2648 Care Volume 41, December 2018

Silva Arslanian,1,2 Fida Bacha,3 Evaluation and Management of Margaret Grey,4,5 Marsha D. Marcus,6 Youth-Onset : Neil H. White,7 and Philip Zeitler8 A Position Statement by the American Diabetes Association Diabetes Care 2018;41:2648–2668 | https://doi.org/10.2337/dci18-0052

Although all types of diabetes result in , the pathophysiology of each type of diabetes is different. These guidelines summarize available data specificto the comprehensive care of youth with type 2 diabetes. The objective is to enrich the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology, its management, and the prevention of associated complications.

PATHOPHYSIOLOGY Glucose homeostasis is maintained by a balance between secretion from the pancreatic b-cells and sensitivity to insulin in skeletal muscle, adipose tissue, and liver (1). When insulin sensitivity declines, insulin secretion must increase to maintain glucose tolerance, and, in most youth, decreased insulin sensitivity due to puberty POSITION STATEMENT 1Division of Pediatric Endocrinology, Metabo- and/or obesity is compensated by increased insulin secretion. However, when b-cells lism, and Diabetes Mellitus, University of Pitts- cannot secrete sufficient insulin to compensate for , abnormalities burgh, Pittsburgh, PA in glucose homeostasis ensue, potentially progressing to and type 2 2Center for Pediatric Research in Obesity and diabetes as b-cell function deteriorates further (2–9). The relationship between Metabolism, UPMC Children’s Hospital of Pitts- b-cell function and insulin sensitivity in adults and youth has been demonstrated burgh, Pittsburgh, PA 3Children’s Nutrition Research Center, Texas to be a hyperbolic function and can be described mathematically as the product of Children’s Hospital and Baylor College of Med- insulin sensitivity and b-cell function, called the disposition index (DI) (1). The DI icine, Houston, TX essentially expresses the amount of insulin being secreted relative to the degree 4Yale School of Nursing, New Haven, CT 5Yale School of Medicine, New Haven, CT of insulin resistance and is a constant for a given degree of glucose tolerance in any 6 one individual. University of Pittsburgh School of Medicine, Pittsburgh, PA Overweight and obesity are major acquired contributors to the development of 7Washington University School of Medicine in insulin resistance, particularly in the face of the physiologic insulin resistance St. Louis, St. Louis, MO characteristic of puberty. Robust pancreatic b-cell compensatory insulin secretion 8Children’s Hospital Colorado and University of maintains normal glucose homeostasis. However, in adolescents with obesity who Colorado School of Medicine, Aurora, CO develop type 2 diabetes, there is severe peripheral and hepatic insulin resistance, with Corresponding author: Silva Arslanian, silva. ;50% lower peripheral insulin sensitivity than peers with obesity without diabetes, [email protected]. along with increased fasting hepatic glucose production and inadequate first- and This position statement was reviewed and ap- proved by the American Diabetes Assoication second-phase insulin secretion, resulting in ;85% lower DI (2). Additional abnor- Professional Practice Committee and ratified malities in youth with type 2 diabetes include impaired glucose sensitivity of insulin by the American Diabetes Association Board of secretion, lower serum adiponectin concentrations, and reduced incretin effect Directors in September 2018. (3,9–13). While upregulation of a-cell function with hyperglucagonemia has been For further information on the ADA evidence- implicated in the pathophysiology of type 2 diabetes in adults (14,15), there are grading system and the levels of evidence, please limited data in youth with type 2 diabetes, with studies showing either hyper- see Table 1 in the American Diabetes Associa- ’ glucagonemia or no difference from control subjects without diabetes (3,11,16,17). tion s Introduction section of the Standards of Medical Care in Diabetesd2018. Diabetes Care Cross-sectional and longitudinal studies in youth with obesity along the spectrum of 2018;41(Suppl. 1):S2, https://doi.org/10.2337/ glycemia from normoglycemia to prediabetes to type 2 diabetes show, as in adults, dc18-SINT01. that b-cell failure with declining insulin secretion relative to insulin sensitivity results The authors are solely responsible for the con- in prediabetes and type 2 diabetes in high-risk youth (5–9,18–21). Importantly, tents of this article, which do not necessarily however, prior to reaching the American Diabetes Association (ADA)-defined fast- represent the official views of the NIDDK. ing and oral (OGTT)-stimulated glycemic cut points for the © 2018 by the American Diabetes Association. diagnosis of prediabetes, youth, like adults, already demonstrate declining b-cell Readers may use this article as long as the work – is properly cited, the use is educational and not function relative to insulin sensitivity (6 8). Also, youth with A1C in the at-risk/ for profit, and the work is not altered. More infor- prediabetes category ($5.7 to ,6.5%) demonstrate impaired b-cell function mation is available at http://www.diabetesjournals compared with those with A1C ,5.7% (22). A combination of obesity, genetics, .org/content/license. care.diabetesjournals.org Arslanian and Associates 2649

the hormonal milieu, incretins and/or in Adolescents and Youth (TODAY) stress and/or depressed mood (48,49) their effect, and metabolic alterations, cohort, one-third were born after a preg- and sleep-related disorders (50–52). such as glucotoxicity and/or lipotoxicity, nancy complicated by preexisting diabe- are likely to contribute to deteriorating tes or GDM (35). In the SEARCH for Risk Assessment and Diagnostic b-cell function against the backdrop of Diabetes in Youth (SEARCH) study, a Criteria insulin resistance, eventually culminating population-based study of the epide- Recommendations in prediabetes and type 2 diabetes in at- miology of type 1 and type 2 diabetes c Risk-based screening for prediabe- risk youth. Based on the baseline data in youth in the U.S., exposure to mater- tes and/or type 2 diabetes should from the Restoring Insulin Secretion nal GDM or pregestational diabetes and be considered after the onset of (RISE) study (23,24), there appear to maternal obesity were independently puberty or after 10 years of age, be important differences in insulin sensi- associated with type 2 diabetes in ado- whichever occurs earlier, in chil- tivity and b-cell function between youth lescents, with intrauterine exposure to dren and adolescents who are over- and adults with similar degrees of dys- these two risk factors present in 47.2% weight (BMI $85th percentile) or glycemia, including greater insulin resis- of type 2 diabetes in the cohort (36). obese (BMI $95th percentile) and tance for any degree of adiposity and Age of onset of type 2 diabetes was also who have one or more additional greater insulin secretion for any degree younger in those exposed to diabetes risk factors for diabetes (see Table 1 of insulin resistance in youth compared during gestation. for evidence grading). with adults. Incidence and prevalence of type 2 c If tests are normal, repeat testing diabetes are highest among youth from at a minimum of 3-year intervals E, RISK, SCREENING, AND DIAGNOSIS a minority race/ethnicity (37), likely as or more frequently if BMI is in- Risk Factors a consequence of many factors, includ- creasing. C Nonmodifiable risk factors for youth- ing genetics, metabolic characteristics, c Fasting plasma glucose, 2-h plasma onset type 2 diabetes include genetics/ cultural/environmental influences, and glucose after 75-g OGTT, or A1C can epigenetics, manifested as a strong fam- quality of and access to health care. be used to test for prediabetes or ily history of type 2 diabetes in first- or Several studies have demonstrated sig- diabetes. B second-degree relatives; being the off- nificant differences by race/ethnicity in spring of a pregnancy complicated by insulin sensitivity and secretion that Risk-based screening for prediabetes mellitus (GDM); mi- might heighten the risk of type 2 diabetes and/or type 2 diabetes is timed after nority race/ethnicity; and physiologic (38–42). the onset of puberty or after 10 years of insulin resistance of puberty. Metabolic Type 2 diabetes typically occurs in age, whichever occurs earlier, because evidence of genetic susceptibility can adolescents at midpuberty (for example, the majority of youth-onset type 2 di- be detected in the first decade of life, the mean age of diagnosis was 14 years abetes occurs during puberty, as stated manifested as impaired insulin sensitivity in the TODAY study) (43), most likely above, andrarely in prepubertal children. and reduced insulin secretion in other- precipitated by the physiologic, but However, some youth with obesity may wise healthy youth with a family history transient, pubertal insulin resistance have earlier onset of puberty than usual, of type 2 diabetes (25). This genetic sus- aggravating the preexisting metabolic necessitating screening before 10 years ceptibility, when combined with environ- challenges of obesity. Cross-sectional and of age. In addition, in North America mental factors conducive to obesity and longitudinal studies show that insulin almost all youth with type 2 diabetes a sedentary lifestyle, may ultimately sensitivity declines by 25–30% as youth are overweight/obese, hence the re- translate to type 2 diabetes. Indeed, in transition from prepuberty to puberty commendation to screen youth with a study of youth with obesity, a genetic (44–46). In the presence of normally func- overweight/obesity. In other parts of the risk score for b-cell dysfunction from tioning b-cells, puberty-related insulin world where youth with type 2 diabetes five single nucleotide polymorphisms resistance is compensated by increased are not necessarily overweight and/or was associated with a higher chance of insulin secretion/hyperinsulinemia, such obese, clinical judgment should guide prediabetes and type 2 diabetes (26). that DI remains normal. In youth who are whom to screen. Although there is no Dozens of specific genetic variants linked predisposed to develop prediabetes robust evidence-based rationale for the to type 2 diabetes have been identified and/or type 2 diabetes, b-cell compensa- proposed frequency of testing, increas- in adults (27,28), but these only account tion is inadequate with progressive de- ing BMI has been shown to be a predic- for about 10% of its heritability (29,30). cline in the DI, ultimately resulting in tor of deteriorating glycemia and Particular genetic variants that predis- dysglycemia (46,47). progression to type 2 diabetes (21). pose to diabetes in youth have been In youth-onset type 2 diabetes, the Therefore, clinicians caring for youth identified in Oji-Cree Native Canadians major modifiable risk factors are obesity with overweight/obesity with continued (31) and African American youth (32), and lifestyle habits of excess nutritional increase in their BMI should be aware of but information in other populations is intake, low physical activity, and in- the need for more frequent screening. only now emerging. creased sedentary behaviors with de- The laboratory glycemia-based diag- Evidence from both animal and hu- creased energy expenditure, resulting nostic criteria for diabetes and predia- man studies suggests that maternal obe- in the surplus of energy being stored betes are the same for youth and adults, sity and GDM contribute to obesity and as body fat. Other potentially modifiable regardless of type of diabetes (Table type 2 diabetes in youth (33,34). In the risk factors for type 2 diabetes in ado- 2) (53). However, these criteria are Treatment Options for Type 2 Diabetes lescents and young adults include chronic extrapolated from adults, and the 2650 Position Statement Diabetes Care Volume 41, December 2018

Table 1—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic acceptable approach but should be children and adolescents* in a clinical setting based on sound clinical judgment, rec- Criteria ognition of the strengths and weak- nesses of each test, and the facilities and Testing should be considered in youth* who are overweight ($85%) or obese ($95%) A and who have one or more additional risk factors based on the strength of their association with resources available. diabetes: c Maternal or GDM during the child’s gestation A Confirming Diabetes Type c Family history of type 2 diabetes in first- or second-degree relative A c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Recommendations Islander) A c Children and adolescents with c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis overweight/obesity in whom the nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational- age birth weight) B diagnosis of type 2 diabetes is being considered should have a panel of *After the onset of puberty or after 10 years of age, whichever occurs earlier. pancreatic autoantibodies tested to exclude the possibility of auto- immune . B epidemiological studies that formed the effective at identifying glycemic abnor- c Genetic evaluation to exclude fi basis for both glucose and A1C de nitions malities on CGM, but the glycemic pat- monogenic diabetes should also of diabetes did not include pediatric terns differ (57); abnormal A1C was be based on clinical characteristics populations. Therefore, the exact rele- associated with higher overall and night- and presentation. B vance of these definitions for pediatric time average glucose on CGM, while populations remains unclear until more abnormal OGTT was associated with As stated above, youth with type 2 di- data become available. more time spent above the normal glu- abetes in the U.S. are characteristically The A1C test is universally available cose range during the day. Institution of overweight and/or obese, in mid- to late and can be performed any time of the day A1C screening in a large primary care puberty, with overrepresentation of mi- without need for fasting. However, sev- network increased provider adherence nority ethnic/racial groups and females eral studies have questioned its validity in to screening recommendations com- (4,43,59). The clinical presentation varies the pediatric population because of poor pared with OGTT screening while iden- widely from asymptomatic or minimally sensitivity for identifying children with tifying the same prevalence of type 2 symptomatic, diagnosed incidentally dysglycemia and underestimation of the diabetes (58). Furthermore, in this during routine laboratory testing, to a prevalence of prediabetes and diabetes cohort, the progression to clinically severe presentation with symptomatic – fi (54 56). Fasting and OGTT criteria have con rmed diabetes was substantially hyperglycemia, weight loss, metabolic . not been validated in youth, either. more likely for those with A1C 6% decompensation, – Studies using continuous glucose mon- (18.4%) than for those with levels 5.7 (DKA), or hyperglycemic hyperosmolar itoring (CGM) in youth with obesity dem- 6.0% (1.3%). Therefore, screening with nonketotic (HHNK) syndrome (4). onstrated that A1C and OGTT are equally fasting glucose, OGTT, or A1C is an Obesity is a consistent feature of youth-onset type 2 diabetes in the Table 2—Criteria for the diagnosis of prediabetes and diabetes U.S. However, because of the escalating Prediabetes rates of obesity in the general popula- tion, children with both type 1 diabetes A1C 5.7% to ,6.5% (39 to ,48 mmol/mol). The test should be performed in a laboratory using and monogenic diabetes are also more fi a method that is NGSP certi ed and standardized to the DCCT assay. likely to be overweight/obese than in the IFG: fasting glucose $100 but ,126 mg/dL ($5.6 but ,7.0 mmol/L). past (60), making the clinical distinction IGT: 2-h plasma glucose $140 but ,200 mg/dL ($7.8 but ,11.1 mmol/L) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load between type 2 diabetes and obese containing the equivalent of 1.75 mg/kg (max 75 g) anhydrous glucose dissolved in water.* type 1 or monogenic diabetes difficult. This was illustrated in the TODAY study Diabetes in which, of the 1,206 youth clinically A1C $6.5% ($48 mmol/mol). The test should be performed in a laboratory using a method diagnosed with type 2 diabetes and fi that is NGSP certi ed and standardized to the DCCT assay.* screened for circulating GAD65 and OR IA2 antibodies, 118 (9.8%) were antibody FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* positive (Ab1) (61). Even though these OR 1 2-h plasma glucose $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed Ab individuals had clinical character- as described by the World Health Organization, using a glucose load containing the istics that overlapped with the antibody- 2 equivalent of 1.75 mg/kg (max 75 g) anhydrous glucose dissolved in water* negative (Ab ) youth, they were less OR likely to be obese, have features of In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma metabolic syndrome, have a family his- . glucose 200 mg/dL (11.1 mmol/L). tory of diabetes, be female, or be from a FPG, fasting plasma glucose; IFG, ; IGT, impaired glucose tolerance; max, minority race/ethnicity, indicating a phe- maximum. *In the absence of unequivocal hyperglycemia, result should be confirmed by notype more similar to their peers with repeat testing. type 1 diabetes. Pathophysiologically, care.diabetesjournals.org Arslanian and Associates 2651

Ab2 youth with obesity are more insulin diabetes, genetic testing for monogenic complications (77–79), many of which resistant than Ab1 youth with obesity, forms of diabetes should be considered are associated with poor glycemic con- while Ab1 youth have more severe in- as well (67–69). trol, and rapid deterioration with in- sulin deficiency (61–64). Fasting and creasing A1C. Finally, youth with type 2 stimulated C-peptide are significantly diabetes can be expected to have lower in Ab1 youth with obesity and GLYCEMIC TARGETS long disease duration and, therefore, diabetes, though with appreciable over- Recommendations continued risk for accumulation of 2 lap (63). Moreover, Ab youth are more c A1C should be measured every glycemia-related complications. Taken likely to exhibit features of the metabolic 3 months. E together, this evidence suggests that syndrome (elevated systolic blood pres- c A reasonable A1C goal for most a more stringent A1C target can and 1 sure and ALT), while Ab youth have children and adolescents with should be attained in youth with type 2 significantly more frequent ketonuria at type 2 diabetes treated with oral diabetes. initial presentation (61,64). The reported agents alone is ,7%. More strin- The evidence is insufficient regarding rates of positive pancreatic autoanti- gent A1C goals (such as ,6.5%) the value of SMBG and how often test- bodies in youth clinically diagnosed with may be appropriate for selected ing should be performed by youth with type 2 diabetes vary from 10% to 75% individual patients if they can be type 2 diabetes not on insulin therapy. (4,62), likely depending on the ratio of achieved without significant hypo- Until such data become available, the type 1 and type 2 diabetes in the pop- glycemia or other adverse effects frequency of SMBG should be individu- ulation. The clinical distinction between of treatment. Appropriate patients alized, taking into account patient and youth with type 2 diabetes and youth might include those with short family burden, the value of the informa- with obesity and type 1 or monogenic duration of diabetes and lesser tion obtained and how it will be used to diabetes is further blurred because youth degrees of b-cell dysfunction and adjust therapy, and the associated hy- with type 2 diabetes often present with patients treated with lifestyle or poglycemia risk. some degree of ketosis, including DKA metformin only who achieve sig- fi (65). ni cant weight improvement. E LIFESTYLE MANAGEMENT The distinction between these forms c A1C targets for youth on insulin Diabetes Education and of diabetes in youth with obesity has should be individualized, taking Self-Management Skills important implications for treatment into account the relatively low 1 (66), since Ab youth present more rate of in youth- Recommendation like individuals with type 1 diabetes, onset type 2 diabetes. E c All youth with type 2 diabetes and progressing to insulin requirement c Home self-monitoring of blood glu- their families should receive compre- more rapidly (61), and are at risk for cose (SMBG) regimens should be hensive diabetes self-management other autoimmune disorders. Therefore, individualized, taking into consid- education/support that is specific measurement of pancreatic autoanti- eration the pharmacologic treat- to youth with type 2 diabetes and is bodies is recommended in all youth ment of the patient. E culturally competent. B with clinical characteristics of type 2 di- abetes. This testing should include Previous target A1C guidelines by the It has been well established that di- GAD65 and IA2 antibodies, along with ADA and the International Society for abetes education is necessary, but not insulin autoantibody in individuals who Pediatric and Adolescent Diabetes for sufficient, to enhance self-management have not yet been exposed to exogenous youth with type 2 diabetes ranged in people with diabetes (80,81). The insulin. The benefit of measurement of from ,6.5% to ,7.0% (70,71) and majority of these studies, however, fo- ZnT8 antibody in individuals with phe- ,7.5% (72), mostly based on expert cused on adults with type 2 diabetes notypic type 2 diabetes is not yet clear. opinion and extrapolated from youth and/or youth with type 1 diabetes. Since We further recommend that antibod- with type 1 diabetes and adults with the population of youth with type 2 ies be measured in a laboratory aligned type 2 diabetes. However, accumulating diabetes is more likely to be of minority with the National Institute of Diabetes evidence provides support for more ethnic/racial background thanthose with and Digestive and Kidney Diseases appropriate goals. The TODAY study type 1 diabetes, and materials devel- (NIDDK) Pancreatic Autoantibody Stan- showed that hypoglycemia is rare in oped for adults may not address issues dardization Program because currently adolescents with type 2 diabetes, even of development in youth, culturally available commercial assays may not be with insulin therapy (73), suggesting that appropriate programs specific to youth sufficiently sensitive or specific. How- more stringent A1C targets are accept- with type 2 diabetes and their families ever, in all cases, clinical judgment and able. Also in TODAY, individuals with an are necessary. Unfortunately, there are the presence of other risk factors for A1C of .6.3% after 3 months of met- no randomized clinical trials of educa- type 1 diabetes or type 2 diabetes should formin or an increasing A1C, even in the tion and support programs for youth be considered in making the diagnosis, nondiabetes range (74), had a substan- with type 2 diabetes. Nonetheless, de- and the health care team should remain tially increased risk for loss of glycemic scriptive reports suggest that programs open to reconsidering the initial diagno- control, likely reflecting a greater de- that focus on building knowledge and sis. Since 4.5–8.0% of youth with clinical gree of b-cell dysfunction (75,76). Fur- skills appropriate to this population are features suggestive of type 2 diabetes thermore, individuals with youth-onset important in ensuring adequate self- have been found to have monogenic type 2 diabetes have high rates of management. 2652 Position Statement Diabetes Care Volume 41, December 2018

In the TODAY trial (81), the diabetes cohort of youth with type 2 diabetes c Patients should be screened for education program included content reported symptoms of disordered eating smoking and alcohol use at diag- about type 2 diabetes physiology and behaviors, such as skipping insulin, vom- nosis and regularly thereafter. C treatment, building skills of healthy eat- iting, and using diet pills or laxatives, ing habits, carbohydrate counting, por- and these behaviors were associated The ADA position statement on the pro- tion sizes, reading food labels, glucose with poorer glycemic control in females vision of psychosocial care for people monitoring, and ketone testing, as well as (89). Binge eating rates in the TODAY living with diabetes recognizes the pro- problem solving, risk reduction, and liv- cohort were high (26%) and were asso- found influence of psychosocial factors ing with diabetes. Full mastery of the ciated with more severe obesity, psycho- on health outcomes and well-being (84). program was achieved in an average of logical symptoms of disordered eating, The recommendations herein are con- 5.5 90-min sessions. Factors associated and symptoms of depression (94). sistent with those outlined in that posi- with shorter time to mastery included More research is needed to evaluate tion statement, an important resource more recent diagnosis and not having to rates of diagnosable psychiatric disor- for more detailed information about life- use a translator, while sex, primary lan- ders, trauma, victimization, and psycho- course issues and assessment of psycho- guage of the youth and family, individual tropic drug use in youth with type 2 social comorbidities. versus group sessions, or site of delivery diabetes. It also is important to elucidate Most youth with type 2 diabetes come were not. These program materials are the relationships among obesity, psychi- from racial and ethnic minority groups, available from the ADA as “Be Healthy atric disorders, and medication regimens have low socioeconomic status, and Today” (82). Given the lack of clinical because many of the drugs prescribed have a family history of diabetes trials of various educational approaches, for diabetes and psychiatric disorders (37,85,86). Families often experience it is unclear that this program is superior are associated with weight gain and in- to other approaches. Nonetheless, the multiple stressors including food insecu- creased concerns about eating, shape, program provides effective, engaging rity, employment and housing instability, and weight (95,96). fi materials for youth with type 2 diabetes and dif culties with access to treatment; Finally, in accord with the ADA’s Stan- that were designed specifically for this youth also may have been exposed to dards of Medical Care in Diabetesd2018 population. Until comparative trials of early adversity, which has been shown to (97), preconception counseling should various approaches are completed, di- affect health over time (87). Providers be provided starting at puberty for all abetes education using these materials should personalize approaches to diabe- girls of childbearing potential in order to is appropriate (83). tes management to minimize barriers to increase understanding of risk related care, enhance adherence, and maximize to diabetes and improve health prior to response to treatment by taking into conception. In the TODAY study (98), Psychosocial Factors consideration the sociocultural context despite counseling on pregnancy reduc- of the patient and their family. tion designed specifically for youth with Recommendations Youth with type 1 diabetes have high type 2 diabetes, 10.2% of the females in c Providers should assess social con- rates of diabetes distress and psychiatric the cohort became pregnant over an text, including potential food in- symptoms and diagnoses (in particular, average of 3.8 years of study participa- security, housing stability, and depression and disordered eating behav- tion. Of note, 26.4% of pregnancies financial barriers, and apply that iors) necessitating ongoing surveillance ended in a miscarriage, stillbirth, or in- information to treatment deci- of mental and behavioral health. Evi- trauterine death, and 20.5% of the live- sions. E dence about psychiatric disorders and born infants had a major congenital c Use patient-appropriate standard- symptoms in youth with type 2 diabetes anomaly. These data confirm the impor- ized and validated tools to assess is limited (88–92), but given the socio- tance of educating young women with diabetes distress and mental/ cultural context and the medical burden, type 2 diabetes to time their pregnancies behavioral health in youth with as well as preexisting obesity-associated to reduce risks to themselves and their type 2 diabetes, with attention comorbidities together with type 2 di- offspring. More research regarding preg- to symptoms of depression and abetes, ongoing surveillance of mental nancy outcomes in youth with type 2 disordered eating behaviors, and health/behavioral health isalso indicated diabetes is needed. refer to specialty care when indi- in youth with type 2 diabetes. cated. B Symptoms of depression and disor- Lifestyle Modification, Weight c When choosing glucose-lowering dered eating are common in youth with Management, Exercise, and Nutrition or other medications for youth type 2 diabetes and associated with with overweight/obesity and type Recommendations poorer glycemic control (89). The prev- 2 diabetes, consider medication c alence of clinically significant symptoms Youth with overweight/obesity and adherence and treatment effects type 2 diabetes and their families of depression among youth with type 2 on weight. E should be provided with develop- diabetes was reported to be 8.6% in the c Starting at puberty, preconception mentally and culturally appropriate SEARCH cohort of youth with type 1 and counseling should be incorporated comprehensive lifestyle programs type 2 diabetes (89) and 14.8% in the into routine diabetes clinic visits that are integrated with diabetes TODAY cohort of youth with type 2 di- for all females of childbearing po- management aiming to achieve 7– abetes (93). In addition, more than 25% tential. A 10% decrease in excess weight. C of females and males in the SEARCH care.diabetesjournals.org Arslanian and Associates 2653

were modest (103), those who re- An important first step is to integrate c Given the necessity of long-term ceived usual care showed increases in diabetes care and education, such as the weight control and lifestyle man- BMI over the period of observation, approach used in the TODAY trial, with agement for children and adoles- while the intervention group had con- ongoing lifestyle intervention for obesity cents with type 2 diabetes, lifestyle tinued improvements in body com- management (106) to maximize the im- intervention should be based on a position and insulin resistance relative pact of medical and lifestyle interven- chronic care model and offered in to those who did not receive weight tions over time. Comprehensive chronic the context of diabetes care. E management. care models have been recommended c Youth with diabetes, like all chil- The most pertinent evidence regard- for youth with obesity and chronic illness dren, should be encouraged to ing the impact of lifestyle interventions (112,113). participate in at least 30–60 min for youth with type 2 diabetes comes With the exception of orlistat, weight of moderate to vigorous physical from the TODAY study (104), where the loss medications are not approved for activity at least 5 days per week goal was to achieve 7–10% decrease in use in youth. The Endocrine Society (and strength training on at least percent overweight. The addition of life- guidelines for pediatric obesity (106) 3 days per week) B and should be style intervention to metformin mono- review the limited evidence for effec- encouraged to decrease sedentary therapy was not associated with durable tiveness of current weight-loss medica- behavior. C metabolic control beyond that of met- tions and recommends that their use be c Nutrition for youth with type 2 formin alone. Youth receiving metformin restricted to the research setting. More diabetes, like all children, should plus lifestyle intervention showed short- research into possible pharmacologic ap- focus on healthy eating patterns term, but not sustained, weight loss and proaches to augment lifestyle interven- that emphasize consumption of improvements in body composition rel- tions and their role in type 2 diabetes in nutrient-dense, high-quality foods ative to those in the two other interven- youth is urgently needed. and decrease consumption of tion groups (105). While 31% of youth calorie-dense, nutrient-poor foods, who received lifestyle intervention particularly sugar-added bever- achieved the preplanned goal of a de- ages. B PHARMACOLOGIC APPROACHES crease of $7% in percent overweight TO GLYCEMIC MANAGEMENT c The utility of pharmacotherapy for through 24 months of intervention, this weight reduction in youth with Recommendations result did not differ significantly from type 2 diabetes remains limited c Initiate pharmacologic therapy, in that obtained with metformin mono- in the absence of approved, effec- addition to lifestyle therapy, at di- therapy and no predictors of successful tive, and safe medications and the agnosis of type 2 diabetes. A weight loss were identified. However, lack of clinical trials in youth with c In incidentally diagnosed or meta- irrespective of treatment assignment, type 2 diabetes. B bolically stable patients (A1C sustained weight losses $7% of excess ,8.5% and asymptomatic), met- body weight were associated with im- Lifestyle modification programs that formin is the initial pharmacologic provements in A1C, HDL, and C-peptide incorporate evidence-informed behav- treatment of choice if renal func- (105), indicating that obesity manage- ioral strategies to promote changes in tion is normal. A ment remains a crucial goal. diet and physical activity (99) are a cor- c Youth with marked hyperglycemia Components of a comprehensive pe- nerstone of treatment for adults with (blood glucose $250 mg/dL, A1C diatric lifestyle intervention are well es- type 2 diabetes because the resulting $8.5%) without acidosis at diag- tablished (106,107), including those for reductions of 5–7% of initial body weight nosis who are symptomatic with youth with severe obesity (108). These are associated with improvements in polyuria, polydipsia, nocturia, and/ include the involvement of family at a or weight loss should be treated blood glucose levels and other risk pa- developmentally appropriate level and initially with basal insulin while rameters. Much less is known about the evidence-based behavioral strategies to metformin is initiated and titrated. impact of lifestyle interventions in youth facilitate enduring changes in nutrition B with type 2 diabetes, although 90% are and physical activity. Guidelines for phys- c In patients with ketosis/ overweight or obese. Family-based be- ical activity and nutrition are based on ketoacidosis, treatment with sub- havioral weight management programs those recommended by the American cutaneous or intravenous insulin in school-aged children without diabetes Academy of Pediatrics (2007) (107) and should be initiated to rapidly cor- have a modest, but positive, impact on the Endocrine Society (2017) (106). rect the hyperglycemia and the weight and cardiometabolic risk factors Youth with type 2 diabetes frequently metabolic derangement. Once but are less effective in adolescents and have severe obesity, and it is particularly acidosis is resolved, metformin children with more severe obesity (100– important that behavior change goals should be initiated while subcuta- 102). Intensive weight management, for diet and activity incorporate step- neous insulin therapy is continued. when compared with usual treatment, wise, achievable targets developed in A can have sustained benefits over a 2- conjunction with the youth and family c In individuals presenting with se- year period for ethnically and racially di- members, as appropriate. vere hyperglycemia (blood glucose verse inner-city children and adolescents Youth with type 2 diabetes will face $600 mg/dL), assess for HHNK with an average BMI .35 (102,103). increasing severity of obesity and diabe- syndrome. A Although BMI changes in treated youth tes complications as they age (109–111). 2654 Position Statement Diabetes Care Volume 41, December 2018

In the clinical setting, only a minority of Initial treatment of the youth with obe- c In patients initially treated with youth with type 2 diabetes are on lifestyle sity and diabetes must take into account insulin and metformin who are management alone (114,115) because it that diabetes type is often uncertain in meeting glucose targets based is often inadequate for achieving and fi onhomebloodglucosemonitoring, the rst few weeks of treatment owing to maintaining the desired level of glycemic insulin can be tapered over 2– overlap in presentation and that a sub- control and BMI improvement, with the 6 weeks by decreasing the insulin stantial percentage of youth with type 2 percentage of patients remaining on dose 10–30% every few days. B diabetes will present with clinically sig- lifestyle intervention alone declining fur- c If the glycemic target is no longer nificant ketoacidosis (65). Therefore, im- ther by 1 year (115). Therefore, in most met using metformin alone, or if mediate therapy should address the cases, the addition of pharmacologic in- contraindications or intolerable hyperglycemia and associated metabolic tervention early in the disease is war- side effects of metformin develop, derangements irrespective of ultimate ranted. As in adults, the pharmacologic basal insulin therapy should be diabetes type, with adjustment of ther- intervention should be a stepped pro- initiated. B apy once metabolic compensation has cess. However, since only metformin and c If the combination of metformin been established and subsequent infor- insulin are currently approved for the plus basal insulin is ineffective at treatment of diabetes in patients under mation, such as antibody results, be- achieving or maintaining glycemic 18 years old, the approach in youth is comes available. targets, more intensive approaches more limited. Figure 1 provides an approach to initial to insulin therapy may be initiated. treatment. E Initial Treatment Metformin c The use of nonapproved medica- Initial treatment of youth-onset type 2 Metforministhe preferreddrug forinitial tions in youth with type 2 diabetes diabetes should include metformin and/ treatment of type 2 diabetes in adults is not recommended outside of or insulin alone or in combination, based and youth. In the TODAY study, 48.3% of research trials. B on the metabolic status of the patient. youth with type 2 diabetes who were

Figure 1—Management of new-onset diabetes in overweight youth suspected to have type 2 diabetes based on risk factors listed in Table 1. MDI, multiple daily injections. care.diabetesjournals.org Arslanian and Associates 2655

enrolled, with less than 2 years (median data suggest that adolescents with long-acting insulin or initiation of multi- 8 months) of diabetes duration, main- type 2 diabetes who present initially ple daily injections of basal and premeal tained adequate glycemic control (A1C with DKA, ketosis, or symptomatic hy- rapid-acting insulin should be consid- ,8.0%) on metformin alone for up to perglycemia can be managed success- ered, though adherence to the latter 6 years (104). However, youth were more fully with metformin alone, at least may be a barrier. likely than adults to require additional initially after a short course of insulin Because severe insulin resistance is pharmacologic treatment to meet glyce- therapy to establish glycemic stability characteristic of youth with type 2 di- mic targets, with the other 51.7% of (117). For example, in the TODAY study, abetes, basal insulin doses above 1.5 youth on metformin requiring insulin more than 90% of the subjects screened units/kg/day may be required to achieve by 4 years, with a median time to treat- for study participation were initially con- adequate glycemic control, particularly ment failure of 11.8 months. trolled adequately on metformin alone for those youth with elevated A1C and Asymptomatic youth with presumptive regardless of prior insulin therapy (117). glucotoxicity and youth who are in mid- type 2 diabetes who present in a stable However, these TODAY participants were to late puberty. In these circumstances, metabolic state and have A1C ,8.5% frequently contacted and closely moni- it may be appropriate to use more con- should be started on metformin as initial tored by the research staff, a situation centrated insulin preparations (U-300 therapyifrenalfunctionisnormal.Asymp- that may not be feasible in a clinical glargine [Toujeo], U-200 Tresiba, U-200 tomatic patients with A1C $8.5% may setting. Whether or not early treatment Humalog, U-500 regular) to avoid large- also be given an initial trial of metformin with insulin provides unique benefits in volume injections that may further di- monotherapy at the discretion of the youth with type 2 diabetes remains ques- minish medication adherence. health care provider, especially if the tionable. The recently completed RISE The most significant adverse effect patient and family situation suggest the Pediatric Medication Study in youth of insulin therapy in type 2 diabetes, as promise of excellent adherence to life- with obesity with impaired glucose toler- in type 1 diabetes, is hypoglycemia. Al- style change recommendations. ance or recent-onset type 2 diabetes did though the incidence of hypoglycemia The recommended approach to met- not demonstrate benefits of 3 months of in youth with type 2 diabetes is low, formin initiation is to start with a dose basal insulin glargine followed by 9 even with insulin therapy (73), patients of 500–1,000 mg/day and gradually es- months of metformin compared with treated with insulin should be educated calate it every 1–2 weeks, depending on metformin alone for 12 months in pre- about avoidance, recognition, and treat- patient tolerability, to the recommended serving or restoring b-cell function (118). ment of hypoglycemia and should be therapeutic dose of 1,000 mg b.i.d. It remains to be determined if longer instructed on the use of glucagon for Slower dosage escalation may be needed periods of insulin treatment may prove treatment of severe hypoglycemia. Also, fi if gastrointestinal side effects occur and, bene cial in preserving b-cell function. since insulin may result in weight gain, in some cases, the maximum dose may not involvement of a nutritionist in patient be achievable. Extended-release metfor- Ongoing Therapy care and education is essential when When the individualized glycemic target min may have fewer gastrointestinal side insulin is initiated. can no longer be met with metformin effects and be more convenient for the alone, or if metformin intolerance or patient, but there are no studies in youth Other Therapies renal insufficiency develops, insulin ther- Other than insulin and metformin, there comparing extended-release metformin apy should be initiated. This can be done are currently more than 25 medications in to the standard metformin preparation. alone or in combination with metformin, 10 general classes that are commercially Metformin Plus Insulin unless metformin is contraindicated. Be- availableandFDA-approvedfortreatment Youthwithmarkedhyperglycemia(blood cause studies indicate that adherence of type 2 diabetes in adults in the U.S. glucose $250 mg/dL and/or A1C $8.5%) with insulin therapy is a challenge in (Table3).Itshouldbenoted,however,that without acidosis at diagnosis but who youth with type 2 diabetes (73,119), none of these are currently approved for are symptomatic with polyuria, polydip- starting with a single daily dose of a use in youth (,18 years old), and while sia, nocturia, and/or weight loss should long-acting insulin analog (glargine some of these agents have undergone be treated initially with basal insulin [Lantus, Basalglar, Toujeo], detemir or are currently undergoing pharmaco- while concurrently initiating and titrat- [Levemir], or degludec [Tresiba]) may kinetic, pharmacodynamics, and safety/ ing metformin. In patients with ketosis/ be preferred. Premixed insulins may be tolerability testing in small pediatric ketoacidosis at diagnosis, treatment with appropriate in some circumstances. studies, no efficacy or long-term safety subcutaneous or intravenous insulin should If the combination of metformin at the results have yet been reported in youth. be initiated to rapidly correct the hyper- maximum tolerated dose (up to 1,000 mg Although the TODAY study demon- glycemia and the metabolic derangement. b.i.d.) plus basal insulin at a maximum strated that the addition of rosiglitazone Once acidosis is resolved, metformin dose of 1.5 units/kg/day is ineffective at to metformin improved the durability of should be initiated while subcutane- achieving the glycemic target, medica- glycemic control (treatment failure rate ous insulin therapy is continued (116). tion adherence should be actively ad- 38.6% for metformin plus rosiglitazone In individuals presenting with severe dressed. When combined metformin vs. 51.7% for metformin alone) with no hyperglycemia (blood glucose $600 and basal insulin therapy does not increased rate of adverse events over a mg/dL), assess for HHNK syndrome. achieve targets, and in the absence of 3–6 year period in youth with recent- Once glycemic stability is achieved, other approved drugs to treat diabetes in onset type 2 diabetes, it is premature insulin may not be needed. Limited youth (,18 years old), higher doses of to recommend its widespread use in 2656 Position Statement Diabetes Care Volume 41, December 2018

Table 3—Drugs for treating type 2 diabetes in adults (not including insulin or insulin analogs) but not yet approved in youth except for metformin Available drugs in Approved in Drug class this class Mechanism of action Significant adverse effects patients ,18 years old Biguanides Metformin Decreases insulin resistance; reduces Gastrointestinal Yes hepatic glucose production; increases Lactic acidosis peripheral glucose uptake; decreases gastrointestinal absorption of glucose Sulfonylureas Glipizide Stimulates secretion of insulin from the Hypoglycemia No Glimepiride b-cell Weight gain Glyburide Meglitinides Repaglinide Stimulates glucose-dependent secretion Hypoglycemia No Nateglinide of insulin from the b-cell URI Diarrhea Headache a-Glucosidase Acarbose Delays absorption of glucose by Flatulence No inhibitors Miglitol intestines by inhibiting breakdown of Diarrhea complex sugars Abdominal cramps GLP-1 agonists Exenatide Incretin effect; slows gastric emptying; Acute pancreatitis No Liraglutide enhances postprandial insulin C-cell hyperplasia/ medullary Dulaglutide biosynthesis;improvesb-cellfunction; thyroid carcinoma Lixisenatide decreases appetite Nausea/vomiting Albiglutide Hypoglycemia Semaglutide Diarrhea Headache DPP-4 inhibitors Saxagliptin Inhibits DPP-4 enzyme, reducing Acute pancreatitis No Sitagliptin endogenous GLP-1 breakdown URI Alogliptin UTI Linagliptin Nasopharyngitis Headache Amylin analog Pramlintide Inhibits postprandial glucagon secretion; Hypoglycemia No delays gastric emptying; improves Nausea satiety Anorexia Abdominal pain Thiazolidinediones Rosiglitazone PPAR-g inhibitor; increases insulin Edema No Pioglitazone sensitivity in liver, muscle, and adipose Weight gain tissue; decreases hepatic glucose Anemia output Elevated liver enzymes SGLT-2 inhibitors Canagliflozin Allows more glucose tobe excretedin the Euglycemic ketoacidosis No Dapagliflozin urine and hence lowers blood glucose UTI Empagliflozin Candidal vulvovaginitis Ertugliflozin Bile acid Colesevelam Mechanism for glucose lowering is Gastrointestinal (gas, nausea, No sequestrant unknown diarrhea, abdominal pain) Weakness Muscle pain Dopamine-2 Bromocriptine Modulates hypothalamic regulation of Nausea/vomiting No agonist (quick release) metabolism; increases insulin Fatigue sensitivity Dizziness Headache DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; PPAR, peroxisome proliferator–activated receptor; SGLT2, sodium–glucose cotransporter 2; URI, upper respiratory infection; UTI, urinary tract infection.

youth with type 2 diabetes, especially implementation and completion of treatment options for this population of since its use is not approved in the pe- such studies have been slow and patients. diatric population. Even though many many barriers have been identified of the newer agents approved in the (111). Therefore, we recommend that METABOLIC SURGERY

adult population are promising and the use of these medications in youth Recommendations may have particular benefits in youn- with type 2 diabetes be avoided outside c Metabolic surgery may be consid- ger individuals with diabetes, we can- of research trials. However, collabo- ered for the treatment of adoles- not recommend widespread use of ration among investigators, pharma- cents with type 2 diabetes who are these medications until additional ceutical sponsors, and governmental markedly obese (BMI .35 kg/m2) studies are completed. Unfortunately, regulators is urgently needed to expand care.diabetesjournals.org Arslanian and Associates 2657

youth with type 2 diabetes from the macrovascular risk burden and a sub- and who have uncontrolled Teen-Longitudinal Assessment of Bariat- stantial increase in the risk of cardiovas- glycemia and/or serious co- ric Surgery (Teen-LABS) cohort who had cular morbidity and mortality at an morbidities despite lifestyle and undergone a bariatric surgical procedure earlier age than those individuals diag- pharmacologic intervention. A with youth with medically treated type 2 nosed later in life (148). The higher c Metabolic surgery should be per- diabetes from the TODAY cohort. Dur- complication risk in earlier-onset type formed only by an experienced ing 2 years, A1C decreased from 6.8% to 2 diabetes is likely to be related to surgeon working as part of a well- 5.5% in Teen-LABS and increased from prolonged lifetime exposure to hy- organized and engaged multidis- 6.4% to 7.8% in TODAY, BMI decreased perglycemia and other atherogenic risk ciplinary team including surgeon, by 29% in Teen-LABS and increased by factors, including insulin resistance, dys- endocrinologist, nutritionist, behav- 3.7% in TODAY, elevated blood pres- lipidemia, hypertension, and chronic ioral health specialist, and nurse. A sure decreased from 45% to 20% of par- inflammation. These diabetes comorbid- ticipants in Teen-LABS and increased ities also appear to be higher than in Bariatric or metabolic surgery, includ- from 22% to 41% in TODAY, and dys- youth with type 1 diabetes despite ing Roux-en-Y gastric bypass, vertical lipidemia decreased from 72% to 24% in shorter diabetes duration and lower sleeve gastrectomy, laparoscopic adjust- Teen-LAB versus no appreciable change A1C (149). In addition, the progression able gastric banding, laparoscopic in TODAY (142). of vascular abnormalities appears to gastric plication, and biliopancreatic di- Overall, studies in both adults and be more pronounced in type 2 diabe- version, has been shown to significantly adolescents suggest that those who tes diagnosed earlier in life compared reduce weight, BMI (120), and cardio- undergo bariatric surgery earlier in with type 1 diabetes of similar duration, vascular comorbidities (121) in adults the course of diabetes (that is, at a including ischemic heart disease and with obesity and is now considered a younger age or with higher baseline stroke (150,151). standard component of care for adults b-cell function) have a higher remission with morbid obesity. Metabolic surgery rate despite similar weight loss (143). Ini- Nephropathy is also an effective strategy for preven- tial diabetes remission rates in adults tion (122,123) and treatment of type 2 Recommendations range between 40% and 70%, whereas c Blood pressure should be mea- diabetes in obese and severely obese in adolescents the reported initial rates $ 2 – sured at every visit. A (BMI 30 kg/m ) adults (124 129) and is areashighas68–100% (144). The long- c Blood pressure should be opti- now endorsed as part of the algorithm term durability of these remissions is un- mized to reduce risk and/or slow for treating type 2 diabetes in adults known and will require longer follow-up. the progression of diabetic kidney (127). Short-term and long-term complica- disease. A Over the last decade, weight-loss sur- tions of metabolic surgery need to be c If blood pressure is .95th percen- gery has been increasingly performed in taken into consideration. In Teen-LABS, tile for age, sex, and height, in- adolescents with obesity, but the long- 13% of adolescents required a second creased emphasis should be term experience remains limited. The operative procedure and another 13% placed on lifestyle management current guidelines for metabolic sur- required an endoscopic procedure be- to promote weight loss. If blood gery in adolescents generally include cause of a complication (145). In the . 2 fi pressure remains above the 95th BMI 35 kg/m with signi cant comor- recent Teen-LABS/TODAY comparison, . 2 percentile after 6 months, antihy- bidities or BMI 40 kg/m with or with- 30% of the youth with diabetes under- pertensive therapy should be ini- out comorbidities (106,130–140). The going surgical intervention required re- tiated. C Endocrine Society Clinical Practice Guide- admission and/or reoperation (142). c Initial therapeutic options include line on Pediatric Obesity discusses bar- Postoperative nutritional complications ACE inhibitors or angiotensin recep- iatric surgery for the management of (vitamin B , thiamine, and vitamin D 12 tor blockers. Other blood pressure– pediatric obesity in detail, and interested deficiency) are also prevalent. Long-term lowering agents may be added as readers can refer to it (106). Briefly, follow-up and further research is re- needed. C positive outcomes of metabolic surgery quired to better understand the mech- c Protein intake should be at the have included remission of type 2 dia- anisms by which metabolic surgery recommended daily allowance of betes, improvements in glucose homeo- improves type 2 diabetes and the short- 0.8 g/kg/day. E stasis in youth without diabetes, term and long-term benefits and risks c Urine albumin/creatinine ratio improvement in surrogate markers of of this procedure in youth. Quality of (UACR) should be obtained at insulin sensitivity and secretion, resolu- life and economic (cost-benefit) analy- the time of diagnosis and annually tion of sleep apnea, improvements in ses will also be important components thereafter. An elevated UACR nonalcoholic fatty liver disease (NAFLD), of ongoing follow-up and research (.30 mg/g creatinine) should be and improvements in cardiovascular dis- (146,147). confirmed on two of three sam- ease (CVD) risk factors, among others ples. B (106,134–141). Direct comparison be- c Estimated glomerular filtration tween the medical management of youth PREVENTION AND MANAGEMENT rate (eGFR) should be determined with type 2 diabetes and bariatric surgery OF DIABETES COMPLICATIONS at the time of diagnosis and annu- outcome, both short- and long-term, is Youth-onset type 2 diabetes is associ- ally thereafter. E very limited. A recent study compared ated with significant microvascular and 2658 Position Statement Diabetes Care Volume 41, December 2018

risk of nephropathy is much higher in myelinated fibers with numbness, tin- c In nonpregnant youth with diabe- youth with type 2 diabetes (158–161). gling, and poor balance along with re- tes and hypertension, either an ACE Spot UACR is generally recommended duced or absent reflexes, vibration inhibitor or an angiotensin recep- for screening of urinary albumin excre- perception, and monofilament sensa- tor blocker is recommended for tion, with an abnormal value confirmed tion. The “gold standard” for the diag- those with modestly elevated on two of three consecutive tests ob- nosis of DPN includes careful neurologic UACR (30–299 mg/g creatinine) tained on different days within a 3- to examination to rule out other potential D and strongly recommended for 6-month period. Results can be affected causes of neuropathy and nerve conduc- those with UACR .300 mg/g cre- by orthostatic proteinuria, marked hy- tion velocity studies. The Diabetes Con- atinine and/or eGFR ,60 mL/min/ perglycemia, exercise, menstruation, trol and Complications Trial (DCCT), 1.73 m2. E recent intercourse, and sample contam- which used a combination of examina- c For those with nephropathy, con- ination. eGFR can be calculated from tion by a neurologist, nerve conduction tinued monitoring (yearly UACR, serum creatinine and the patient’s height velocity testing, and autonomic neurop- eGFR, serum K) may aid in assessing using the Schwartz equation. However, athy testing, clearly showed that im- adherence and detecting progres- recent studies suggest that this under- proved glycemic control reduced the sion of disease. E estimates hyperfiltration, which is highly incidence of , both c Referral to nephrology is recom- prevalent in youth with type 2 diabetes, DPN and autonomic, by 44–60%. mended in case of uncertainty of and a combined estimation using serum However, most large prospective etiology, worsening UACR, or de- creatinine and serum cystatin C is pref- studies have not been able to include crease in eGFR. E erable when available (162). the gold standard of nerve conduction In addition to optimizing glycemia, studies and have utilized less invasive Diabetic kidney disease is diagnosed in control of hypertension is important and less expensive approaches to the the presence of elevated albumin excre- to prevent and slow the progression diagnosis of diabetic neuropathy. The tion and decreased eGFR and is the of nephropathy. Therapeutic options in- most commonly used is the Michigan leading cause of end-stage renal disease clude the use of ACE inhibitors or angio- Neuropathy Screening Instrument (152). Elevated UACR or albuminuria, tensin receptor blockers (152,163–165). (MNSI). The MNSI is a self-administered defined as .30 mg/g creatinine, and If not tolerated, a calcium channel questionnaire (MNSIQ) and an examina- hyperfiltration, defined as an eGFR be- blocker or diuretic or combination ther- tion (MNSIE) for foot abnormalities, tween 120 mL/min/1.73 m2 and 150 apy may be required if hypertension does distal vibration perception, and ankle mL/min/1.73 m2 (153,154), are early ab- not normalize on single-agent therapy. reflexes; the MNSI has been validated normalities that indicate increased risk in adults with type 1 diabetes as a screen- of progression to diabetic kidney disease ing tool for neuropathy (166–169). It fi Neuropathy (154,155). Overt nephropathy is de ned should be noted, however, that the $ as persistent proteinuria 500 mg/day Recommendations MNSIE does not include an assessment $ or UACR 300 mg/g creatinine and an c Youth with type 2 diabetes should of small-fiber dysfunction. , 2 eGFR 60 mL/min/1.73 m . be screened for the presence of Evidence of diabetic neuropathy using fi Albuminuria and hyper ltration de- neuropathy by foot examination at the MNSI was found in 26% of youth with tected early in youth with type 2 diabe- diagnosis and annually. The exam- type 2 diabetes in the SEARCH study (168) tes may occur because of obesity before ination should include inspection, and in 21% of an Australian cohort using the onset of diabetes (156) and can be assessment of foot pulses, pinprick thermal (small fiber) and vibration (large related to early vascular dysfunction and 10-g monofilament sensation fiber) threshold testing (149). In addition, (157). In TODAY, the prevalence of micro- tests, testing of vibration sensa- more than half of the cohort had evi- albuminuria was 6.3% at randomization tion using a 128-Hz tuning fork, dence of autonomic neuropathy (pupil- (mean 7.8 months since diagnosis of and ankle reflexes. C lary reactivity) after a median duration diabetes) and increased to 16.6% over c Prevention should focus on achiev- of diabetes of 1.3 years (149). In an Indian 3 years (79). This coincided with pro- ing glycemic goals. C cohort of mean age 16 years at diagnosis, gression of dyslipidemia (from 4.5% at the prevalence of neuropathy increased baseline to 11%) and hypertension (from Diabetic neuropathy can manifest as from 3% in those with diabetes dura- 11.6% at baseline up to 33%) (78,79) distal polyneuropathy (DPN), mononeu- tion ,5 years to 49% in those with despite standardized therapy for these ropathy, and/or autonomic neuropathy. duration .15 years (170). In the SEARCH comorbidities. The main determining Mononeuropathies are uncommon. DPN study, the prevalence of abnormal MNSI factor in albuminuria progression was is usually the earliest clinically apparent was significantly higher in youth with A1C, with 17% higher risk of developing manifestation of neuropathy in persons type 2 diabetes compared with those albuminuria per 1% increase in A1C (79), with diabetes and most commonly with type 1 diabetes after adjustment for consistent with findings in other studies presents with paresthesia, numbness, age and sex. This association was no (149). Modifiable risk factors include or pain in the feet. DPN generally affects longer significant after adjustment for obesity, dyslipidemia, hypertension, the small myelinated fibers first with the covariates of diabetes duration, waist and glycemia (152). In some ethnic burning or stabbing pain and reduced circumference, blood pressure, HDL cho- groups, particularly Pima Indians and or absent thermal and pinprick sen- lesterol, and microalbuminuria (168). In First Nations people in Canada, the sation. It then progresses to larger the Australian cohort, the prevalence of care.diabetesjournals.org Arslanian and Associates 2659

peripheral and autonomic neuropathy in of 4.9 years was 13.7%, with no evidence in clinical laboratories have been advo- adolescents with type 2 diabetes was of macular edema or proliferative reti- cated to indicate abnormality (180). similar to that of the type 1 diabetes nopathy (77). Retinopathy was associ- Among the noninvasive diagnostic tests, cohort despite shorter diabetes duration ated with older age (19.1 vs. 17.9 years), MRI/MRS are currently the preferred (1.3 vs. 6.8 years) and lower A1C (7.3% vs. longer duration of diabetes (5.6 vs. 4.7 imaging modalities, though of limited 8.5%) (149). In adolescents with type 1 years), and higher A1C (8.3% vs. 6.9%). clinical application (181). Liver ultra- diabetes, data from the DCCT support the Moreover, the odds ratio for retinopathy sound, though a widely available clini- importance of intensive glycemic ther- increased with increasing A1C, age, and cal tool, is operator dependent and apy and reduction of A1C for the preven- duration of diabetes (77). In the SEARCH detects liver fat .30% with sensitivity tion of diabetic neuropathy (171,172). study, the prevalence of retinopathy of 80%, but sensitivity is lower with So far, such data do not exist in youth using retinal photography was 42% lower degrees of fatty infiltration and with type 2 diabetes. at a mean age of 21 years and mean the presence of morbid obesity. Hence, The ADA recommends that assess- duration of type 2 diabetes of 7.2 years its value in the early diagnosis of NAFLD ment for symmetric DPN should in- (175). A1C and LDL cholesterol were is limited (181). Among the noninva- clude a careful history and assessment significantly higher among those with sive modalities, elastography is useful of either temperature or pinprick sensa- retinopathy compared with those with- in evaluating advanced fibrosis and cir- tion (small-fiber function) and vibration out. In Pima Indians, retinopathy was rhosis (181) and is gaining wider accep- sensation using a 128-Hz tuning fork (for detected only after age 20 years and only tance. Liver biopsy remains the gold large-fiber function). All patients should after 5 years of diabetes duration (158). standard for diagnosis and staging of have annual 10-g monofilament testing However, by 30 years of age, retinopathy liver disease and the only way to differ- to identify feet at risk for ulceration and had developed in 45% of this population entiate between nonalcoholic steato- amputation (173). Since it appears that (158). hepatitis and hepatic steatosis. Treatment youth with type 2 diabetes develop DPN options for NAFLD remain limited, with at least as frequently as adults, youth weight loss being most effective. Ther- with type 2 diabetes should be screened NAFLD apeutic agents tested in randomized at the same frequency: at diagnosis and Recommendations clinical trials in youth include metformin, annually. c Evaluation for NAFLD (by measur- vitamin E, and cysteamine, with no clear ing ALT and AST) should be done at established benefit on histologic out- diagnosis of type 2 diabetes and comes or sustained reduction in ALT Retinopathy annually thereafter. B (182–184). Recommendations c Referral to gastroenterology c Screening for retinopathy should should be considered for persis- Obstructive Sleep Apnea be performed by dilated fundo- tently elevated or worsening trans- scopy or retinal photography at aminases. B Recommendation or soon after diagnosis and annu- c Screening for symptoms of ob- ally thereafter. C The prevalence of dysglycemia in youth structive sleep apnea (OSA) should c Optimizing glycemia is recom- with NAFLD is higher than in those be done at each visit, and referral mended to decrease the risk or slow without NAFLD (176). In a multicenter to a pediatric sleep specialist for the progression of retinopathy. B cohort of youth with NAFLD, primarily of evaluation and a polysomnogram, c Less frequent examination (every Hispanic descent, a third of the children if indicated, is recommended. OSA 2 years) may be considered if there with NAFLD had abnormalities in glucose should be treated when docu- is adequate glycemic control and a metabolism; 23.4% had prediabetes and mented. B normal eye exam. C 6.5% had type 2 diabetes (176). More- over, type 2 diabetes in youth is associ- Sleep disturbance (insufficient or dis- refers to changes ated with greater NAFLD histologic rupted sleep, circadian rhythm dysreg- in the small vessels of the retina with the severity than in adults, which may ulation) and OSA are increasingly occurrence of hemorrhages, microaneu- imply a heightened risk of progression recognized as being associated with rysms, exudates, or abnormal vessels. The to fibrosis, cirrhosis, and hepatic failure obesity (185–189), insulin resistance prevalence of retinopathy in youth with (176,177). Therefore, it is particularly in adults and children (52,190–195), type 2 diabetes is reported to be between important to evaluate for NAFLD in youth and type 2 diabetes in adults (196– 2% and 40%, depending on the method- with obesity and type 2 diabetes. For 199), as well as risk for future CVD ology used, the age of the participants, screening, transaminase levels are a clin- (200). Experimental sleep restriction and the duration of diabetes. The prev- ical tool that is widely available and has a results in decreased glucose clearance alence is higher with greater duration good sensitivity for the detection of more and postprandial glucose elevation of the disease, although retinopa- advanced stages of hepatitis or fibrotic (193,201), decrease in glucose effective- thy has been reported at diagnosis changes, but these tests are not disease ness, and variable decrease in insulin (149,170,174). In the TODAY study, the specific; therefore, other causes of sensitivity (190,192,202). OSA may in- prevalence of early retinopathy by digital chronic liver disease should be ruled fluence glycemic regulation in individ- fundus photography at a mean age of out (178,179). Recently, population- uals with diabetes; in adults with type 18.1yearsandmeandurationofdiabetes based cutoffs lower than those used 2 diabetes, treatment of OSA with 2660 Position Statement Diabetes Care Volume 41, December 2018

continuous positive airway pressure has versus regular menses had higher total c Optimal cholesterol goals are LDL been associated with improvement in testosterone, free androgen index, BMI, ,100 mg/dL (2.6 mmol/L), HDL the glycemic profile (203), decreased and AST and lower sex hormone–binding .35 mg/dL (0.905 mmol/L), A1C, and improvement in insulin sensi- globulin and estradiol (215). Treatment triglycerides ,150 mg/dL (1.7 tivity indices (204) as well as inflamma- of PCOS in adolescents includes lifestyle mmol/L). E tion (205) in some, but not all, studies. changes (216–218), the use of oral con- c If LDL cholesterol is .130 mg/dL, Further study is needed. traceptive pills (OCPs), and insulin sen- blood glucose control should be sitizers, such as metformin (213). maximized and dietary counsel- However, the use of some OCPs has ing should be provided using the Polycystic Ovary Syndrome been associated with unfavorable ef- American Heart Association Step Recommendations fects on indices of insulin sensitivity 2 diet. E c Evaluate for polycystic ovary (219) and lipid profile (220). The use c If LDL cholesterol remains above syndrome (PCOS) in female ado- of metformin therapy for 3–12 months goal after 6 months of dietary in- lescents with type 2 diabetes, in- was associated with decrease in serum tervention, initiate therapy with cluding laboratory studies when androgens, improvement in lipid profile, statin, with goal of LDL ,100 indicated. B induction of ovulation, and improvement mg/dL. B c Oral contraceptives for treatment in glucose tolerance and insulin sensitiv- c If triglycerides are .400 mg/dL of PCOS are not contraindicated for ity (216,221,222). Therefore, in girls with (4.7 mmol/L) fasting or .1,000 girls with type 2 diabetes. C type 2 diabetes and PCOS, treatment mg/dL (11.6 mmol/L) nonfasting, c Metformin in addition to lifestyle with metformin in addition to lifestyle optimize glycemia and begin fi- modification islikelytoimprovethe modification is likely to improve the brate, with a goal of ,400 mg/dL menstrual cyclicity and hyperan- metabolic dysfunction associated with (4.7 mmol/L) fasting (to reduce risk drogenism in girls with type 2 di- PCOS and may improve menstrual cy- for pancreatitis). C abetes. E clicity and hyperandrogenism (213,218). However,forthegirlsintheTODAY Although there have been no long- PCOS affects 5–10% of females in the study, all of whom received metformin, term studies of the outcome of reproductive age-group and is charac- there was no treatment group (met- cholesterol-lowering therapy in youth terized by hyperandrogenism and amen- formin alone, metformin plus lifestyle, with type 2 diabetes, studies in youth orrhea or oligomenorrhea secondary to and metformin plus rosiglitazone) ef- with familial hypercholesterolemia have chronic anovulation (206,207). The prev- fect on menses or sex steroids at 12 shown reduction in carotid intima-media alence of PCOS is significantly higher in and24monthsandnoassociationofsex thickness (IMT) with the use of statins adolescent girls with obesity compared steroids with surrogate estimates of in- (223,224), with similar efficacy and side with adolescent girls without overweight/ sulin sensitivity or secretion (215). De- effects as in adults. However, in a recent obesity (208), but the prevalence in spite the potential negative effects of multicenter, multinational study of youth adolescent girls with type 2 diabetes is OCPs, which may not be shared by all with type 1 diabetes, statin use did not not well studied. Insulin resistance with OCPs, on metabolic status and cardio- fi compensatory hyperinsulinemia are vascular risk, hormonal contraceptive have a signi cant effect on carotid IMT metabolic features in both adult women therapy is more effective at addressing despite reductions in total LDL choles- with PCOS with and without overweight/ the symptoms of hyperandrogenism terol and triglyceride concentrations obesity (209) and in adolescent girls with and anovulation and is not contrain- (225). Although longitudinal, interven- PCOS compared with control subjects of dicatedinfemaleyouthwithtype2 tional data with statins in youth-onset similar age, body composition, and ab- diabetes (213). type 2 diabetes are not yet available, dominal adiposity (210). In adolescent statin therapy in youth with type 2 di- abetes who do not meet LDL targets girls with PCOS and obesity, this in- CVD creased insulin resistance when com- following lifestyle change intervention bined with impaired b-cell function Recommendation is considered a reasonable approach predisposes to prediabetes and type 2 c Intensive lifestyle interventions and aligned with overall recommenda- diabetes (211), with higher prevalence focusing on weight loss, dyslipide- tions for dyslipidemia (226), given that of impaired glucose tolerance (30%) and mia, hypertension, and dysglyce- dyslipidemia in youth tracks into adult- type 2 diabetes (3.7%) (212). Therefore, mia are important to prevent overt hood and is anticipated to confer in- it is important to obtain a menstrual macrovascular disease in early creased cardiovascular risk. Similarly, history and evaluate female adolescents adulthood. E though there have been no studies of with type 2 diabetes for signs and symp- the use of fibrates in youth with type 2 toms of hyperandrogenism (irregular Dyslipidemia diabetes and hypertriglyceridemia to prevent pancreatitis, extrapolation menses, hirsutism, acne) and to initiate Recommendations appropriate diagnostic evaluation for from studies in adults supports the c Lipid testing should be performed PCOSif indicated (213,214).In the TODAY use of these agents for severe hyper- when initial glycemic control has cohort, 21% of adolescent girls who triglyceridemia in adolescents. Adoles- been achieved and annually there- were $1-year postmenarche had irreg- cent girls treated with statins or fibrates after. B ular menses. Those with irregular menses should receive counseling on potential care.diabetesjournals.org Arslanian and Associates 2661

risk to the fetus and be encouraged to with adverse cardiac measures (240), chronological age, for those diagnosed use effective birth control. though there was a protective effect between 15 and 30 years of age (246). of cardiorespiratory fitness on functional Taken together, these data raise signif- measures of cardiac structure and func- icant concern regarding the long-term Cardiac Function Testing tion in this group of largely sedentary outcome of youth-onset type 2 diabetes Recommendation youth (241). Overall, studies to date and support the importance of aggres- c Routine screening for heart disease indicate significant vascular dysfunction sive management of glycemia and CVD with electrocardiogram, echocar- and greater risk of progression to overt risk factors in these youth. diogram, or stress testing is not CVD in youth with obesity and type 2 recommended in asymptomatic diabetes. The vascular dysfunction may youth with type 2 diabetes. B begin prior to the diagnosis of type 2 TRANSITIONING FROM PEDIATRIC diabetes as a result of obesity and insulin TO ADULT CARE Macrovascular disease involves coro- resistance. Recommendation nary, cerebral, and peripheral arterial In adults, type 2 diabetes is associated c Youth with type 2 diabetes should disease. In adults, type 2 diabetes is with an increased risk of mortality, with be transferred to an adult-oriented associated with doubling of risk for cardiac disease as a major cause of death diabetes specialist when deemed CVD, including coronary heart disease (242); the excess mortality is related to appropriate by the patient and and stroke as well as increased risk of worse glycemic control, impaired renal provider. E heart failure, after adjusting for age, sex, function, and younger age at diabetes smoking status, BMI, and systolic blood diagnosis (243). Youth-onset type 2 di- The process of transferring the pedi- pressure (227). Diabetes duration is im- abetes appears to be associated with an atric patient to an adult health care plicated as a major risk factor for CVD earlier onset of complications and an provider is a challenge that has only (228,229), though there may also be a increased mortality risk compared with recently received attention in the liter- worsened risk of CVD with early onset of type 1 diabetes (109,244,245). In a Swed- ature but is now recognized to be “im- type 2 diabetes (228,230). While overt ish study, type 2 diabetes diagnosed portant and should begin well before cardiovascular events are not expected in between 15 and 34 years of age was patients are transferred” (247). Both the youth with type 2 diabetes, epidemio- associated with a higher standardized Society for Adolescent Medicine (248) logical and clinical studies show that the mortality ratio than type 1 diabetes and the American Academy of Pediatrics, atherosclerotic process starts during (2.9 and 1.8, respectively), with an in- along with other associations (249), have childhood (231), with strong relation- creased hazard ratio for males versus position statements related to transition ships between childhood obesity, females (P 5 0.0002) (244). Similarly, an of care for those with chronic diseases elevated blood pressure, low HDL cho- epidemiological study from Australia and special medical needs that empha- lesterol, and coronary artery disease in reported a significant mortality excess size the importance of a gradual and adulthood (232–235). Furthermore, over 15–30 years of follow-up in individ- collaborative process starting a year or studies of vascular function have dem- uals diagnosed with type 2 diabetes longer before the actual transition is to onstrated subclinical vascular disease in between 15 and 30 years of age com- occur. Published literature on this sub- adolescents with obesity and type 2 di- paredwithtype1diabetes,withahazard ject recommends progressive implemen- abetes, including elevated aortic pulse ratio of 2.0 (95% CI 1.2–3.2), despite tation as eight developmentally linked wave velocity, a marker of vascular stiff- shorter average disease duration (26.9 steps (250,251). ness (236), and increased carotid IMT, a vs. 36.5 years, P 5 0.01) and similar The ADA, in partnership with the other structural measure of atherosclerosis, glycemic control (109). The mortality organizations of the ADA Transitions compared with normoglycemic youth excess was related to an excess of car- Working Group (252), developed posi- with and without overweight/obesity diovascular deaths in those with type 2 tion statements in 2011 (252), in (237). In the SEARCH study, youth diabetes (50% vs. 30%, P , 0.05). In First 2014 (253), and in 2018 (254). Even with type 2 diabetes had worse arterial Nations individuals, increased mortality for youth with type 1 diabetes, deficien- stiffness than those with type 1 diabetes, with type 2 diabetes is reported in re- cies and gaps in the transition process attributed to greater central adiposity lation to end-stage renal disease (159) have been demonstrated in observa- and hypertension but not related to and is significantly higher than in indi- tional cross-sectional research. These duration of diabetes or glycemic control viduals with youth-onset type 1 diabetes gaps are summarized in recent reviews (238). In studies of obese youth with and (245). In a large cohort of 354 patients (250,252,255) and include minimal em- without type 2 diabetes, carotid IMT was with type 2 diabetes diagnosed between pirical evidence about the best ap- significantly related to glycemia, while 15 and 30 years of age compared with proaches, differences in the style and aortic pulse wave velocity was related to a duration-matched cohort of 1,062 approach to health care delivery be- insulin resistance and inflammation patients diagnosed between 40 and tween pediatric and adult health care (239). In addition, total body and abdom- 50 years old, the negative effect of di- providers, lack of well-defined criteria inal adiposity were significant determi- abetes on morbidity (albuminuria and of readiness for transition or tools to as- nants of coronary artery calcifications in neuropathy scores) and mortality was sess readiness, gaps in health insurance these youth (239). In TODAY, echocar- greatest for those diagnosed at a young coverage, changing social structure as diographic evaluation revealed a rela- age. Standardized mortality adjusting adolescents enter young adulthood, tionship of BMI and blood pressure for duration was highest, at any differences in learning styles of the patient 2662 Position Statement Diabetes Care Volume 41, December 2018

and teaching styles of the provider, and diabetes appear early, resulting in higher glucose concentrations in the nondiabetic lack of health care provider training re- rates of morbidity and mortality com- through the diabetic range in overweight youth. – lated to transition of care. pared with type 1 diabetes. Preexisting Diabetes Care 2011;34:2033 2040 8. Giannini C, Weiss R, Cali A, et al. Evidence for Despite the prevailing evidence of the obesity and its comorbidities might play early defects in insulin sensitivity and secretion need for better transition of care, there a key role in amplifying the complica- before the onset of glucose dysregulation in are no controlled studies of the effec- tions of youth-onset type 2 diabetes. obese youths: a longitudinal study. Diabetes tiveness of such programs in patients Intervention/prevention strategies for 2012;61:606–614 with youth-onset type 2 diabetes. Pa- type 2 diabetes should not be limited to 9. Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R. Beta-cell func- tients with type 1 diabetes have reduced youth with dysglycemia only, but youth tion across the spectrum of glucose tolerance in dropout from medical care, increased with obesity at large. obese youth. Diabetes 2005;54:1735–1743 number of visits, and reduced pregnancy In closing, the present guidelines 10. Kobayashi K, Amemiya S, Higashida K, et al. loss, DKA, and severe hypoglycemia dur- are based on current data, experi- Pathogenic factors of glucose intolerance in ing the transition period using a “navi- ence, opinion, and gained “wisdom.” obese Japanese adolescents with type 2 diabe- tes. Metabolism 2000;49:186–191 gator” to assist young adults (18–30 However, we anticipate that future 11. Elder DA, Prigeon RL, Wadwa RP, Dolan LM, years old) (256–258). guidelines will change as more scientific D’Alessio DA. Beta-cell function, insulin sensitiv- Since emerging adults with type 2 di- data emerge to support evidence-based ity, and glucose tolerance in obese diabetic and abetes express similar concerns related recommendations. nondiabetic adolescents and young adults. J Clin – to transition from pediatric to adult Endocrinol Metab 2006;91:185 191 12. Druet C, Tubiana-Rufi N, Chevenne D, Rigal health care providers (259), the same O, Polak M, Levy-Marchal C. Characterization of principles discussed above and steps to Duality of Interest. S.A. has served on a data insulin secretion and resistance in type 2 diabetes facilitate transition that apply to those monitoring committee for AstraZeneca, data of adolescents. J Clin Endocrinol Metab 2006;91: with type 1 diabetes should be consid- safety monitoring board for Boehringer Ingelheim, 401–404 and advisory boards for Eli Lilly, Novo Nordisk, ’ ered in type 2 diabetes. 13. Elder DA, Woo JG, D Alessio DA. Impaired and Sanofi-Aventis and has received research b-cell sensitivity to glucose and maximal insulin grants from Eli Lilly and Novo Nordisk through secretory capacity in adolescents with type 2 her institution. F.B. has received grant sup- diabetes. Pediatr Diabetes 2010;11:314–321 CONCLUSIONS port through her institution from Johnson & 14. Defronzo RA. Banting Lecture. From the Even though our knowledge of youth- Johnson and AstraZeneca. M.D.M. has served triumvirate to the ominous octet: a new para- on the scientific advisory committee of WW digm for the treatment of type 2 diabetes onset type 2 diabetes has increased International, Inc. P.Z. has served as a study mellitus. Diabetes 2009;58:773–795 tremendously over the last two decades, design consultant for Daichii Sankyo, Merck, 15. Tahrani AA, Bailey CJ, Del Prato S, Barnett robust and evidence-based data are still Boeringer Ingelheim, Janssen, and Eli Lilly (all AH. Management of type 2 diabetes: new and limited regarding diagnostic and thera- contracts with the University of Colorado) and future developments in treatment. Lancet 2011; as a member of a data safety monitory board for peutic approaches and prevention of 378:182–197 Novo Nordisk. No other potential conflicts of 16. Umpaichitra V, Bastian W, Taha D, Banerji complications. The current-day informa- interest relevant to this article were reported. MA, AvRuskin TW, Castells S. C-peptide and tion indicates that there are fundamen- glucagon profiles in minority children with tal differences in insulin sensitivity and References type 2 diabetes mellitus. J Clin Endocrinol Metab b-cell function between youth and adults 1. Kahn SE, Prigeon RL, McCulloch DK, et al. 2001;86:1605–1609 with prediabetes and type 2 diabetes, Quantification of the relationship between in- 17. Weiss R, D’Adamo E, Santoro N, Hershkop K, Caprio S. Basal a-cell up-regulation in obese which could possibly explain why some sulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. insulin-resistant adolescents. J Clin Endocrinol youth develop type 2 diabetes decades Diabetes 1993;42:1663–1672 Metab 2011;96:91–97 earlier than adults (23,24,260,261). 2. Gungor N, Bacha F, Saad R, Janosky J, 18. Bacha F, Gungor N, Lee S, Arslanian SA. In Youth are more insulin resistant and Arslanian S. Youth type 2 diabetes: insulin re- vivo insulin sensitivity and secretion in obese have b-cells that are hyperresponsive sistance, beta-cell failure, or both? Diabetes Care youth: what are the differences between normal – glucose tolerance, impaired glucose tolerance, to stimulation compared with adults 2005;28:638 644 3. Michaliszyn SF, Mari A, Lee S, et al. b-Cell and type 2 diabetes? Diabetes Care 2009;32: (23,24,260,261). Puberty-related physio- function, incretin effect, and incretin hormones 100–105 logic insulin resistance, particularly in in obese youth along the span of glucose toler- 19. Goran MI, Bergman RN, Avila Q, et al. Im- obese youth, may play a role in this ance from normal to prediabetes to type 2 di- paired glucose tolerance and reduced b-cell heightened insulin resistance. It remains abetes. Diabetes 2014;63:3846–3855 function in overweight Latino children with a positive family history for type 2 diabetes. J Clin an enigma, though, why some individuals 4. Umpierrez GE (Ed.). Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Alexan- Endocrinol Metab 2004;89:207–212 with youth-onset type 2 diabetes dem- dria, VA, American Diabetes Association, 2014 20. Weigensberg MJ, Ball GDC, Shaibi GQ, Cruz onstrate durable control and others do 5. Bacha F, Lee S, Gungor N, Arslanian SA. From ML, Goran MI. Decreased b-cell function in not (74). Furthermore, type 2 diabetes pre-diabetes to type 2 diabetes in obese youth: overweight Latino children with impaired fasting appears to be more aggressive in youth pathophysiological characteristics along the glucose. Diabetes Care 2005;28:2519–2524 spectrum of glucose dysregulation. Diabetes 21. Weiss R, Taksali SE, Tamborlane WV, Burgert than adults, with a faster rate of de- Care 2010;33:2225–2231 TS, Savoye M, Caprio S. Predictors of changes in terioration of b-cell function (76) and 6. Tfayli H, Lee S, Arslanian S. Declining b-cell glucose tolerance status in obese youth. Diabe- poorer response to glucose-lowering function relative to insulin sensitivity with in- tes Care 2005;28:902–909 medications (104). Future research creasing fasting glucose levels in the nondiabetic 22. Sjaarda LA, Michaliszyn SF, Lee S, et al. HbA1c should probe the mechanisms responsi- range in children. Diabetes Care 2010;33:2024– diagnostic categories and b-cell function relative – 2030 to insulin sensitivity in overweight/obese ado- ble for this youth adult contrast in the 7. Burns SF, Bacha F, Lee SJ, Tfayli H, Gungor N, lescents. Diabetes Care 2012;35:2559–2563 various aspects of type 2 diabetes. Lastly, Arslanian SA. Declining b-cell function relative to 23. RISE Consortium. Metabolic contrasts be- complications in youth with type 2 insulin sensitivity with escalating OGTT 2-h tween youth and adults with impaired glucose care.diabetesjournals.org Arslanian and Associates 2663

tolerance or recently diagnosed type 2 diabetes: 40. Hasson RE, Adam TC, Davis JN, et al. Ethnic 56. LeeJM,WuE-L,TariniB,HermanWH,YoonE. I. observations using the hyperglycemic clamp. differences in insulin action in obese African- Diagnosis of diabetes using hemoglobin A1c: Diabetes Care 2018;41:1696–1706 American and Latino adolescents. J Clin Endo- should recommendations in adults be extrapo- 24. RISE Consortium. Metabolic contrasts be- crinol Metab 2010;95:4048–4051 lated to adolescents? J Pediatr 2011;158:947– tween youth and adults with impaired glucose 41. Bacha F, Gungor N, Lee S, Arslanian SA. Type 952.e3 tolerance or recently diagnosed type 2 diabetes: 2 diabetes in youth: are there racial differences in 57. Chan CL, Pyle L, Newnes L, Nadeau KJ, Zeitler II. observations using the oral glucose tolerance b-cell responsiveness relative to insulin sensi- PS, Kelsey MM. Continuous glucose monitoring test. Diabetes Care 2018;41:1707–1716 tivity? Pediatr Diabetes 2012;13:259–265 and its relationship to hemoglobin A1c and oral 25. Arslanian SA, Bacha F, Saad R, Gungor N. 42. Weiss R, Dziura JD, Burgert TS, Taksali SE, glucose tolerance testing in obese and predia- Family history of type 2 diabetes is associated Tamborlane WV, Caprio S. Ethnic differences in betic youth. J Clin Endocrinol Metab 2015;100: with decreased insulin sensitivity and an im- beta cell adaptation to insulin resistance in obese 902–910 paired balance between insulin sensitivity and children and adolescents. Diabetologia 2006;49: 58. Love-Osborne KA, Sheeder JL, Nadeau KJ, insulin secretion in white youth. Diabetes Care 571–579 Zeitler P. Longitudinal follow up of dysglycemia 2005;28:115–119 43. Copeland KC, Zeitler P, Geffner M, et al.; in overweight and obese pediatric patients. 26. Giannini C, Dalla Man C, Groop L, et al. Co- TODAY Study Group. Characteristics of adoles- Pediatr Diabetes 2018;19:199–204 occurrence of risk alleles in or near genes mod- cents and youth with recent-onset type 2 di- 59. Gungor N, Hannon T, Libman I, Bacha F, ulating insulin secretion predisposes obese youth abetes: the TODAY cohort at baseline. J Clin Arslanian S. Type 2 diabetes mellitus in youth: to prediabetes. Diabetes Care 2014;37:475–482 Endocrinol Metab 2011;96:159–167 the complete picture to date. Pediatr Clin North 27. Sartorius T, Staiger H, Ketterer C, et al. 44. Goran MI, Gower BA. Longitudinal study on Am 2005;52:1579–1609 Association of common genetic variants in the pubertal insulin resistance. Diabetes 2001;50: 60. DuBose SN, Hermann JM, Tamborlane WV, MAP4K4 locus with prediabetic traits in hu- 2444–2450 et al.; Type 1 Diabetes Exchange Clinic Network mans. PLoS One 2012;7:e47647 45. Hannon TS, Janosky J, Arslanian SA. Longi- and Diabetes Prospective Follow-up Registry. 28. KwakSH, Park KS. Geneticsof type 2 diabetes tudinal study of physiologic insulin resistance Obesity in youth with type 1 diabetes in Ger- and potential clinical implications. Arch Pharm and metabolic changes of puberty. Pediatr Res many, Austria, and the United States. J Pediatr Res 2013;36:167–177 2006;60:759–763 2015;167:627–632.e4 29. So H-C, Gui AHS, Cherny SS, Sham PC. 46. Ball GDC, Huang TT-K, Gower BA, et al. 61. Klingensmith GJ, Pyle L, Arslanian S, et al.; Evaluating the heritability explained by known Longitudinal changes in insulin sensitivity, insulin TODAY Study Group. The presence of GAD and susceptibility variants: a survey of ten complex secretion, and b-cell function during puberty. IA-2 antibodies in youth with a type 2 diabetes diseases. Genet Epidemiol 2011;35:310–317 J Pediatr 2006;148:16–22 phenotype: results from the TODAY study. Di- 30. Billings LK, Florez JC. The genetics of type 2 47. Kelly LA, Lane CJ, Weigensberg MJ, Toledo- abetes Care 2010;33:1970–1975 diabetes: what have we learned from GWAS? Corral CM, Goran MI. Pubertal changes of insulin 62. Hannon TS, Arslanian SA. The changing face Ann N Y Acad Sci 2010;1212:59–77 sensitivity, acute insulin response, and b-cell of diabetes in youth: lessons learned from stud- 31. Gill-Carey O, Hattersley AT. Genetics and function in overweight Latino youth. J Pediatr ies of type 2 diabetes. Ann N Y Acad Sci 2015; type 2 diabetes in youth. Pediatr Diabetes 2007; 2011;158:442–446 1353:113–137 8(Suppl. 9):42–47 48. Carnethon MR, Kinder LS, Fair JM, Stafford 63. Bacha F, Gungor N, Lee S, de las Heras J, 32. Dabelea D, Dolan LM, D’Agostino R Jr, et al. RS, Fortmann SP. Symptoms of depression as a Arslanian S. Indices of insulin secretion during a Association testing of TCF7L2 polymorphisms risk factor for incident diabetes: findings from liquid mixed-meal test in obese youth with di- with type 2 diabetes in multi-ethnic youth. the National Health and Nutrition Examination abetes. J Pediatr 2013;162:924–929 Diabetologia 2011;54:535–539 Epidemiologic Follow-up Study, 1971-1992. 64. Tfayli H, Bacha F, Gungor N, Arslanian S. 33. Dabelea D. The predisposition to obesity Am J Epidemiol 2003;158:416–423 Phenotypic type 2 diabetes in obese youth: and diabetes in offspring of diabetic mothers. 49. Hannon TS, Rofey DL, Lee S, Arslanian SA. insulin sensitivity and secretion in islet cell Diabetes Care 2007;30(Suppl. 2):S169–S174 Depressive symptoms and metabolic markers of antibody-negative versus -positive patients. Di- 34. McMillen IC, Rattanatray L, Duffield JA, et al. risk for type 2 diabetes in obese adolescents. abetes 2009;58:738–744 The early origins of later obesity: pathways and Pediatr Diabetes 2013;14:497–503 65. Pinhas-Hamiel O, Dolan LM, Zeitler PS. Di- mechanisms. Adv Exp Med Biol 2009;646:71–81 50. Cappuccio FP, D’Elia L, Strazzullo P, Miller abetic ketoacidosis among obese African- 35. Chernausek SD, Arslanian S, Caprio S, et al. MA. Quantity and quality of sleep and incidence American adolescents with NIDDM. Diabetes Relationship between parental diabetes and of type 2 diabetes: a systematic review and Care 1997;20:484–486 presentation of metabolic and glycemic function meta-analysis. Diabetes Care 2010;33:414– 66. Smith RJ, Nathan DM, Arslanian SA, Groop L, in youth with type 2 diabetes: baseline findings 420 Rizza RA, Rotter JI. Individualizing therapies in from the TODAY trial. Diabetes Care 2016;39: 51. Hannon TS, Lee S, Chakravorty S, Lin Y, type 2 diabetes mellitus based on patient char- 110–117 Arslanian SA. Sleep-disordered breathing in acteristics: what we know and what we need to 36. Dabelea D, Mayer-Davis EJ, Lamichhane AP, obese adolescents is associated with visceral know. J Clin Endocrinol Metab 2010;95:1566– et al. Association of intrauterine exposure to adiposity and markers of insulin resistance. 1574 maternal diabetes and obesity with type 2 Int J Pediatr Obes 2011;6:157–160 67. Kleinberger JW, Copeland KC, Gandica RG, diabetes in youth: the SEARCH Case-Control 52. Koren D, Levitt Katz LE, Brar PC, Gallagher PR, et al. Monogenic diabetes in overweight and Study. Diabetes Care 2008;31:1422–1426 Berkowitz RI, Brooks LJ. Sleep architecture and obese youth diagnosed with type 2 diabetes: the 37. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; glucose and insulin homeostasis in obese ado- TODAY clinical trial. Genet Med 2018;20:583– SEARCH for Diabetes in Youth Study. 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J Clin Endocrinol Metab 2013;98: 509–517 fasting plasma glucose in a multiethnic middle- 4055–4062 39. Bacha F, Saad R, Gungor N, Janosky J, school cohort. Diabetes Care 2013;36:429– 69. Hattersley AT, Greeley SAW, Polak M, et al. Arslanian SA. Obesity, regional fat distribution, 435 ISPAD 2018 Consensus Guidelines: the diagno- and syndrome X in obese black versus white 55. Nowicka P, Santoro N, Liu H, et al. Utility of sis and management of monogenic diabetes adolescents: race differential in diabetogenic hemoglobin A1c for diagnosing prediabetes and in children and adolescents. Pediatr Diabetes. and atherogenic risk factors. J Clin Endocrinol diabetes in obese children and adolescents. Di- 17 September 2018 [Epub before print]. DOI: Metab 2003;88:2534–2540 abetes Care 2011;34:1306–1311 10.1111/pedi.12772 2664 Position Statement Diabetes Care Volume 41, December 2018

70. Zeitler P, Fu J, Tandon N, et al.; International 86. Naughton MJ, Ruggiero AM, Lawrence JM, ethnically diverse pediatric population. Pediat- Society for Pediatric and Adolescent Diabetes. et al.; SEARCH for Diabetes in Youth Study Group. rics 2011;127:402–410 ISPAD Clinical Practice Consensus Guidelines Health-related quality of life of children and 104. TODAY Study Group. A clinical trial to main- 2014. Type 2 diabetes in the child and ado- adolescents with type 1 or type 2 diabetes tain glycemic control in youth with type 2 dia- lescent. Pediatr Diabetes 2014;15(Suppl. 20): mellitus: SEARCH for Diabetes in Youth Study. betes. N Engl J Med 2012;366:2247–2256 26–46 Arch Pediatr Adolesc Med 2008;162:649–657 105. Marcus MD, Wilfley DE, El Ghormli L, et al.; 71. Zeitler P, Arslanian S, Fu J, et al. Type 2 di- 87. Whalen DJ, Belden AC, Tillman R, Barch DM, TODAY Study Group. Weight change in the abetes mellitus (T2DM) in youth. Pediatr Di- Luby JL. 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