–323 nice Kennedy Shriver National Institute of Child als with type 2 diabetes detected by screening 45. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness Health and Human Development (NICHD) (ADDITION-Europe): a cluster-randomised trial. of screening strategies for identifying pediatric Maternal-Fetal Medicine Units (MFMU) Network. Lancet 2011;378:156–167 diabetes mellitus and dysglycemia. JAMA Pediatr Carpenter-Coustan compared with National 30. Herman WH, Ye W, GriffinSJ,etal.Early 2013;167:32–39 Diabetes Data Group criteria for diagnosing ges- detection and treatment of type 2 diabetes re- 46. American Diabetes Association. Type 2 dia- tational diabetes. Obstet Gynecol 2016;127: duce cardiovascular morbidity and mortality: a betes in children and adolescents. Diabetes 893–898 simulation of the results of the Anglo-Danish- Care 2000;23:381–389 62. Werner EF, Pettker CM, Zuckerwise L, et al. Dutch study of intensive treatment in people 47. Lawrence JM, Contreras R, Chen W, Sacks Screening for gestational diabetes mellitus: are with screen-detected diabetes in primary care DA. Trends in the prevalence of preexisting the criteria proposed by the International Asso- (ADDITION-Europe). Diabetes Care 2015;38: diabetes and gestational diabetes mellitus ciation of the Diabetes and Pregnancy Study 1449–1455 among a racially/ethnically diverse population Groups cost-effective? Diabetes Care 2012;35: 31. Kahn R, Alperin P, Eddy D, et al. Age at ini- of pregnant women, 1999–2005. Diabetes Care 529–535 tiation and frequency of screening to detect 2008;31:899–904 63. Duran A, Saenz´ S, Torrejon´ MJ, et al. Intro- type 2 diabetes: a cost-effectiveness analysis. 48. McIntyre HD, Sacks DA, Barbour LA, et al. duction of IADPSG criteria for the screening and Lancet 2010;375:1365–1374 Issues with the diagnosis and classification of diagnosis of gestational diabetes mellitus re- 32. Araneta MR, Kanaya A, Hsu WC, et al. Op- hyperglycemia in early pregnancy. Diabetes sults in improved pregnancy outcomes at a timum BMI cut points to screen Asian Ameri- Care 2016;39:53–54 lower cost in a large cohort of pregnant women: cans for type 2 diabetes. Diabetes Care 2015; 49. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO the St. Carlos Gestational Diabetes Study. Dia- 38:814–820 Study Cooperative Research Group. Hyperglycemia betes Care 2014;37:2442–2450 S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 40, Supplement 1, January 2017

64. Wei Y, Yang H, Zhu W, et al. International with later diabetes onset and higher HbA1c 78. Onady GM, Stolfi A. Insulin and oral agents Association of Diabetes and Pregnancy Study level. Diabet Med 2014;31:466–471 for managing cystic fibrosis-related diabetes. Group criteria is suitable for gestational diabetes 71. Naylor RN, John PM, Winn AN, et al. Cost- Cochrane Database Syst Rev 2016;4:CD004730 mellitus diagnosis: further evidence from China. effectiveness of MODY genetic testing: translat- 79. Moran A, Brunzell C, Cohen RC, et al.; CFRD Chin Med J (Engl) 2014;127:3553–3556 ing genomic advances into practical health Guidelines Committee. Clinical care guidelines 65. Feldman RK, Tieu RS, Yasumura L. Gestational applications. Diabetes Care 2014;37:202–209 for cystic fibrosis–related diabetes: a position diabetes screening: the International Association 72. Hattersley A, Bruining J, Shield J, Njolstad P, statement of the American Diabetes Association of the Diabetes and Pregnancy Study Groups Donaghue KC. The diagnosis and management and a clinical practice guideline of the Cystic Fibrosis compared with Carpenter-Coustan screening. of monogenic diabetes in children and adolescents. Foundation, endorsed by the Pediatric Endocrine – Obstet Gynecol 2016;127:10–17 Pediatr Diabetes 2009;10(Suppl. 12):33–42 Society. Diabetes Care 2010;33:2697 2708 66. Ethridge JK Jr, Catalano PM, Waters TP. 73. Rubio-Cabezas O, Hattersley AT, Njølstad 80. Sharif A, Hecking M, de Vries APJ, et al. Pro- Perinatal outcomes associated with the diagno- PR, et al.; International Society for Pediatric ceedings from an international consensus meet- sis of gestational diabetes made by the Interna- and Adolescent Diabetes. ISPAD Clinical Practice ing on posttransplantation diabetes mellitus: tional Association of the Diabetes and Pregnancy Consensus Guidelines 2014. The diagnosis and recommendations and future directions. Am J Transplant 2014;14:1992–2000 Study Groups criteria. Obstet Gynecol 2014;124: management of monogenic diabetes in children 81. Ramirez SC, Maaske J, Kim Y, et al. The as- 571–578 and adolescents. Pediatr Diabetes 2014;15 sociation between glycemic control and clinical 67. Mayo K, Melamed N, Vandenberghe H, (Suppl. 20):47–64 outcomes after kidney transplantation. Endocr Berger H. The impact of adoption of the Inter- 74. Greeley SAW, Naylor RN, Philipson LH, Bell Pract 2014;20:894–900 national Association of Diabetes in Pregnancy GI. Neonatal diabetes: an expanding list of 82. Sharif A, Moore RH, Baboolal K. The use of Study Group criteria for the screening and di- genes allows for improved diagnosis and treat- oral glucose tolerance tests to risk stratify for – agnosis of gestational diabetes. Am J Obstet Gy- ment. Curr Diab Rep 2011;11:519 532 new-onset diabetes after transplantation: an – necol 2015;212:224.e1 224.e9 75. Ode KL, Moran A. New insights into cystic underdiagnosed phenomenon. Transplantation fi 68. Carmody D, Støy J, Greeley SA, Bell GI, brosis-related diabetes in children. Lancet Di- 2006;82:1667–1672 – Philipson LH. A clinical guide to monogenic diabetes Endocrinol 2013;1:52 58 83. Hecking M, Werzowa J, Haidinger M, et al. abetes. In Genetic Diagnosis of Endocrine Disor- 76.MoranA,DunitzJ,NathanB,SaeedA,Holme Novel views on new-onset diabetes after transplan- fi ders. 2nd ed. Weiss RE, Refetoff S, Eds. Philadelphia, B, Thomas W. Cystic brosis-related diabetes: cur- tation: development, prevention and treatment. PA, Elsevier, 2016 rent trends in prevalence, incidence, and mortality. Nephrol Dial Transplant 2013;28:550–566 69. De Franco E, Flanagan SE, Houghton JAL, Diabetes Care 2009;32:1626–1631 84. Hecking M, Kainz A, Werzowa J, et al. Glu- et al. The effect of early, comprehensive geno- 77. Moran A, Pekow P, Grover P, et al.; Cystic cose metabolism after renal transplantation. Di- mic testing on clinical care in neonatal diabetes: Fibrosis Related Diabetes Therapy Study Group. abetes Care 2013;36:2763–2771 an international cohort study. Lancet 2015;386: Insulin therapy to improve BMI in cystic fibrosis- 85. Valderhaug TG, Jenssen T, Hartmann A, 957–963 related diabetes without fasting hyperglycemia: et al. Fasting plasma glucose and glycosylated 70. UrbanovaJ,Ryp´ aćkovˇ aB,Proch´ azkov´ aZ,´ results of the Cystic Fibrosis Related Diabetes hemoglobin in the screening for diabetes melli- et al. Positivity for islet cell autoantibodies in Therapy Trial. Diabetes Care 2009;32:1783– tus after renal transplantation. Transplantation patients with monogenic diabetes is associated 1788 2009;88:429–434