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Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS). The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 years), pubertal stage, and body mass index z-score of 0.1 ± 1.2 and then between testosterone-treated (n = 16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from that in controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (area under the curve > 0.9, P < 0.0001). Multiple saturated free fatty acids were higher in KS, while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial β-oxidation of long-chain saturated fatty acids (enrichment ratio 16, P < 0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from that in males without KS independent of age, obesity, pubertal development, or testosterone treatment status and is suggestive of differences in mitochondrial β-oxidation.

AWARD-PEDS was a Phase 3 trial to assess the efficacy and safety of dulaglutide (DU) , a once-weekly GLP-1 receptor agonist, in youth (10 to In conclusion, in youth with inadequately controlled T2D treated with or without metformin and/or basal insulin, once weekly DU 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control without an effect on BMI through 26 weeks, with a safety profile consistent with that established in adults. Disclosure S. A. Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Eli Lilly and Company, Novo Nordisk. Other Relationship; AstraZeneca. J. Cho: None. T. S. Hannon: Advisory Panel; Eli Lilly and Company. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. L. Chao: None. M. Barrientos: Research Support; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research & Development, LLC, Novo Nordisk. C. C. Boucher-Berry: None. E. Bismuth: None. S. A. Dib: None. D. Cox: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

T2D in youth remains challenging to manage and there is need for an expanded treatment armamentarium. The DINAMO study was designed to overcome recruitment difficulties that plagued previous T2D studies in youth. Within 3 years, DINAMO enrolled 158 patients aged to Disclosure L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. T. Danne: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Research Support; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Stock/Shareholder; DreaMed Diabetes, Ltd. W.V. Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited. G.J. Klingensmith: Research Support; AstraZeneca, Novo Nordisk, Takeda Pharmaceutical Company Limited. Stock/Shareholder; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. C. Schroeder: Employee; Boehringer Ingelheim Inc. D. Neubacher: Employee; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Boehringer Ingelheim Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. S.M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. Research Support; Jaeb Center for Health Research, Provention Bio, Inc. Other Relationship; National Institute of Diabetes and Digestive and Kidney Diseases. Funding Boehringer Ingelheim

Purpose: Up to 1.8% of youth identify as transgender; many will be treated with a gonadotropin-releasing hormone agonist (GnRHa). The impact of GnRHa on insulin sensitivity and body composition in transgender youth is understudied. We aimed to evaluate differences in insulin sensitivity and body composition in transgender youth on GnRHa therapy compared with cisgender youth. Methods: Transgender participants were matched to cisgender participants on age, body mass index, and sex assigned at birth. Transgender males (n=9, ages 10.1–16.0 years) on GnRHa (mean±standard deviation duration of exposure: 20.9±19.8 months) were compared with cisgender females (n=14, ages 10.6–16.2). Transgender females (n=8, ages 12.6–16.1) on GnRHa (11.3±7 months) were compared with cisgender males (n=17, ages 12.5–15.5). Differences in insulin sensitivity (1/[fasting insulin], homeostatic model of insulin resistance [HOMA-IR]), glycemia (hemoglobin A1C [HbA1c], fasting glucose), and body composition (dual-energy X-ray absorptiometry) were evaluated using a mixed linear regression model. Results: Transgender males had lower 1/fasting insulin and higher HOMA-IR (p=0.031, p=0.01, respectively), fasting glucose (89±4 vs. 79±13 mg/dL, p=0.012), HbA1c (5.4±0.2 vs. 5.2±0.2%, p=0.039), and percent body fat (36±7 vs. 32±5%, p=0.042) than matched cisgender females. Transgender females had lower 1/fasting insulin and higher HOMA-IR (p=0.028, p=0.035), HbA1c (5.4±0.1% vs. 5.1±0.2%, p=0.007), percent body fat (31±9 vs. 24±10%, p=0.002), and lower percent lean mass (66±8 vs. 74±10%, p

Context Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the β-cell. Objective Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory β-cell response in youth with obesity. Setting Pediatric academic hospital clinical translational research center. Participants Healthy youth in early puberty [Tanner stage (T) 2-3] with normoglycemia and obesity (n = 44). Intervention Double-blinded placebo-control trial of metformin during puberty (until T5). Main Outcome Measures Insulin sensitivity (Si), insulin response [acute insulin response to glucose (AIRg)], and disposition index (DI), estimated from frequently sampled intravenous glucose tolerance testing; body fat (dual X-ray absorptiometry); and other laboratory parameters, collected at baseline, T4, and T5. Placebo-subtracted treatment effect was calculated using linear mixed models. Results At T5, metformin treatment, adjusting for sex, race, and baseline value, was associated with improved BMI z-score (−0.44 ± 0.16, P = 0.02), percentage body fat (%body fat; −3.4 ± 1.2%, P = 0.06), and waist circumference (−11.3 ± 3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ± 0.87 × 10−4/min−1/μIU/mL, P = 0.34), AIRg (−259 ± 386 μIU/mL, P = 0.51), or DI (508 ± 802 × 10−4/min−1, P = 0.53). High baseline DI predicted longitudinal decline in DI. Conclusions Two years of metformin treatment in obese youth during puberty improved BMI and body fat, but not Si or β-cell function. Of note, high DI in early puberty may be predictive of later decline in DI. Further studies are needed to develop strategies for preservation of β-cell function in youth at risk for type 2 diabetes.

Individualization of therapy based on a person’s specific type of diabetes is one key element of a “precision medicine” approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of Diabetes Care convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10–17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1–5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.

Context Physiologic changes in glucose metabolism are well-described to occur during puberty. However, there are important gaps in understanding the interaction between obesity and the normal physiologic changes during puberty, as well as how these changes could contribute to the increased risk of comorbidities, such as type 2 diabetes and dyslipidemia, in youth with obesity. Objective The objective of this study was to compare longitudinal changes in insulin sensitivity (Si) and secretion during pubertal progression in youth with obesity versus those with normal weight. Design Longitudinal observational study evaluating youth from early puberty (Tanner [T]2-T3) until puberty completion (T5). Setting Pediatric academic hospital Clinical Translational Research Center. Participants Pubertal youth with normal weight (n = 47; 22 female, 25 male) and obesity (n = 37; 23 female, 14 male) Main Outcome Measures Si, insulin response (acute insulin response to glucose, AIRg) and disposition index (DI) by intravenous glucose tolerance test at baseline (T2-T3), T4, and T5 Results Youth with obesity had significantly lower Si and higher AIRg at each time point (P Conclusions Obesity significantly impacts Si during puberty, even at the earliest stages. However, in general, obese youth have adequate β-cell compensation for the significantly reduced Si of puberty. Future studies are needed to better predict the subset of youth who fail to maintain β-cell compensation during puberty.

OBJECTIVE To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4%

Context Early glucose abnormalities in people with cystic fibrosis (PwCF) are commonly detected by continuous glucose monitoring (CGM). Relationships between these CGM abnormalities and oral glucose tolerance testing (OGTT) in PwCF have not been fully characterized. Objective This work aimed to determine the relationship between CGM and common OGTT-derived estimates of β-cell function, including C-peptide index and oral disposition index (oDI) and to explore whether CGM can be used to screen for OGTT-defined prediabetes and cystic fibrosis–related diabetes (CFRD). Methods PwCF not on insulin and healthy controls aged 6 to 25 years were enrolled in a prospective study collecting OGTT and CGM. A subset underwent frequently sampled OGTTs (fsOGTT) with 7-point glucose, insulin, and C-peptide measurements. Pearson correlation coefficient was used to test the association between select CGM and fsOGTT measures. Receiver operating curve (ROC) analysis was applied to CGM variables to determine the cutoff optimizing sensitivity and specificity for detecting prediabetes and CFRD. Results A total of 120 participants (controls = 35, CF = 85), including 69 with fsOGTTs, were included. CGM coefficient of variation correlated inversely with C-peptide index (Cpeptide30-Cpeptide0/Glucose30-Glucose0) (r = –0.45, P Conclusion Greater glycemic variability on CGM correlated with reduced β-cell function. However, CGM performed poorly at discriminating individuals with and without OGTT-defined CFRD and prediabetes. Prospective studies are now needed to determine how well the different tests predict clinically relevant nonglycemic outcomes in PwCF.

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS).The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 yrs), pubertal stage, and body mass index z-score (0.1 ± 1.2), and then between testosterone treated (n=16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (AUC>0.9, p

Objective To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. Study design Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5% - 10% (7.0% - 10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. Results Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% 1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95%CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95%CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. Conclusions These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov:NCT01472367,NCT01760447; EudraCT:2011-002529-23/2014-003583-20,2012-004035-23) This article is protected by copyright. All rights reserved.

Objectives: To compare the characteristics of younger (Y, 10-14 yrs) vs. older (O, 15-17 yrs) patients (pts) with T2D in global clinical trials of sitagliptin as initial oral therapy (IOT, NCT01485614) or as add-on to metformin therapy (AMT, NCT01472367, NCT01760447). Methods: Demographic and baseline glycemic parameters were summarized by age group for pts in the studies (Table). Results: The proportion of females was higher in Y groups and that of Whites greater in O groups. All groups had similar BMI percentiles, despite the Y group being shorter, with lower weight and BMI. Duration of T2D was similar across age groups in the IOT study, but duration was less in Y vs. O in AMT studies. Baseline A1C and FPG were comparable across age groups within a study type. Conclusions: The female preponderance reported in youth with T2D (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038479/) was more apparent in Y groups; it is possible that the proportion of females is lower in O groups, approaching the situation in adults where sex distribution is uniform. Both Y and O pts had similar BMI percentiles. While glycemic parameters were similar across age groups within a study type, duration of diabetes was less in Y pts in AMT studies, suggesting that the need for an additional antihyperglycemic agent may occur sooner in pts diagnosed at a younger age. Disclosure R. S. Newfield: Consultant; Self; Merck Sharp & Dohme Corp. Z. Xu: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. L. W. Scherer: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. S. S. Engel: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. K. D. Kaufman: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Janssen Research & Development, LLC, Merck & Co., Inc. R. Shankar: Employee; Self; AstraZeneca, Merck Sharp & Dohme Corp. A. Deeb: None. M. Y. Jalaludin: Advisory Panel; Self; Novo Nordisk, Research Support; Self; Novo Nordisk. R. Garcia: None. Y. Samoilova: None. C. A. Rosario: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. K. Saha: None. Y. Zhang: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. Funding Merck & Co., Inc.

Objectives: To compare baseline characteristics of 10-17 yr old patients (pts) with T2D from different regions in clinical trials of sitagliptin as initial oral therapy (IOT, NCT01485614) or as add-on to metformin therapy (AMT, NCT01472367, NCT01760447). Methods: Demographic and baseline glycemic parameters of pts randomized in the US or Canada (NA), Latin America (LA), Europe or the Middle East (EM), or Asia Pacific (AP) were summarized by region (Table). Results: The proportion of males varied by region. While racial and ethnic distributions were generally reflective of region, the proportion of Whites in NA was higher than in other reports (e.g., ncbi.nlm.nih.gov/pmc/articles/PMC3038479). AP pts were youngest. Consistent with age, pts in AP were shorter, with lower weight and BMI across trials; however, median BMI percentile was >98% across regions and trial types. Median A1C and FPG ranged from 7.1-7.4% and 118-130.5 mg/dL (IOT) and 7.7-7.9% and 125.5-143.5 mg/dL (AMT). Despite having the lowest FPG, pts in AP (IOT) had the highest A1C. Conclusions: Despite regional differences in race, sex, and anthropometrics, pts were uniformly obese. Baseline glycemic parameters by region were generally comparable, although the younger age (all trials) and lower FPG and higher A1C (IOT) in AP pts may reflect a difference in the pathophysiology of T2D, with greater post-meal rather than fasting dysglycemia. Disclosure M. Y. Jalaludin: Advisory Panel; Self; Novo Nordisk, Research Support; Self; Novo Nordisk. Y. Zhang: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. Z. Xu: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. L. W. Scherer: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. S. S. Engel: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. K. D. Kaufman: Employee; Self; Merck & Co., Inc., Stock/Shareholder; Self; Merck & Co., Inc. R. Shankar: Employee; Self; AstraZeneca, Merck Sharp & Dohme Corp. A. Deeb: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Janssen Research & Development, LLC, Merck & Co., Inc. R. Garcia: None. R. S. Newfield: Consultant; Self; Merck Sharp & Dohme Corp. Y. Samoilova: None. C. A. Rosario: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. K. Saha: None. Funding Merck & Co., Inc.

Background: Young adults with diabetes face transitions in health care (provider, insurance, costs) and commonly have suboptimal glycemic control. We explored healthcare coverage and access to care and their associations with HbA1c, by diabetes type. Methods: In the SEARCH (T1D and T2D) and TODAY (T2D) studies, interviewer-administered surveys collected data on health care coverage at study visits (2017-2019). The associations between healthcare coverage or access and HbA1c were examined separately in T1D and T2D. Results: A total of 1374 participants, mean age 25 years, completed the survey. Mean HbA1c was similar in T1D and T2D for those with public insurance, but higher in T1D with no insurance. Having health insurance and a usual place for diabetes care were associated with lower HbA1c for T1D participants but not for those with T2D (Table). Participants from states with Medicaid eligibility expansion were more likely to have health insurance for T1D: 99% with vs. 91% without expansion; and T2D: 93% with vs. 75% without expansion. Conclusion: Having healthcare coverage and access was associated with better glycemic control for young adults with T1D, but not T2D. Medicaid eligibility expansion was associated with having health insurance. Examining how healthcare access factors affect self-care differently in T1D and T2D is essential. Disclosure C. Pihoker: None. J. Divers: None. P. Zhang: None. D. M. Nathan: None. K. Drews: None. D. Dabelea: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Janssen Research & Development, LLC, Merck & Co., Inc. B. H. Braffett: None. T. Songer: Employee; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc. W. H. Herman: Advisory Panel; Spouse/Partner; Rhythm Pharmaceuticals, Inc., Consultant; Self; RTI International, Other Relationship; Self; American Diabetes Association, American Diabetes Association, American Diabetes Association, International Diabetes Federation, Merck Sharp & Dohme Corp., National Committee for Quality Assurance, National Institute of Diabetes and Digestive and Kidney Diseases, Special Government Employee, Research Support; Spouse/Partner; Nestle. M. Tung: None. S. Kuo: None. A. Bellatorre: None. E. M. Isganaitis: None. E. T. Jensen: None.

Glucose abnormalities exist in the prediabetic state well before a diagnosis of diabetes is made, and continuous glucose monitoring (CGM) is a sensitive method to detect these early abnormalities. Although insufficient data exist to support CGM for diagnosing diabetes, glucose patterns on CGM can provide insight into disease pathophysiology. Our group has used CGM to study early dysglycemia in several populations of youth at risk for diabetes—specifically, type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis–related diabetes (CFRD). We hypothesized that, in youth at risk for different types of diabetes matched by HbA1c, average sensor glucose would be no different, but specific CGM measures might differ among groups. For this analysis, we combined data from three groups of youth: 1 ) antibody-positive (Ab+) children from DAISY (Diabetes Autoimmunity Study in the Young) (1), 2 ) youth with cystic fibrosis (CF) from the Glycemic Monitoring in Cystic Fibrosis Study (NCT02211235, ClinicalTrials.gov), and 3 ) overweight/obese youth with BMI ≥85th percentile at risk for T2D (2). Inclusion criteria were ages 10–18 years and HbA1c

Context As many as 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic health is unknown. Objective To determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender females (CF) and males (CM). Design Pilot, cross-sectional study conducted from 2016–2018. Setting Academic regional transgender referral center. Participants Transgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI. Main Outcome Measures 1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry). Results Total body fat was lower in TM than CF mean ± SD: (29% ± 7% vs 33% ± 7%; P = 0.002) and higher than in CM (28% ± 7% vs 24% ± 9%; P = 0.047). TM had higher lean mass than CF (68% ± 7% vs 64% ± 7%, P = 0.002) and lower than CM (69% ± 7% vs 73% ± 8%; P = 0.029). Insulin sensitivity was not different between the groups. TF had lower body fat than CF (31% ± 7% vs 35% ± 8%; P = 0.033) and higher than CM (28% ± 6% vs 20% ± 10%; P = 0.001). TF had higher lean mass than CF (66% ± 6% vs 62% ± 7%; P = 0.032) and lower than CM (69% ± 5% vs 77% ± 9%; P = 0.001). TF were more insulin resistant than CM (0.078 ± 0.025 vs 0.142 ± 0.064 mL/μU; P = 0.011). Conclusions Transgender adolescents on GAHT have significant differences in body composition compared with cisgender controls, with a body composition intermediate between BMI-matched CMs and CFs. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents. ClinicalTrials.gov NCT02550431

OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin+rosiglitazone or metformin+lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At one-year post-insulin initiation, 253 youth had a mean of 3.9±1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change < 0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within one-year post-insulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c

Objective To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). Study design This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. Results Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. Conclusions Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Background To characterize glucose patterns with continuous glucose monitoring (CGM) in cystic fibrosis (CF) and assess relationships between CGM and clinical outcomes. Methods 110 CF youth and healthy controls (HC), 10–18 years, wore CGM up to 7 days. Correlations between CGM and lung function and BMI z-score change over the prior year were determined. Results Multiple CGM measures were higher in CF Normal Glycemic (CFNG) youth versus HC (peak glucose, excursions >140 mg/dl/day, %time > 140 mg/dl, standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)). Hypoglycemia was no different among groups. In CF, decline in FEV1% and FVC% correlated with maximum CGM glucose, excursions >200 mg/dl/day, SD, and MAGE. Conclusions CFNG youth have higher glucoses and glucose variability than HC on CGM. Higher and more variable glucoses correlate with lung function decline. Whether earlier treatment of CGM abnormalities improves lung function in CF requires further study.

OBJECTIVE Adult women with polycystic ovary syndrome (PCOS) and obesity have an 8-fold increased risk of developing type 2 diabetes (T2D). Our goal was to determine the incidence and risk factors for T2D in adolescents with PCOS and obesity. RESEARCH DESIGN AND METHODS Retrospective chart review of girls aged 11-21 years with confirmed PCOS (oligomenorrhea and hyperandrogenism) diagnosis between July 2013 and Aug 2018 and at least one follow-up visit and BMI >85%ile. T2D incidence, defined with an HbA1c ≥6.5%, was calculated. A nested case-control study with 1:3 matching by race, ethnicity, and BMI was performed to determine predictors of T2D diagnosis. RESULTS Four hundred ninety-three patients with PCOS (age 15.6 ± 1.9 years, BMI 36.2 ± 6.3 kg/m2 ) were identified with a follow-up of 1018 person-years. Twenty-three developed T2D (incidence 22.6/1000 person-years) with diagnosis a median of 1.8 years (2 months-5.5 years) after PCOS diagnosis. T2D risk was higher in girls with a prediabetes HbA1c (5.7%-6.4%) (HR 14.6 [4.8-44.5]) and among Hispanic girls with an elevated HbA1c and alanine aminotransferase (HR 19.0 [3.7-97.2]) at the time of PCOS diagnosis. In the 1:3 matched cohort, T2D risk was 18.7 times higher (OR 18.66 [2.27-153.24]) for every 0.1% increase in HbA1c at the time of PCOS diagnoses. CONCLUSIONS Girls with PCOS and obesity have an 18-fold increase in T2D incidence compared to published rates in non-PCOS youth. Hispanic girls with elevated HbA1c and ALT are at particular risk. Due to the morbidity associated with youth onset T2D, these findings argue for better screening and prevention approaches in this population.

Polycystic ovary syndrome (PCOS) is a common reproductive/metabolic condition associated with obesity, type 2 diabetes (T2D) and depression in adult women. Depression in adults is related to PCOS dermatologic manifestations. Adolescents with obesity with or without T2D have elevated depression symptoms, but data from youth with PCOS and obesity with/without T2D are limited.Our study included girls, aged 11 to 17 years, with obesity and PCOS, PCOS+T2D or T2D, who were newly seen in an obesity complications clinic after March 2016. All participants had Center for Epidemiologic Studies-Depression (CES-D, 20 items) scores obtained within 6 months of PCOS or T2D diagnosis. Data on history of psychiatric diagnosis and treatment, metabolic syndrome and severity of acne and hirsutism were collected through chart review.One hundred five girls (47 with PCOS, 14 with PCOS+T2D, 44 with T2D) had similar age (15±1.8 years) and body mass index z scores (2.2±0.4). CES-D scores ≥16, indicating elevated depression symptoms, and CES-D scores ≥24, indicating severe depression symptoms, were observed in 60% and 30% of girls with PCOS, 78% and 71% of those with PCOS+T2D and 39% and 21% of those with T2D, respectively (p0.0001 for both cutpoints). A higher CES-D score was not associated with severity of hirsutism or acne (p0.05 for both).Adolescents with PCOS and obesity have higher rates of elevated depression symptoms compared with girls with T2D, which is not related to worse dermatologic symptoms. Because depression may impact both PCOS and T2D management and adherence to therapy, greater efforts should be made to screen for and address mental health in adolescents with PCOS and obesity, especially if T2D is present.

In cross-sectional studies, adolescents with T2D show poorer cognition than normoglycemic youth. In the Restoring Insulin Secretion (RISE) Study, we assessed longitudinal relationships between insulin sensitivity, β-cell function and cognition in 72 youth (mean age 14.3±2.0, 10-18 y) with IGT or recently diagnosed T2D, randomized to 12 months of metformin (MET) or 3 months of glargine followed by 9 months of metformin (G/M). Hyperglycemic clamps were used to measure insulin sensitivity and β-cell responses: acute (0-10 min) C-peptide response to glucose, steady-state C-peptide (SSCP) at glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide response (ACPRmax) at glucose >25 mmol/L. A cognitive battery (CogStateTM and story recall) assessed 1) reaction time; 2) visual discrimination; 3) attention and working memory; and 4) learning and episodic memory. A composite measure of cognition was constructed by scaling the sum of the four domain scores. Linear regression models were fit to assess relationships between cognition, treatment and β-cell function. Treatment group models were adjusted for baseline cognitive function, HbA1c and fasting glucose. β-cell models were adjusted for baseline cognitive and β-cell function. Cognitive composite scores improved over the 12-month treatment period (p Disclosure S. Craft: Advisory Panel; Self; vTv Therapeutics. M. Tripputi: None. S. Edelstein: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. A. Claxton: Employee; Self; Alkermes plc. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Barengolts: None. T.S. Hannon: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. B. Mokhlesi: None. K.J. Nadeau: None. A. Sanderlin: None. K.A. Temple: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Merck & Co., Inc. T. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

Objective: ADA definitions of prediabetes are applied to children, yet little is known about the impact of the transient insulin resistance of puberty on glycemia. We aimed to evaluate the longitudinal trajectory of hemoglobin A1c (HbA1c) in youth with normal weight and with obesity as they progressed through puberty. Methods: Youth with normal weight (n=47, 49% female) or obesity (n=37, 62% female) of mixed race/ethnicity (Non-Hispanic White 34%, Hispanic 45%, Non-Hispanic Black 13%) entered the study in Tanner stage 2-3 (T2-3) and were followed until T5. Study visits were done at T2-3, T4, and T5 and included an IV glucose tolerance test, DXA, and fasting laboratory studies. HbA1c was measured by high-performance liquid chromatography and insulin sensitivity (Si), acute insulin response to glucose (AIRg), and disposition index (DI) were calculated. Group differences in HbA1c over time and time-dependent predictors of HbA1c were evaluated by mixed models, with and without adjusting for sex, race/ethnicity, and DXA %Fat. Results: Mean HbA1c was higher in youth with obesity (5.30±0.08%) vs. normal weight (5.10±0.06%, p=0.04) at baseline and each subsequent time point; differences were attenuated by adjusting for %Fat. HbA1c increased from T2/3 to T5 in the whole cohort (0.16±0.05%, p=0.004), and in youth with obesity (+0.18±0.08%, p=0.08), or normal weight (+0.14±0.05%, p=0.02); findings were similar after adjusting for sex, race/ethnicity, and %Fat. In a multivariate model adjusted for sex and race/ethnicity, HbA1c was associated with leptin (β=0.005, p=0.01) and adiponectin (β=-0.01p=0.02); these associations are similar after adjusting for %Fat. HbA1c was not associated with Si, AIRg or DI. Conclusions: Obesity is associated with higher HbA1c than normal weight during puberty. However, HbA1c increased during puberty, independent of body weight and composition. This increase in HbA1c is associated with changes in adipokines, but not with typical predictors of progression to diabetes (Si, DI). Disclosure M.M. Kelsey: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. A.M. Hilkin: None. C. Severn: None. L. Pyle: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Merck & Co., Inc. Funding American Diabetes Association (1-11-JF-23 to M.M.K.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD057022-04); University of Colorado Center for Women’s Health Research; Children’s Hospital Colorado Research Institute; National Institute for Diabetes and Digestive and Kidney Diseases (DK048520-13); National Center for Advancing Translational Sciences (UL1TR001082)

Background The RISE Pediatric Medication Study compared strategies for preserving β-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. Objective Evaluate OGTT measures of glucose and β-cell response through 12 months of intervention and 9 months of medication washout. Participants Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). Methods A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated β-cell response. Results At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in β-cell response. Conclusions G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and β-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.

BACKGROUND: Alternate methods for characterizing oral glucose tolerance tests (OGTT) have emerged as superior to the 2-hour glucose in identifying individuals at risk for type 2 diabetes. The significance of these methods in cystic fibrosis (CF) is unclear. We compared 3 OGTT classifications in youth with CF: 1. curve shape (biphasic vs. monophasic), 2. time to glucose peak (≤30minutes vs. >30minutes), 3. 1-hour glucose (1hG) 30minutes, and/or 1hG ≥155mg/dL). oDI was calculated [1/fasting insulin*(ΔInsulin(0–30min)/ΔGlucose(0–30min))]. Mean oDI, BMI, forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) were compared by OGTT classification. RESULTS: Fifty-two youth with CF participated (mean±SD age 13±4years; 37% male; BMI z-score 0.0±0.8; FEV1 88±16.3%; FVC 97±14.8%). Late time to peak glucose and 1hG ≥155mg/dL identified individuals with lower oDI (p=0.01); traditional OGTT criteria for prediabetes did not. No OGTT classification identified individuals with worse BMI nor pulmonary function. oDI was not associated with BMI, FEV1, or FVC. CONCLUSIONS: Alternate OGTT measures including time to peak glucose and 1hG better identify oDI abnormalities than traditional criteria. Further studies are required to determine whether these alternate methods identify individuals with CF at risk for future clinical decline.

Background Individual health behaviors (ie, eating habits and sedentary lifestyle) are associated with type 2 diabetes (T2D). Health behavior profiles specific to adolescents with T2D have not been described. Objective To identify health behavior profiles in adolescents with T2D and examine how these profiles change over time. Methods Diet (via food frequency questionnaire) and activity behaviors (via 3-day physical activity recall) examined at baseline, 6 months, and 24 months from participants in the the Treatment Options for T2D in Adolescents and Youth (TODAY) study were used for this analysis. Latent profile analysis identified profiles of health behaviors within three time points, and latent transition probabilities were estimated to examine the change from baseline to 6 months (n = 450) and baseline to 24 months (n = 415). Multinomial logistic regressions were used to examine if the assigned TODAY treatment group (Metformin [Met], Met + Rosiglitazone [Rosi], or Met + Lifestyle) predicted change in health behavior profiles. Results Three profiles emerged: "most sedentary," "healthy eaters," and "active and eat most." At 6 months, 50% of males and 29% of females in the Met + Lifestyle treatment group improved in their health behavior profile. Among males only, the Met + Lifestyle treatment group were more likely to improve their profiles from baseline to 6 months (P = .01). Conclusions Three health behavior profiles emerged and shifted over time. A high quality, lifestyle intervention had little effect on improving health behavior profiles. Optimizing outcomes in youth with T2D might require more robust and multifaceted interventions beyond family-level lifestyle, including more extensive psychosocial intervention, novel medication regimen, or bariatric surgery.

OBJECTIVE Pediatric type 2 diabetes prevalence is increasing, with β-cell dysfunction key in its pathogenesis. The RISE Pediatric Medication Study compared two approaches—glargine followed by metformin and metformin alone—in preserving or improving β-cell function in youth with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes during and after therapy withdrawal. RESEARCH DESIGN AND METHODS Ninety-one pubertal, overweight/obese 10–19-year-old youth with IGT (60%) or type 2 diabetes of RESULTS No significant differences were observed between treatment groups at baseline, 12 months, or 15 months in β-cell function, BMI percentile, HbA1c, fasting glucose, or oral glucose tolerance test 2-h glucose results. In both treatment groups, clamp-measured β-cell function was significantly lower at 12 and 15 months versus baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated. CONCLUSIONS In youth with IGT or recently diagnosed type 2 diabetes, neither 3 months of glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of β-cell function. Alternate approaches to preserve β-cell function in youth are needed.

Context Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown. Objective To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl). Design Double-blind, randomized, controlled trial. Setting Single tertiary care referral center. Participants Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12). Interventions Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years. Outcome Measures Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations. Results Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups. Conclusions Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.

OBJECTIVE In cystic fibrosis (CF), hemoglobin A1c (HbA1c) is thought to underestimate glycemia. However, few studies have directly assessed the relationship between HbA1c and average glucose in CF. We determined the relationships among glycemic markers—HbA1c, fructosamine (FA), glycated albumin (%GA), and 1,5-anhydroglucitol (1,5-AG)—and continuous glucose monitoring (CGM) in CF, hypothesizing that alternate markers would better predict average sensor glucose (ASG) than HbA1c. RESEARCH DESIGN AND METHODS CF participants and a group of healthy control subjects (HCs), ages 6–25 years, wore CGM for up to 7 days. Pearson correlations assessed the relationships between CGM variables and HbA1c, FA, %GA, and 1,5-AG. The regression line between HbA1c and ASG was compared in CF versus HC. Linear regressions determined whether alternate markers predicted ASG after adjustment for HbA1c. RESULTS CF (n = 93) and HC (n = 29) groups wore CGM for 5.2 ± 1 days. CF participants were 14 ± 3 years of age and 47% were male, with a BMI z score −0.1 ± 0.8 and no different from HCs in age, sex, or BMI. Mean HbA1c in CF was 5.7 ± 0.8% (39 ± 9 mmol/mol) vs. HC 5.1 ± 0.2% (32 ± 2 mmol/mol) (P < 0.0001). All glycemic markers correlated with ASG (P ≤ 0.01): HbA1c (r = 0.86), FA (r = 0.69), %GA (r = 0.83), and 1,5-AG (r = −0.26). The regression line between ASG and HbA1c did not differ in CF versus HC (P = 0.44). After adjustment for HbA1c, %GA continued to predict ASG (P = 0.0009) in CF. CONCLUSIONS HbA1c does not underestimate ASG in CF as previously assumed. No alternate glycemic marker correlated more strongly with ASG than HbA1c. %GA shows strong correlation with ASG and added to the prediction of ASG beyond HbA1c. However, we are not advocating use of HbA1c for diabetes screening in CF based on these results. Further study will determine whether glycemic measures other than ASG differ among different types of diabetes for a given HbA1c.

Swallowed topical steroids (STS) are the only effective pharmacological therapy for eosinophilic esophagitis (EoE). Thus far, studies of small populations of EoE patients have reported conflicting results in relation to adrenal insufficiency (AI). We sought to measure AI in a clinical setting in children taking STS for EoE. We performed a quality improvement study of pediatric EoE patients seen in a multidisciplinary clinic, who were treated with STS for at least 3 months. Two hundred twenty-five patients completed questionnaires to assess for signs of AI. All patients were requested to have fasting morning cortisol levels completed and if abnormal (

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in β-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.

A strong association exists between weight gain and the development of metabolic diseases, including hypertension, diabetes, and coronary artery disease, as well as increased mortality rates. It is also clear that weight loss can markedly improve insulin resistance (IR) and other markers of adverse health risks in obese individuals. Currently available treatments include diet, exercise, medications, and surgery. Pharmacotherapy for obesity is a treatment approach that has intermediate effectiveness and risk between behavioral therapy and surgery and has been advocated as a “mainstream” treatment option that should be discussed with patients.

Identifying features of obese dysglycemic youth that predict deterioration of glucose homeostasis is key to planning interventions and future management. In RISE, we evaluated β-cell responses by hyperglycemic clamp and 3-h oral glucose tolerance testing (OGTT), and glycemic progression in 91 obese 10-19 year old youth with impaired glucose tolerance (IGT, 60%) or recent-onset type 2 diabetes (T2D, 40%). Outcomes were measured at baseline (BAS) and following 12 months (M12) of treatment with metformin alone or glargine for 3 months followed by metformin for 9 months. Both treatment groups were then followed for an additional 9 months after treatment withdrawal (M21) to determine if the interventions preserved or improved β-cell function. Logistic regression models evaluated the predictive value of BAS characteristics on glycemic worsening in these youth. Evaluated features included: sex, race, BMI; HbA1c, fasting and 2-h OGTT glucose, OGTT glucose area under the curve (GAUC); T2D vs. IGT status; β-cell response measures from a hyperglycemic clamp (acute C-peptide response to glucose [ACPRg], steady-state C-peptide, maximal β-cell response [ACPRmax]); and OGTT C-peptide index (CPI, [ΔC-Peptide0-30/ΔGlucose0-30]). Glycemic worsening was defined as >10% increase in GAUC from BAS to M12 (on treatment, n=86) and M21 (9 months off treatment, n=82). Glycemic worsening was not different by randomized treatment or T2D vs. IGT status. No BAS factors predicted M12 on-treatment GAUC status. The odds ratio (OR) for worsening M21 off-treatment GAUC was 3.7 in black youth vs. other races (p=0.02). Per 1 SD, the odds of worsened M21 GAUC was higher with higher BAS fasting glucose (OR 1.7, p=0.03), 2-h glucose (OR 2.0, p=0.01), and GAUC (OR 2.0, p=0.01), and with lower CPGI (OR 0.5, p=0.03) and ACPRg (OR 0.6, p=0.06). In sum, black race, OGTT glycemic variables and early C-peptide responses to oral and intravenous glucose challenges predict responses to treatment withdrawal in youth with IGT and recent-onset T2D. Disclosure K.J. Nadeau: None. S. Edelstein: None. S.A. Arslanian: None. S. Caprio: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. D.A. Ehrmann: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. E. Leschek: None. M. Tripputi: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. R. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

The RISE Pediatric Medication Study showed, in 91 obese 10-19 yo youth with impaired glucose tolerance (IGT, 60%) or recent-onset type 2 diabetes (T2D, 40%), that 12 mo of intervention with metformin alone (M) or glargine for 3 mo followed by metformin for 9 mo (G+M) resulted in no change in BMI or HbA1c and a decline in β-cell function measured by hyperglycemic clamp. These outcomes worsened 3 mo after withdrawal of the interventions. We expand our findings to mo 21 (M21) post randomization (9 mo after withdrawal of M or G+M) using oral glucose tolerance test (OGTT) measures of β-cell responsiveness (C-peptide index, CPI; insulinogenic index, IGI; incremental C-peptide/glucose area under the curve), BMI and HbA1c. Paired t-tests were used to compare treatment groups on changes from baseline (BL, n=91) to mo 12 (M12, n=86) and M21 (n=82), and from treatment withdrawal at M12 to M21. At M12 vs. BL, no measures differed in either group (Table). At M21 vs. BL, HbA1c increased in both groups, and BMI increased and CPI and IGI declined in the G+M group. At M21 vs. M12, BMI, HbA1c, fasting and 2-h glucose increased in both groups, and CPI declined in the G+M group. Our findings contrast with studies in adults showing durable benefits of metformin and insulin on HbA1c and β-cell responsiveness. Further investigation is needed to find effective treatments that prevent progression of dysglycemia in youth with IGT or recent-onset T2D. Disclosure T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S. Edelstein: None. S.A. Arslanian: None. S. Caprio: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. D.A. Ehrmann: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. E. Leschek: None. M. Tripputi: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. K.J. Nadeau: None. R. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

Continuous glucose monitoring (CGM) is frequently used to assess glucose abnormalities in cystic fibrosis (CF) prior to frank diabetes, yet the biological significance of various CGM measures is unclear. Our aim is to identify CGM measures correlated with β-cell function decline in youth with CF. CGM and 2 hour oral glucose tolerance testing (OGTT) were collected in youth with CF and healthy controls (HC). Glucose and insulin were measured at baseline and 30 minutes on OGTT. Insulinogenic index [IGI=(insulin30-insulin0)/(Glucose30-Glucose0)] was used to estimate β-cell function. Eighty-one participants were included in the analysis [15 HC, 13 CF normal glucose tolerance (NGT), 41 CF abnormal glucose tolerance, and 12 CF related diabetes by OGTT]. There were no differences in age (13.6±3.5 years), sex, race, nor BMI z-score among groups. IGI was significantly lower in all CF groups, even CF NGT, compared to HC (p140 mg/dl, and glucose variability (SD and MAGE), but not measures of average nor low glucose, on CGM correlate with declines in β-cell function. Further studies are needed to determine whether these CGM measures predict clinical decline in CF. Disclosure C.L. Chan: None. T.B. Vigers: None. L. Pyle: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.J. Nadeau: None. Funding Cystic Fibrosis Foundation (CHAN16A0, CHAN16GE0); National Institutes of Health (DK094712-04)

Insulin resistance and impaired β-cell function are associated with risk of cognitive decline in adults over 65 y of age. Their impact on cognition in youth and adults 25 mmol/L. The cognitive battery (CogStateTM and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Linear regression models were fit to assess relationships between cognition and clamp measures by age group, adjusted for age, education (adults only), race, sex, and diabetes status. Models including β-cell responses were also adjusted for M/I to account for the role of insulin sensitivity to modulate β-cell function. M/I was not associated with cognitive outcomes for adults or children. For adults, reaction time was slower for participants with worse β-cell function assessed by ACPRg and ACPRmax (p Disclosure S. Craft: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Eli Lilly and Company. A. Claxton: Employee; Self; Alkermes. M. Tripputi: None. S. Edelstein: None. S.A. Arslanian: None. K.A. Temple: None. K.J. Nadeau: None. A. Sanderlin: None. M. Espeland: Research Support; Self; National Institutes of Health. Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals, Inc. B. Mokhlesi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. R. Consortium: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

MK-0431-P083, a 54-week phase III study of the DPP-4 inhibitor sitagliptin as initial oral therapy in patients 10-17 years of age with T2D was initiated in 2012 and completed enrollment in 2018. After informed consent was obtained, patient screening was initiated with a screening visit (V1), followed by a single-blind, placebo run-in (V2) for 1 week, after which they were randomized (V3, N = 201). The changes observed in select laboratory and anthropometric parameters in these 201 patients between V1 and V3 (~25 days), and adverse events (AEs) reported during the 1-week placebo run-in (V2 to V3), were summarized in a preliminary analysis. Results: (mean ± SD [95% confidence interval]) are presented below. Between V1 and V3 (25 ± 7 days, median 23 days), A1C decreased from 7.72 ± 1.02% to 7.49 ± 1.03%, a change (Δ) of -0.23 ± 0.67% [-0.32, -0.13], while FPG was unchanged. Changes were also observed in ALT (Δ: -2.55 ± 11.21 IU [-4.15, -0.95]) and AST (Δ: -1.93 ± 9.08 IU [-3.22, -0.63]). Weight and lipid parameters were unchanged. Between V2 and V3, 75 AEs were reported for 40 patients (~20% of the randomized patients). Of these AEs, 3 were assessed to be drug-related by the investigators: 2 AEs of nervousness and dyspepsia in 1 patient, and an AE of worsening gastroesophageal reflux in another. None of the 75 AEs were assessed to be severe, and none led to discontinuation from the study. These data suggest that changes may be observed in glycemic parameters during a screening period of Disclosure C.A. Rosario: None. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. R. Garcia: None. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. Y. Samoilova: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. A. Pong: None. M. Zilli: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. C.K. Saha: Research Support; Self; Indiana University School of Medicine. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. Funding Merck & Co., Inc.

Approved antihyperglycemic therapies for pediatric patients with T2D are currently limited to metformin (MET) and insulin. SITA is being evaluated in 3 studies in patients 10-17 years of age with T2D: SITA as initial oral therapy, MK-0431 P083; SITA as add-on to MET administered as a fixed dose combination (FDC), MK-0431A P170; and SITA as add-on to MET extended-release administered as a FDC of SITA and MET XR, MK-0431A XR P289. The studies, conducted to fulfill post-marketing requirements, and a Pediatric Investigation Plan (EU), were initiated between 2011 and 2013; enrollment completed in 2018. Study protocols were amended since initiation to accommodate regulatory agency requirements, reduce patient burden related to study conduct, and improve patient accrual. Major amendments to the protocols, their rationales, and their impacts are summarized (Table) and demonstrate the flexibility that may be required to enroll such studies. The impact on enrollment of 2 amendments common to all 3 studies were quantifiable. Of patients randomized after approval of an amendment that broadened the A1C entry criterion (from lower limit of 7.0% to 6.5%), ∼34% in P083, ∼20% in P170 and ∼20% in P289 had a baseline A1C between 6.5% and 6.9%. Of patients randomized after approval of an amendment to include patients on background insulin, 11% of patients in P083, 22% in P170, and 19% in P289 enrolled on background insulin. Disclosure R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. V.P. Pozharskaya: Employee; Self; Merck & Co., Inc. K. Leight: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. A. Deeb: None. R. Garcia: None. C.A. Rosario: None. C.K. Saha: Research Support; Self; Indiana University School of Medicine. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Y. Samoilova: None. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. Funding Merck & Co., Inc.

OBJECTIVE: Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers—hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)—as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG). METHODS: Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined. RESULTS: Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC’s for all alternate markers were low for CFPD (0.52–0.67) and CFRD (0.56–0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45–0.94) and 41% specificity (95% CI: 0.28–0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42–0.8). CONCLUSIONS: All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG.

By 2017 estimates, diabetes mellitus affects 425 million people globally; approximately 90–95% of these have type 2 diabetes. This narrative review highlights two domains of sex differences related to the burden of type 2 diabetes across the life span: sex differences in the prevalence and incidence of type 2 diabetes, and sex differences in the cardiovascular burden conferred by type 2 diabetes. In the presence of type 2 diabetes, the difference in the absolute rates of cardiovascular disease (CVD) between men and women lessens, albeit remaining higher in men. Large-scale observational studies suggest that type 2 diabetes confers 25–50% greater excess risk of incident CVD in women compared with men. Physiological and behavioural mechanisms that may underpin both the observed sex differences in the prevalence of type 2 diabetes and the associated cardiovascular burden are discussed in this review. Gender differences in social behavioural norms and disparities in provider-level treatment patterns are also highlighted, but not described in detail. We conclude by discussing research gaps in this area that are worthy of further investigation.

ContextUp to 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender affirming hormone therapy (GAHT) on cardiometabolic health is unknown.ObjectiveTo determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared to cisgender females (CF) and males (CM).DesignPilot, cross-sectional study conducted from 2016-2018.Setting. Academic regional transgender referral center.ParticipantsTransgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI.Main Outcome Measure(s)1/[fasting insulin] and body composition (dual-energy absorptiometry, DXA).ResultsTotal body fat was lower in TM than CF (29±7 vs. 33±7%, p=0.002) and higher than CM (28±7 vs. 24±9%, p=0.047). TM had higher lean mass than CF (68±7 vs. 64±7%, p=0.002) and lower than CM (69± vs. 73±8%, p=0.029). Insulin sensitivity was not different between the groups.TF had lower body fat than CF (31±7 vs. 35±8%, p=0.033) and higher than CM (28±6 vs. 20±10, p=0.001). TF had higher lean mass than CF (66±6 vs. 62±7%, p=0.032) and lower than CM (69±5 vs. 77±9%, p=0.001). TF were more insulin resistant than CM (0.078±0.025 vs. 0.142±0.064, p=0.011).ConclusionsTransgender adolescents on GAHT have significant differences in body composition compared to cisgender controls, with a body composition intermediate between BMI-matched cisgender males and females. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents.PrecisTransgender youth on gender affirming hormone therapy have differences in their percent fat and lean mass compared to cisgender (non-transgender) youth.

Background. The incidence of youth-onset type 2 diabetes in obese youth is tightly linked with the physiologic insulin resistance of puberty. The Health Influences of Puberty (HIP) Study was a placebo-controlled trial of metformin to test whether metformin mitigates the decrease in insulin sensitivity and β-cell function seen in obese youth during puberty. Methods. Obese (BMI ≥95%ile) non-diabetic youth (n=23) were randomized to metformin (n=11) or placebo (n=12) early in puberty (Tanner 2-3 [T2-3]) and treated until the end of puberty, Tanner 5 (T5) (mean treatment time 2.3+ 0.6 yrs). Exclusion criteria: pre-diabetes or diabetes, measured by oral glucose tolerance testing, obesity co-morbidities requiring medications, and medications affecting glucose metabolism. Study visits at baseline and treatment completion were performed following a 3-day energy-balanced diet and activity restriction and included intravenous glucose tolerance testing, fasting laboratory measures, anthropometrics, and body composition (DXA). Bergman’s minimal model was used to estimate insulin sensitivity (Si), insulin secretion (acute insulin response to glucose [AIRg]), and disposition index (DI). T-tests/chi-square were used to assess group differences in change (T5-T2/3) over time; linear regression models were used to adjust for sex, race/ethnicity, and baseline Tanner stage. Results: Baseline participant characteristics were: 65% female, 83% Hispanic, 70% T2, age 10.8+1.2 years, BMI z-score 2.3±0.35. There were no significant treatment group differences in baseline characteristics. Metformin treatment was associated with significant improvements in %body fat (-3.5±4.4 vs. 0.33±3.5%, p=0.04), and leptin (-4.1±13.7 vs. 18.2±17.7 ng/mL, p=0.003) and a smaller increase in waist circumference (2.21±10.32 vs. 14.1±7.87 cm, p=0.006). Metformin-associated improvement in BMI z-score was not statistically significant (-0.08±0.31 v. 0.15±0.13, p=0.20). There were no significant treatment group differences in insulin sensitivity or secretion; metformin vs. placebo: Si (0.26±3.2 v. -1.1±3.9x10-4/min-1/μIU/mL, p=0.37), AIRg (-397±1217 vs. -240±1151 μIU/mL, p=0.54), or DI (-1012±2326 vs. -1701±3261x10-4/min-1, p=0.56). Conclusions: Two years of metformin treatment during puberty in obese youth was associated with improvements in body fat and leptin. However, these improvements were not associated with improved insulin sensitivity or β-cell function. Larger studies are needed to better understand potential metabolic benefits of metformin treatment in obese youth during puberty, a critical window of metabolic change.

Context: Obesity is known to impact reproductive function in adults, but little is known about its effects on reproductive hormones during puberty or sex differences in these effects. Objective: To assess sex differences in effects of obesity on reproductive hormones and their relationship to insulin sensitivity and secretion. Design: Cross-sectional study including anthropometrics, serum and urine reproductive hormone concentrations, and intravenous glucose tolerance testing (IVGTT) to assess acute insulin response to glucose (AIRg) and insulin sensitivity (Si). Setting: Outpatient academic clinical research center. Patients: Fifty-one normal weight (NW, BMI-Z=-0.11 +/- 0.77, age=11.5 +/- 1.7 years) and 53 obese (BMI-Z=2.22 +/- 0.33, age=10.9 +/- 1.5 years) girls (n=54) and boys (n=50), Tanner stage 2-3. Results: Obese boys had lower total testosterone (p

Summary The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS) features. To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones [gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)], and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 pre-pubertal boys with KS age 4–12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. A total of 80% of this pre-pubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, LDL, and lower HDL (p

Dysglycemia in the cystic fibrosis (CF) population is widespread and screening via oral glucose tolerance tests (OGTT) can be burdensome. Our primary aim was to investigate 1,5-anhydroglucitol (1,5AG), fructosamine (FA), glycated albumin (%GA), and hemoglobin A1c (HbA1c) as screening tests for cystic fibrosis-related prediabetes (CFPD) and cystic fibrosis-related diabetes (CFRD) in youth with CF as defined by the OGTT 2-hour glucose (2hG). Our secondary aim was to determine if alternate screening tests can identify those with better or worse lung function (forced expiratory volume in 1 second, FEV1%; forced vital capacity, FVC%). Youth 10-18 years with CF had 1,5AG, FA, %GA, HbA1c, and a 2 hour OGTT collected during a single study visit. Pearson’s correlation coefficient determined the correlation between all 4 glycemic estimates and 2hG. Receiver Operative Characteristic (ROC) curves were generated. The Youden Index determined optimal cut points for predicting CFPD (2hG≥140-200 mg/dL) and CFRD (2hG≥200 mg/dL). Lung function measures above and below these cutpoints were compared. Fifty-eight youth with CF participated (2hG Disclosure K.L. Tommerdahl: None. J.T. Brinton: None. T.B. Vigers: None. K.J. Nadeau: None. P. Zeitler: Consultant; Self; Daiichi Sankyo Company, Limited, Merck & Co., Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Boehringer Ingelheim GmbH. C.L. Chan: None.

Objective To examine the prevalence of metabolic syndrome (MetS) in youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Prevalence of MetS (ATP III definition) was compared at baseline (n = 679) and at 6 (n = 625) and 24 months (n = 545) using chi-square tests. Laboratory data were examined between MetS classifications at each time point using ANOVA. Results Baseline prevalence of MetS was 75.8% and did not differ by treatment group or change over time. MetS was more common in females (83.1%) than males (62.3%; P

The optimal screening test for diabetes and prediabetes in obese youth is controversial.We examined whether glycosylated hemoglobin (HbA1c) or the oral glucose tolerance test (OGTT) is a better predictor of free-living glycemia as measured by continuous glucose monitoring (CGM).This was a cross-sectional study of youth 10-18 years old, body mass index (BMI) 85th percentile or greater, with diabetes risk factors.Participants (n = 118) with BMI 85th percentile or greater, not on medications for glucose management, were recruited from primary care and pediatric endocrinology clinics around Denver, Colorado.HbA1c, fasting plasma glucose, and 2-hour glucose were collected and all participants wore a blinded CGM for 72 hours.CGM outcomes were determined and descriptive statistics calculated. Performance characteristics at current American Diabetes Association cutpoints were compared with CGM outcomes.CGM data were successfully collected on 98 obese youth. Those with prediabetes had significantly higher average glucose, area under the curve (AUC), peak glucose, and time greater than 120 and greater than 140 mg/dL (P.01) on CGM than youth with normal HbA1c or OGTT. HbA1c had a greater magnitude of correlation to CGM average glucose, AUC, and minimum glucose; 2-hour glucose had a greater magnitude of correlation to CGM SD, peak glucose, and time greater than 140 and greater than 200 mg/dL. However, there were no overall differences in the strength comparisons between 2-hour glucose and HbA1c correlations to CGM outcomes.In obese youth, HbA1c and 2-hour glucose performed equally well at predicting free-living glycemia on CGM, suggesting that both are valid tests for dysglycemia screening.

Objective The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. Research design and methods Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. Main outcome measures Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. Results Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. Conclusions Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.