2. Classification and Diagnosis of Diabetes

Transcription

1 S8 Diabetes Care Volume 38, Supplement 1, January Classifiation and Diagnosis of Diabetes Amerian Diabetes Assoiation Diabetes Care 2015;38(Suppl. 1):S8 S16 DOI: /d15-S005 CLASSIFICATION Diabetes an be lassified into the following general ategories: POSITION STATEMENT 1. Type 1 diabetes (due to b-ell destrution, usually leading to absolute insulin defiieny) 2. Type 2 diabetes (due to a progressive insulin seretory defet on the bakground of insulin resistane) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the seond or third trimester of pregnany that is not learly overt diabetes) 4. Speifi types of diabetes due to other auses, e.g., monogeni diabetes syndromes (suh as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exorine panreas (suh as ysti fibrosis), and drug- or hemial-indued diabetes (suh as in the treatment of HIV/AIDS or after organ transplantation) This setion reviews most ommon forms of diabetes but is not omprehensive. For additional information, see the Amerian Diabetes Assoiation (ADA) position statement Diagnosis and Classifiation of Diabetes Mellitus (1). Assigning a type of diabetes to an individual often depends on the irumstanes present at the time of diagnosis, with individuals not neessarily fitting learly into a single ategory. For example, some patients annot be learly lassified as having type 1 or type 2 diabetes. Clinial presentation and disease progression may vary onsiderably in both types of diabetes. The traditional paradigms of type 2 diabetes ourring only in adults and type 1 diabetes only in hildren are no longer aurate, as both diseases our in both ohorts. Oasionally, patients with type 2 diabetes may present with diabeti ketoaidosis (DKA). Children with type 1 diabetes typially present with the hallmark symptoms of polyuria/polydipsia and oasionally with DKA. The onset of type 1 diabetes may be variable in adults and may not present with the lassi symptoms seen in hildren. However, diffiulties in diagnosis may our in hildren, adolesents, and adults, with the true diagnosis beoming more obvious over time. DIAGNOSTIC TESTS F DIABETES Diabetes may be diagnosed based on A1C riteria or plasma gluose riteria, either the fasting plasma gluose (FPG) or the 2-h plasma gluose (2-h PG) value after a 75-g oral gluose tolerane test (OGTT) (1,2) (Table 2.1). The same tests are used to both sreen for and diagnose diabetes. Diabetes may be identified anywhere along the spetrum of linial senarios: in seemingly lowrisk individuals who happen to have gluose testing, in symptomati patients, and in higher-risk individuals whom the provider tests beause of a suspiion of diabetes. The same tests will also detet individuals with prediabetes. A1C The A1C test should be performed using a method that is ertified by the NGSP and standardized or traeable to the Diabetes Control and Compliations Trial (DCCT) referene assay. Although point-of-are (POC) A1C assays may be NGSP ertified, profiieny testing is not mandated for performing the test, so use of POC assays for diagnosti purposes may be problemati and is not reommended. The A1C has several advantages to the FPG and OGTT, inluding greater onveniene (fasting not required), greater preanalytial stability, and less day-to-day perturbations during stress and illness. These advantages must be balaned by Suggested itation: Amerian Diabetes Assoiation. Classifiation and diagnosis of diabetes. Se. 2. In Standards of Medial Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1):S8 S by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered.

2 are.diabetesjournals.org Position Statement S9 Table 2.1 Criteria for the diagnosis of diabetes A1C $6.5%. The test should be performed in a laboratory using a method that is NGSP ertified and standardized to the DCCT assay.* FPG $126 mg/dl (7.0 mmol/l). Fasting is defined as no alori intake for at least 8h.* 2-h PG $200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as desribed by the WHO, using a gluose load ontaining the equivalent of 75 g anhydrous gluose dissolved in water.* In a patient with lassi symptoms of hyperglyemia or hyperglyemi risis, a random plasma gluose $200 mg/dl (11.1 mmol/l). *In the absene of unequivoal hyperglyemia, results should be onfirmed by repeat testing. greater ost, the limited availability of A1C testing in ertain regions of the developing world, and the inomplete orrelation between A1C and average gluose in ertain individuals. It is important to take age, rae/ ethniity, and anemia/hemoglobinopathies into onsideration when using the A1C to diagnose diabetes. Age The epidemiologial studies that formed the framework for reommending A1C to diagnose diabetes only inluded adult populations. Therefore, it remains unlear if A1C and the same A1C ut point should be used to diagnose diabetes in hildren and adolesents (3 5). Rae/Ethniity A1C levels may vary with patients rae/ ethniity (6,7). For example, Afrian Amerians may have higher A1C levels than non-hispani whites despite similar fasting and postgluose load gluose levels. A reent epidemiologial study found that, when mathed for FPG, Afrian Amerians (with and without diabetes) had higher A1C levels than non- Hispani whites, but also had higher levels of frutosamine and glyated albumin and lower levels of 1,5-anhydrogluitol, suggesting that their glyemi burden (partiularly postprandially) may be higher (8). Hemoglobinopathies/Anemias Interpreting A1C levels in the presene of ertain hemoglobinopathies and anemia may be problemati. For patients with an abnormal hemoglobin but normal red ell turnover, suh as those with the sikle ell trait, an A1C assay without interferene from abnormal hemoglobins should be used. An updated list of interferenes is available at In onditions assoiated with inreased red ell turnover, suh as pregnany (seond and third trimesters), reent blood loss or transfusion, erythropoietin therapy, or hemolysis, only blood gluose riteria should be used to diagnose diabetes. Fasting and 2-Hour Plasma Gluose In addition to the A1C test, the FPG and 2-h PG may also be used to diagnose diabetes (Table 2.1). The onordane between the FPG and 2-h PG tests is imperfet, as is the onordane between A1C and either gluose-based test. National Health and Nutrition Examination Survey (NHANES) data indiate that an A1C ut point of $6.5% identifies one-third fewer ases of undiagnosed diabetes than a fasting gluose ut point of $126 mg/dl (7.0 mmol/l) (9). Numerous studies have onfirmed that, ompared with these A1C and FPG ut points, the 2-h PG value diagnoses more people with diabetes. Of note, the lower sensitivity of A1C at the designated ut point may be offset by the test s ease of use and failitation of more widespread testing. Unless there is a lear linial diagnosis (e.g., a patient in a hyperglyemi risis or with lassi symptoms of hyperglyemia and a random plasma gluose $200 mg/dl), it is reommended that the same test be repeated immediately using a new blood sample for onfirmation beause there will be a greater likelihood of onurrene. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is onfirmed. If two different tests (suh as A1C and FPG) are both above the diagnosti threshold, this also onfirms the diagnosis. On the other hand, if a patient has disordant results from two different tests, then the test result that is above the diagnosti ut point should be repeated. The diagnosis is made on the basis of the onfirmed test. For example, if a patient meets the diabetes riterion of the A1C (two results $6.5%), but not FPG (,126 mg/dl [7.0 mmol/l]), that person should nevertheless be onsidered to have diabetes. Sine all the tests have preanalyti and analyti variability, it is possible that an abnormal result (i.e., above the diagnosti threshold), when repeated, will produe a value below the diagnosti ut point. This senario is least likely for A1C, more likely for FPG, and most likely for the 2-h PG, espeially if the gluose samples are olleted at room temperature and not entrifuged promptly. Barring laboratory error, suh patients will likely have test results near the margins of the diagnosti threshold. The health are professional should follow the patient losely and repeat the test in 3 6 months. CATEGIES OF INCREASED RISK F DIABETES (PREDIABETES) Reommendations Testing to assess risk for future diabetes in asymptomati people should be onsidered in adults of any age who are overweight or obese (BMI $25 kg/m 2 or $23 kg/m 2 in Asian Amerians) and who have one or more additional risk fators for diabetes. For all patients, partiularly those who are overweight or obese, testing should begin at age 45 years. B If tests are normal, repeat testing arried out at a minimum of 3- year intervals is reasonable. C To test for prediabetes, the A1C, FPG, and 2-h PG after 75-g OGTT are appropriate. B In patients with prediabetes, identify and, if appropriate, treat other ardiovasular disease (CVD) risk fators. B Testing to detet prediabetes should be onsidered in hildren and adolesents who are overweight or obese and who have two or more additional risk fators for diabetes. E Desription In 1997 and 2003, the Expert CommitteeonDiagnosisandClassifiation of Diabetes Mellitus (10,11) reognized a group of individuals whose gluose levels did not meet the riteria for diabetes but were too high to be onsidered

3 S10 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015 Table 2.2 Criteria for testing for diabetes or prediabetes in asymptomati adults 1. Testing should be onsidered in all adults who are overweight (BMI $25 kg/m 2 or $23 kg/m 2 in Asian Amerians) and have additional risk fators: physial inativity first-degree relative with diabetes high-risk rae/ethniity (e.g., Afrian Amerian, Latino, Native Amerian, Asian Amerian, Paifi Islander) women who delivered a baby weighing.9 lb or were diagnosed with GDM hypertension ($140/90 mmhg or on therapy for hypertension) HDL holesterol level,35 mg/dl (0.90 mmol/l) and/or a triglyeride level.250 mg/dl (2.82 mmol/l) women with polyysti ovary syndrome A1C $5.7%, IGT, or IFG on previous testing other linial onditions assoiated with insulin resistane (e.g., severe obesity, aanthosis nigrians) history of CVD 2. For all patients, partiularly those who are overweight or obese, testing should begin at age 45 years. 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with onsideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status. normal. Prediabetes is the term used for individuals with impaired fasting gluose (IFG) and/or impaired gluose tolerane (IGT) and indiates an inreased risk for the future development of diabetes. IFG and IGT should not be viewed as linial entities in their own right but rather risk fators for diabetes (Table 2.2) andcvd.ifg and IGT are assoiated with obesity (espeially abdominal or viseral obesity), dyslipidemia with high triglyerides and/or low HDL holesterol, and hypertension. Diagnosis In 1997 and 2003, the Expert Committee on Diagnosis and Classifiation of Diabetes Mellitus (10,11) defined IFG as FPG levels mg/dl ( mmol/l)andigtas2-hpgafter75-g OGTT levels mg/dl ( mmol/l). It should be noted that the WorldHealthOrganization(WHO)and numerous diabetes organizations define the IFG utoff at 110 mg/dl (6.1 mmol/l). As with the gluose measures, several prospetive studies that used A1C to predit the progression to diabetes demonstrated a strong, ontinuous assoiation between A1C and subsequent diabetes. In a systemati review of 44,203 individuals from 16 ohort studies with a follow-up interval averaging 5.6 years (range years), those with an A1C between % had a substantially inreased risk of diabetes (5-year inidene from 9to25%).AnA1Crangeof % had a 5-year risk of developing diabetes between 25 50% and a relative risk 20 times higher ompared with an A1C of 5.0% (12). In a ommunity-based study of Afrian Amerian and non- Hispani white adults without diabetes, baseline A1C was a stronger preditor of subsequent diabetes and ardiovasular events than fasting gluose (13). Other analyses suggest that an A1C of 5.7% is assoiated with a diabetes risk similar to that of the high-risk partiipants in the Diabetes Prevention Program (DPP) (14). Hene, it is reasonable to onsider an A1C range of % as identifying individuals with prediabetes. As with those with IFG and/or IGT, individuals with an A1C of % should be informed of their inreased risk for diabetes and CVD and ounseled about effetive strategies to lower their risks (see Setion 5. Prevention or Delay of Type 2 Diabetes). Similar to gluose measurements, the ontinuum of risk is urvilinear, so as A1C rises, the diabetes risk rises disproportionately (12). Aggressive interventions and vigilant follow-up should be pursued for those onsidered at very high risk (e.g., those with A1C.6.0%). Table 2.3 summarizes the ategories of prediabetes. For reommendations regarding risk fators and sreening for prediabetes, see p. S12 ( Testing for Type 2 Diabetes and Prediabetes in Asymptomati Adults and Testing for Type 2 Diabetes and Prediabetes in Children and Adolesents ). TYPE 1 DIABETES Reommendation Inform the relatives of patients with type 1 diabetes of the opportunity to be tested for type 1 diabetes risk, but only in the setting of a linial researh study. E Immune-Mediated Diabetes This form, previously alled insulindependent diabetes or juvenile-onset diabetes, aounts for 5 10% of diabetes and is due to ellular-mediated autoimmune destrution of the panreati b-ells. Autoimmune markers inlude islet ell autoantibodies, autoantibodies to insulin, autoantibodies to GAD (GAD65), autoantibodies to the tyrosine phosphatases IA-2 and IA-2b, and autoantibodies to zin transporter 8 (ZnT8). Type 1 diabetes is defined by the presene of one or more of these autoimmune markers. The disease has strong HLA assoiations, with linkage to the DQA and DQB genes. These HLA-DR/DQ alleles an be either predisposing or protetive. Therateofb-ell destrution is quite variable, being rapid in some individuals (mainly infants and hildren) and slow in others (mainly adults). Children and adolesents may present with ketoaidosis as the first manifestation of the disease. Others have modest fasting hyperglyemia that an rapidly hange to severe hyperglyemia and/or ketoaidosis with infetion or other stress. Adults may retain suffiient b-ell funtion to prevent ketoaidosis for many years; suh individuals eventually beome dependent on insulin for survival and are at risk for ketoaidosis. At this latter stage of the disease, there is little or no insulin seretion, as manifested by low or undetetable levels of plasma C-peptide. Immune-mediated diabetes Table 2.3 Categories of inreased risk for diabetes (prediabetes)* FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) (IFG) 2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) (IGT) A1C % *For all three tests, risk is ontinuous, extending below the lower limit of the range and beoming disproportionately greater at higher ends of the range.

4 are.diabetesjournals.org Position Statement S11 ommonly ours in hildhood and adolesene, but it an our at any age, even in the 8th and 9th deades of life. Autoimmune destrution of b-ells has multiple geneti predispositions and is also related to environmental fators that are still poorly defined. Although patients are not typially obese when they present with type 1 diabetes, obesity should not prelude the diagnosis. These patients are also prone to other autoimmune disorders suh as Graves disease, Hashimoto s thyroiditis, Addison s disease, vitiligo, elia disease, autoimmune hepatitis, myasthenia gravis, and perniious anemia. Idiopathi Diabetes Some forms of type 1 diabetes have no known etiologies. These patients have permanent insulinopenia and are prone to ketoaidosis, but have no evidene of autoimmunity. Although only a minority of patients with type 1 diabetes fall into this ategory, of those who do, most are of Afrian or Asian anestry. Individuals with this form of diabetes suffer from episodi ketoaidosis and exhibit varying degrees of insulin defiieny between episodes. This form of diabetes is strongly inherited, laks immunologial evidene for b-ell autoimmunity, and is not HLA assoiated. An absolute requirement for insulin replaement therapy in affeted patients may ome and go. Testing for Type 1 Diabetes The inidene and prevalene of type 1 diabetes is inreasing (15). Type 1 diabeti patients often present with aute symptoms of diabetes and markedly elevated blood gluose levels, and some are diagnosed with life-threatening ketoaidosis. Several studies suggest that measuring islet autoantibodies in relatives of those with type 1 diabetes may identify individuals who are at risk for developing type 1 diabetes. Suh testing, oupled with eduation about diabetes symptoms and lose follow-up in an observational linial study, may enable earlier identifiation of type 1 diabetes onset. There is evidene to suggest that early diagnosis may limit aute ompliations (16) and extend long-term endogenous insulin prodution (17). A reent study reported the risk of progression to type 1 diabetes from the time of seroonversion to autoantibody positivity in three pediatri ohorts from Finland, Germany, and the U.S. Of the 585 hildren who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (16,18). These findings are highly signifiant beause, while the German group was reruited from offspring of parents with type 1 diabetes, the Finnish and Amerian groups were reruited from the general population. Remarkably, the findings in all three groups were the same, suggesting that the same sequene of events led to linial disease in both sporadi and geneti ases of type 1 diabetes. While there is urrently a lak of aepted sreening programs, one should onsider referring relatives of those with type 1 diabetes for antibody testing for risk assessment in the setting of a linial researh study ( Widespread linial testing of asymptomati low-risk individuals is not urrently reommended due to lak of approved therapeuti interventions. Higher-risk individuals may be tested, but only in the ontext of a linial researh setting. Individuals who test positive will be ounseled about the risk of developing diabetes, diabetes symptoms, and DKA prevention. Numerous linial studies are being onduted to test various methods of preventing type 1 diabetes in those with evidene of autoimmunity ( TYPE 2 DIABETES Reommendations Testing to detet type 2 diabetes in asymptomati people should be onsidered in adults of any age who are overweight or obese (BMI $25 kg/m 2 or $23 kg/m 2 in Asian Amerians) and who have one or more additional risk fators for diabetes. For all patients, partiularly those who are overweight or obese, testing should begin at age 45 years. B If tests are normal, repeat testing arried out at a minimum of 3-year intervals is reasonable. C To test for diabetes, the A1C, FPG, and 2-h PG after 75-g OGTT are appropriate. B In patients with diabetes, identify and, if appropriate, treat other CVD risk fators. B Testing to detet type 2 diabetes should be onsidered in hildren andadolesentswhoareoverweight or obese and who have two or more additional risk fators for diabetes. E Desription This form, previously referred to as noninsulin-dependent diabetes or adultonset diabetes, aounts for ;90 95% of all diabetes. Type 2 diabetes enompasses individuals who have insulin resistane and usually relative (rather than absolute) insulin defiieny. At least initially, and often throughout their lifetime, these individuals may not need insulin treatment to survive. There are various auses of type 2 diabetes. Although the speifi etiologies are not known, autoimmune destrution of b-ells does not our, and patients do not have any of the other known auses of diabetes. Most, but not all, patients with type 2 diabetes are obese. Obesity itself auses some degree of insulin resistane. Patients who are not obese by traditional weight riteria may have an inreased perentage of body fat distributed predominantly in the abdominal region. Ketoaidosis seldom ours spontaneously in type 2 diabetes; when seen, it usually arises in assoiation with the stress of another illness suh as infetion. Type 2 diabetes frequently goes undiagnosed for many years beause hyperglyemia develops gradually and at earlier stages is often not severe enough for the patient to notie the lassi diabetes symptoms. Nevertheless, suh patients are at an inreased risk of developing marovasular and mirovasular ompliations. Whereaspatientswithtype2diabetes may have insulin levels that appear normal or elevated, the higher blood gluose levels in these patients would be expeted to result in even higher insulin values had their b-ell funtion been normal. Thus, insulin seretion is defetive in these patients and insuffiient to ompensate for insulin resistane. Insulin resistane may improve with weight redution and/or pharmaologial treatment of hyperglyemia but is seldom restored to normal. The risk of developing type 2 diabetes inreases with age, obesity, and lak of physial ativity. It ours more frequently

5 S12 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015 in women with prior GDM, in those with hypertension or dyslipidemia, and in ertain raial/ethni subgroups (Afrian Amerian, Amerian Indian, Hispani/ Latino, and Asian Amerian). It is often assoiated with a strong geneti predisposition, more so than type 1 diabetes. However, the genetis of type 2 diabetes is poorly understood. Testing for Type 2 Diabetes and Prediabetes in Asymptomati Adults Prediabetes and diabetes meet riteria for onditions in whih early detetion is appropriate. Both onditions are ommon and impose signifiant linial and publi health burdens. There is often a long presymptomati phase before the diagnosis of type 2 diabetes. Simple tests to detet prelinial disease are readily available. The duration of glyemi burden is a strong preditor of adverse outomes. There are effetive interventions that prevent progression from prediabetes to diabetes (see Setion 5. Prevention or Delay of Type 2 Diabetes) and redue the risk of diabetes ompliations (see Setion 8. Cardiovasular Disease and Risk Management and Setion 9. Mirovasular Compliations and Foot Care). Approximately one-quarter of people with diabetes in the U.S. are undiagnosed. Although sreening of asymptomati individuals to identify those with prediabetes or diabetes might seem reasonable, rigorous linial trials to prove the effetiveness of suh sreening have not been onduted and are unlikely to our. A large European randomized ontrolled trial ompared the impat of sreening for diabetes and intensive multifatorial intervention with that of sreening and routine are (19). General pratie patients between the ages of years were sreened for diabetes and randomized by pratie to intensive treatment of multiple risk fators or routine diabetes are. After 5.3 years of follow-up, CVD risk fators were modestly but signifiantly improved with intensive treatment ompared with routine are, but the inidene of first CVD events or mortality was not signifiantly different between the groups (19). The exellent are provided to patients in the routine are group and the lak of an unsreened ontrol arm limit our ability to prove that sreening and early intensive treatment impat outomes. Mathematial modeling studies suggest that sreening, beginning at age 30 or 45 years and independent of risk fators, may be ost-effetive (,$11,000 per qualityadjusted life-year gained) (20). Additional onsiderations regarding testing for type 2 diabetes and prediabetes in asymptomati patients inlude the following: Age Testing reommendations for diabetes in asymptomati adults are listed in Table 2.2. Age is a major risk fator for diabetes. Testing should begin at age 45 years for all patients, partiularly those who are overweight or obese. BMI and Ethniity Testingshouldbeonsideredinadults of any age with BMI $25 kg/m 2 and one or more additional risk fators for diabetes. However, reent data (21) and evidene from the ADA position statement BMI Cut Points to Identify At-Risk Asian Amerians for Type 2 Diabetes Sreening (22)suggestthattheBMI ut point should be lower for the Asian Amerian population. For diabetes sreening purposes, the BMI ut points fall onsistently between kg/m 2 (sensitivity of 80%) for nearly all Asian Amerian subgroups (with levels slightly lower for Japanese Amerians). This makes a rounded ut point of 23 kg/m 2 pratial. In determining a single BMI ut point, it is important to balane sensitivity and speifiity so as to provide a valuable sreening tool without numerous false positives. An argument an be made to push the BMI ut point to lower than 23 kg/m 2 in favor of inreased sensitivity; however, this would lead to an unaeptably low speifiity (13.1%). Data from the WHO also suggest that a BMI $23 kg/m 2 should be used to define inreased risk in Asian Amerians (23). Evidene also suggests that other populations may benefit fromlower BMI ut points. For example, in a large multiethni ohort study, for an equivalent inidene rate of diabetes, a BMI of 30 kg/m 2 in non-hispani whites was equivalent to a BMI of 26 kg/m 2 in Afrian Amerians (24). Mediations Certain mediations, suh as gluoortioids, thiazide diuretis, and atypial antipsyhotis (25), are known to inrease the risk of diabetes and should be onsidered when asertaining a diagnosis. Diagnosti Tests The A1C, FPG, and 2-h PG after 75-g OGTT are appropriate for testing. It should be noted that the tests do not neessarily detet diabetes in the same individuals. The effiay of interventions for primary prevention of type 2 diabetes (26 32) has primarily been demonstrated among individuals with IGT, not for individuals with isolated IFG or for those with prediabetes defined by A1C riteria. Testing Interval The appropriate interval between tests is not known (33). The rationale for the 3-year interval is that with this interval, the number of false-positive tests that require onfirmatory testing will be redued and individuals with false-negative tests will be retested before substantial time elapses and ompliations develop (33). Community Sreening Ideally, testing should be arried out within a health are setting beause of the need for follow-up and treatment. Community testing outside a health are setting is not reommended beause people with positive tests may not seek, or have aess to, appropriate follow-up testing and are. Community testing may also be poorly targeted; i.e., it may fail to reah the groups most at risk and inappropriately test those at very low risk or even those who have already been diagnosed. Testing for Type 2 Diabetes and Prediabetes in Children and Adolesents In the last deade, the inidene and prevalene of type 2 diabetes in adolesents has inreased dramatially, espeially in ethni populations (15). Reent studies question the validity of A1C in the pediatri population, espeially among ertain ethniities, and suggest OGTT or FPG as more suitable diagnosti tests (34). However, many of these studies do not reognize that diabetes diagnosti riteria are based on longterm health outomes, and validations are not urrently available in the pediatri population (35). The ADA aknowledges the limited data supporting A1C for diagnosing diabetes in hildren and adolesents. However, aside from rare instanes, suh as ysti fibrosis and hemoglobinopathies, the ADA ontinues to reommend A1C in this ohort (36,37). The modified reommendations of the ADA onsensus report Type 2 Diabetes in Children and Adolesents are summarized in Table 2.4.

6 are.diabetesjournals.org Position Statement S13 Table 2.4 Testing for type 2 diabetes or prediabetes in asymptomati hildren* Criteria Overweight (BMI.85th perentile for age and sex, weight for height.85th perentile, or weight.120% of ideal for height) Plus any two of the following risk fators: Family history of type 2 diabetes in first- or seond-degree relative Rae/ethniity (Native Amerian, Afrian Amerian, Latino, Asian Amerian, Paifi Islander) Signs of insulin resistane or onditions assoiated with insulin resistane (aanthosis nigrians, hypertension, dyslipidemia, polyysti ovary syndrome, or smallfor-gestational-age birth weight) Maternal history of diabetes or GDM during the hild s gestation Age of initiation: age 10 years or at onset of puberty, if puberty ours at a younger age Frequeny: every 3 years *Persons aged #18 years. GESTATIONAL DIABETES MELLITUS Reommendations Test for undiagnosed type 2 diabetes at the first prenatal visit in those with risk fators, using standard diagnosti riteria. B Test for GDM at weeks of gestation in pregnant women not previously known to have diabetes. A Sreen women with GDM for persistent diabetes at 6 12 weeks postpartum, using the OGTT and linially appropriate nonpregnany diagnosti riteria. E WomenwithahistoryofGDM should have lifelong sreening for the development of diabetes or prediabetes at least every 3 years. B WomenwithahistoryofGDM found to have prediabetes should reeive lifestyle interventions or metformin to prevent diabetes. A Definition For many years, GDM was defined as any degree of gluose intolerane that was first reognized during pregnany (10), regardless of whether the ondition may have predated the pregnany or persisted after the pregnany. This definition failitated a uniform strategy for detetion and lassifiation of GDM, but it was limited by impreision. The ongoing epidemi of obesity and diabetes has led to more type 2 diabetes in women of hildbearing age, resulting in an inrease in the number of pregnant women with undiagnosed type 2 diabetes (38). Beause of the number of pregnant women with undiagnosed type 2 diabetes, it is reasonable to test women with risk fators for type 2 diabetes (Table 2.2) at their initial prenatal visit, using standard diagnosti riteria (Table 2.1). Women with diabetes in the first trimester would be lassified as having type 2 diabetes. GDM is diabetes diagnosed in the seond or third trimester of pregnany that is not learly overt diabetes. Diagnosis GDM arries risks for the mother and neonate. Not all adverse outomes are of equal linial importane. The Hyperglyemia and Adverse Pregnany Outome (HAPO) study (39), a large-sale (;25,000 pregnant women) multinational ohort study, demonstrated that risk of adverse maternal, fetal, and neonatal outomes ontinuously inreased as a funtion of maternal glyemia at weeks, even within ranges previously onsidered normal for pregnany. For most ompliations, there was no threshold for risk. These results have led to areful reonsideration of the diagnosti riteria for GDM. GDM diagnosis (Table 2.5) an be aomplished with either of two strategies: 1. One-step 75-g OGTT or 2. Two-step approah with a 50-g (nonfasting) sreen followed by a 100-g OGTT for those who sreen positive Different diagnosti riteria will identify different degrees of maternal hyperglyemia and maternal/fetal risk, leading some experts to debate, and disagree on, optimal strategies for the diagnosis of GDM. One-Step Strategy In the 2011 Standards of Care (40), the ADA for the first time reommended that all pregnant women not known to have prior diabetes undergo a 75-g OGTT at weeks of gestation, basedonareommendationoftheinternational Assoiation of the Diabetes and Pregnany Study Groups (IADPSG) (41). The IADPSG defined diagnosti ut points for GDM as the average gluose values (fasting, 1-h, and 2-h PG) in the HAPO study at whih odds for adverse outomes reahed 1.75 times the estimated odds of these outomes at the mean gluose levels of the study population. This one-step strategy was antiipated to signifiantly inrease the inidene of GDM (from 5 6% to ;15 20%), primarily beause only one abnormal value, not two, beame suffiient to make the diagnosis. The ADA reognized that the antiipated inrease in the inidene of GDM would have signifiant impat on the osts, medial infrastruture apaity, and potential for inreased medialization of pregnanies previously ategorized as normal, but reommended these diagnosti riteria hanges in the ontext of worrisome worldwide inreases in obesity and diabetes rates with the intent of optimizing gestational outomes for women and their offspring. The expeted benefits to these pregnanies and offspring are inferred from intervention trials that foused on women with lower levels of hyperglyemia than identified using older GDM diagnosti riteria and that found modest benefits inluding redued rates of largefor-gestational-age births and preelampsia (42,43). It is important to note that 80 90% of women being treated for mild GDM in two randomized ontrolled trials (whose gluose values overlapped with the thresholds reommended by the IADPSG) ould be managed with lifestyle therapy alone. Data are laking on how the treatment of lower levels of hyperglyemia affets a mother s risk for the development of type 2 diabetes in the future and her offspring s riskfor obesity, diabetes, and other metaboli dysfuntion. Additional well-designed linial studies are needed to determine the optimal intensity of monitoring and treatment of women with GDM diagnosed by the one-step strategy. Two-Step Strategy In 2013, the National Institutes of Health (NIH) onvened a onsensus development onferene on diagnosing GDM. The 15-member panel had representatives from obstetris/gyneology, maternalfetal mediine, pediatris, diabetes researh, biostatistis, and other related fields to onsider diagnosti riteria (44). The panel reommended the two-step approah of sreening with a 1-h 50-g

7 S14 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015 Table 2.5 Sreening for and diagnosis of GDM One-step strategy Perform a 75-g OGTT, with plasma gluose measurement when patient is fasting and at 1 and 2h,at24 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 gluose values are met or exeeded: Fasting: 92 mg/dl (5.1 mmol/l) 1 h: 180 mg/dl (10.0 mmol/l) 2 h: 153 mg/dl (8.5 mmol/l) Two-step strategy Step 1: Perform a 50-g GLT (nonfasting), with plasma gluose measurement at 1 h, at weeks of gestation in women not previously diagnosed with overt diabetes. If the plasma gluose level measured 1 h after the load is $140 mg/dl* (7.8 mmol/l), proeed 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 gluose levels (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exeeded: Carpenter/Coustan (56) or NDDG (57) Fasting 95 mg/dl (5.3 mmol/l) 105 mg/dl (5.8 mmol/l) 1 h 180 mg/dl (10.0 mmol/l) 190 mg/dl (10.6 mmol/l) 2 h 155 mg/dl (8.6 mmol/l) 165 mg/dl (9.2 mmol/l) 3 h 140 mg/dl (7.8 mmol/l) 145 mg/dl (8.0 mmol/l) NDDG, National Diabetes Data Group. *The ACOG reommends a lower threshold of 135 mg/dl (7.5 mmol/l) in high-risk ethni populations with higher prevalene of GDM; some experts also reommend 130 mg/dl (7.2 mmol/l). gluose load test (GLT) followed by a 3-h 100-g OGTT for those who sreen positive, a strategy ommonly used in the U.S. Key fators reported in the NIH panel s deision-making proess were the lak of linial trial interventions demonstrating the benefits of the one-step strategy and the potential negative onsequenes of identifying a large new group of women with GDM, inluding medialization of pregnany with inreased interventions and osts. Moreover, sreening with a 50-g GLT does not require fasting and is therefore easier to aomplish for many women. Treatment of higher threshold maternal hyperglyemia, as identified by the two-step approah, redues rates of neonatal marosomia, large-for-gestational-age births, and shoulder dystoia, without inreasing small-for-gestational-age births (45). The Amerian College of Obstetriians and Gyneologists (ACOG) updated its guidelines in 2013 and supported the two-step approah (46). Future Considerations The onfliting reommendations from expert groups undersore the fat that there are data to support eah strategy. The deision of whih strategy to implement must therefore be made based on the relative values plaed on fators thathaveyettobemeasured(e.g.,ostbenefit estimation, willingness to hange pratie based on orrelation studies rather than linial intervention trial results, relative role of ost onsiderations, and available infrastruture loally, nationally, and internationally). As the IADPSG riteria have been adopted internationally, further evidene has emerged to support improved pregnany outomes with ost savings (47) and may be the preferred approah. In addition, pregnanies ompliated by GDM per IADPSG riteria, but not reognized as suh, have omparable outomes to pregnanies diagnosed as GDM by the more stringent two-step riteria (48). There remains strong onsensus that establishing a uniform approah to diagnosing GDM will benefit patients, aregivers, and poliymakers. Longer-term outome studies are urrently underway. MONOGENIC DIABETES SYNDROMES Monogeni defets that ause b-ell dysfuntion, suh as neonatal diabetes and MODY, represent a small fration of patients with diabetes (,5%). These forms of diabetes are frequently haraterized by onset of hyperglyemia at an early age (generally before age 25 years). Neonatal Diabetes Diabetes diagnosed in the first 6 months of life has been shown not to be typial autoimmune type 1 diabetes. This so-alled neonatal diabetes an either be transient or permanent. The most ommon geneti defet ausing transient disease is a defet on ZAC/HYAMI imprinting, whereas permanent neonatal diabetes is most ommonly a defet in the gene enoding the Kir6.2 subunit of the b-ell K ATP hannel. Diagnosing the latter has impliations, sine suh hildren an be well managed with sulfonylureas. Maturity-Onset Diabetes of the Young MODY is haraterized by impaired insulin seretion with minimal or no defets in insulin ation. It is inherited in an autosomal dominant pattern. Abnormalities at six geneti loi on different hromosomes have been identified to date. The most ommon form is assoiated with mutations on hromosome 12 in a hepati transription fator referred to as hepatoyte nulear fator (HNF)-1a. A seond form is assoiated with mutations in the gluokinase gene on hromosome 7p and results in a defetive gluokinase moleule. Gluokinase onverts gluose to gluose-6-phosphate, the metabolism of whih, in turn, stimulates insulin seretion by the b-ell. The less ommon forms of MODY result from mutations in other transription fators, inluding HNF-4a,HNF-1b, insulin promoter fator (IPF)-1, and NeuroD1. Diagnosis Readily available ommerial geneti testing now enables a true geneti diagnosis. It is important to orretly diagnose one of the monogeni forms of diabetes beause these hildren may be inorretly diagnosed with type 1 or type 2 diabetes, leading to suboptimal treatment regimens and delays in diagnosing other family members (49). The diagnosis of monogeni diabetes should be onsidered in hildren with the following findings: Diabetes diagnosed within the first 6 months of life Strong family history of diabetes but without typial features of type 2 diabetes (nonobese, low-risk ethni group)

8 are.diabetesjournals.org Position Statement S15 Mild fasting hyperglyemia ( mg/dl [ mmol/l]), espeially if young and nonobese Diabetes with negative autoantibodies and without signs of obesity or insulin resistane CYSTIC FIBROSIS RELATED DIABETES Reommendations Annual sreening for ysti fibrosis related diabetes (CFRD) with OGTT should begin by age 10 years in all patients with ysti fibrosis who do not have CFRD. B A1C as a sreening test for CFRD is not reommended. B Patients with CFRD should be treated with insulin to attain individualized glyemi goals. A In patients with ysti fibrosis and IGT without onfirmed diabetes, prandial insulin therapy should be onsidered to maintain weight. B Annual monitoring for ompliations of diabetes is reommended, beginning 5 years after the diagnosis of CFRD. E CFRD is the most ommon omorbidity in people with ysti fibrosis, ourring in about 20% of adolesents and 40 50% of adults. Diabetes in this population is assoiated with worse nutritional status, more severe inflammatory lung disease, and greater mortality from respiratory failure. Insulin insuffiieny related to partial fibroti destrution of the islet mass is the primary defet in CFRD. Genetially determined funtion of the remaining b-ells and insulin resistane assoiated with infetion and inflammation may also play a role. While sreening for diabetes before the age of 10 years an identify risk for progression to CFRD in those with abnormal gluose tolerane, there appears to be no benefit withrespet to weight, height, BMI, or lung funtion ompared with those with normal gluose tolerane,10 years of age. The use of ontinuous gluose monitoring may be more sensitive than OGTT to detet risk for progression to CFRD, but this likely needs more evidene. Enouraging data suggest that improved sreening (50,51) and aggressive insulin therapy have narrowed the gap in mortality between ysti fibrosis patients with and without diabetes and have eliminatedthesexdiffereneinmortality(52). Reent trials omparing insulin with oral repaglinide showed no signifiant differene between the groups. However, another study ompared three different groups: premeal insulin aspart, repaglinide, or oral plaebo in ysti fibrosis patients with abnormal gluose tolerane. Patients all had weight loss; however, in the insulin-treated group, this pattern was reversed, and they gained 0.39 (6 0.21) BMI units (P ). Patients in the repaglinide-treated group had initial weight gain, but this was not sustained by 6 months. The plaebo group ontinued to lose weight (53). Insulin remains the most widely used therapy for CFRD (54). Reommendations for the linial management of CFRD an be found in the ADA position statement Clinial Care Guidelines for Cysti Fibrosis Related Diabetes: A Position Statement of the Amerian Diabetes Assoiation and a Clinial Pratie Guideline of the Cysti Fibrosis Foundation, Endorsed by the Pediatri Endorine Soiety (55). Referenes 1. Amerian Diabetes Assoiation. Diagnosis and lassifiation of diabetes mellitus. Diabetes Care 2014;37(Suppl. 1):S81 S90 2. The International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32: Nowika P, Santoro N, Liu H, et al. Utility of hemoglobin A 1 for diagnosing prediabetes and diabetes in obese hildren and adolesents. Diabetes Care 2011;34: Garía de Guadiana Romualdo L, González Morales M, Albaladejo Otón MD, et al. 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Preservation of panreati b-ell funtion and prevention of type 2 diabetes by pharmaologial treatment of insulin resistane in high-risk Hispani women. Diabetes 2002;51: Chiasson J-L, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Researh Group. Aarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lanet 2002;359: Gerstein HC, Yusuf S, Bosh J, et al.; DREAM (Diabetes REdution Assessment with ramipril and rosiglitazone Mediation) Trial Investigators. Effet of rosiglitazone on the frequeny of diabetes in patients with impaired gluose tolerane or impaired fasting gluose: a randomised ontrolled trial. Lanet 2006;368: Ramahandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modifiation and metformin prevent type 2 diabetes in Asian Indian subjets with impaired gluose tolerane (IDPP-1). 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