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Context Prenatal exposures, including undernutrition, overnutrition, and parental diabetes, are recognized risk factors for future cardiometabolic disease. There are currently no data on effects of parental diabetes on disease progression or complications in youth-onset type 2 diabetes (T2D). Objective We analyzed effects of parental diabetes history on glycemic outcomes, β-cell function, and complications in a US cohort of youth-onset T2D. Methods Participants (N = 699) aged 10 to 17 years with T2D were enrolled at 15 US centers and followed for up to 12 years as part of the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 follow-up studies. Information about diabetes diagnosis in biological mothers was available for 621 participants (never = 301; before or during pregnancy = 218; after pregnancy = 102) and in biological fathers for 519 (no diabetes = 352; paternal diabetes = 167). Results Maternal, but not paternal, diabetes was associated with loss of glycemic control over time, defined as glycated hemoglobin A1c greater than or equal to 8% for more than 6 months (P = .001). Similarly, maternal, but not paternal, diabetes was associated with increased risk of glomerular hyperfiltration (P = .01) and low heart rate variability (P = .006) after 12 years of follow-up. Effects were largely independent of age, sex, race/ethnicity, and household income. Maternal diabetes during vs after pregnancy had similar effects on outcomes. Conclusion Maternal diabetes, regardless of whether diagnosed during vs after pregnancy, is associated with worse glycemic control, glomerular hyperfiltration, and reduced heart rate variability in youth with T2D in TODAY. The strong associations of diabetes outcomes with maternal diabetes suggest a possible role for in utero programming.

Context Vertical sleeve gastrectomy (VSG) is an increasingly common tool to achieve weight loss and improve metabolic health in adolescents and young adults with obesity, although it may adversely affect bone health. Objective This work aimed to evaluate the effect of VSG on bone health in youth. Methods An observational 2-year study was conducted at a tertiary care center of 66 patients aged 13 to 24 years with moderate-to-severe obesity meeting criteria for VSG. The patients underwent VSG (n = 30) or nonsurgical (n = 36) management per the decision of patient and clinical team. Main outcome measures included dual-energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of bone mineral density (BMD), geometry, and microarchitecture. Results VSG patients achieved 25.3 ± 2.0% weight loss at 2 years (P < .001) while control subjects gained 4.0 ± 2.0% (P = .026). Total hip BMD declined 8.5 ± 1.0% following VSG compared with 0.1 ± 1.0% gain in controls (P < .001), with similar results at the femoral neck (P < .001). Total volumetric BMD (vBMD) decreased both at the distal radius and tibia following VSG (P < .001) driven primarily by trabecular vBMD loss (P < .001). Two-year changes in cortical vBMD did not differ between groups, though cortical porosity decreased following VSG both at the radius and tibia (P = .048 and P < .001). Cortical thickness increased in controls but not in VSG (P = .022 and P = .002 for between-group comparisons at the radius and tibia, respectively). Following VSG, estimated failure load decreased at the radius and did not demonstrate the physiologic increases at the tibia observed in controls. Conclusion VSG leads to progressive changes in bone health over 2 years, and may lead to increased skeletal fragility in adolescents and young adults.

Objective: To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes and to assess the impact of fasting glucose variability on the clinical course of type 2 diabetes. Research Design and Methods: 457 TODAY participants, mean age 14 years and diabetes duration Results: Higher baseline HbA1c concentration, lower beta-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with type 2 diabetes. Higher cumulative HbA1c concentration over 4 years and greater fasting glucose variability over a year’s time within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in fasting glucose at or above 8.3% predicted future loss of glycemic control and development of comorbidities. Conclusions: Higher baseline HbA1c concentration and fasting glucose variability during year 1 accurately predicted youth with type 2 diabetes who will experience metabolic decompensation and comorbidities and may be useful tools for clinicians when considering early intensification of therapy.

Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children. We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up. >All participants were normal weight at baseline (BMIZ −0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm2), VAT (2.0 [95% CI 0.1, 3.8] mm2), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD). Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia.

Globally, the proportion of new diagnoses of youth-onset diabetes represented by type 2 diabetes is increasing, and youth with type 2 diabetes commonly have complications and comorbidities, as well as a higher rate of mortality. In this review, we summarise what is known about the natural progression of youth-onset type 2 diabetes from published clinical trials and large-scale prospective epidemiological studies. It is important to note that the robust pathophysiological and treatment data specifically related to individuals with a diabetes onset at ≤20 years of age largely hails from the USA. Youth-onset type 2 diabetes is characterised by pathophysiological heterogeneity and inadequate glycaemic control, highlighting the need for new treatment approaches and innovative study designs in populations of varied genetic and cultural backgrounds.

Context Pediatric obesity is now recognized as a chronic disease; yet few treatment options exist besides lifestyle modification therapy and bariatric surgery. We describe the limited availability of United States Food and Drug Administration (FDA)–approved antiobesity medications for adolescents and compare this to what is available for adults. We offer a rationale for off-label prescribing to assist with lifestyle modification therapy. We also highlight the need for more pharmacotherapy options and additional research into novel treatments for pediatric obesity. Case Description We describe a patient who is struggling with managing her weight and starting to develop complications of obesity. We offer a framework in which off-label prescribing may be beneficial to patients who have been engaging in lifestyle modification therapy yet fail to see improvement. Conclusion Lifestyle modification therapy is necessary but often insufficient in stimulating clinically meaningful weight loss when used alone in children and adolescents who struggle with weight management. Until more FDA-approved antiobesity medications are available, pediatricians may be able to help more patients achieve weight reduction goals by familiarizing themselves with the responsible use of off-label medications and implementing these tools to improve clinical outcomes. There is a critical need for more pharmacotherapy options to help pediatric patients in managing their weight and preventing or improving the insidious complications resulting from untreated obesity.

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.

This analysis compared microvascular and cardiac outcomes from women in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, originally diagnosed with youth-onset Type 2 diabetes between the ages of 10-17 yrs, who experienced a pregnancy lasting 20 wks during the course of the study vs. those without. Pregnancy information was obtained prospectively by self-report followed by medical record review. Neuropathy and nephropathy were assessed annually. Retinopathy, echocardiography, and arterial stiffness were assessed twice during the study. Women with a history of pregnancy prior to the initial assessment were excluded. Of the 4women in TODAY, 116 reported a pregnancy lasting ≥ 20 weeks, with 67 having a single pregnancy and 49 with multiple pregnancies. The mean age at first pregnancy was 21.6 yrs. and mean diabetes duration 8 yrs. At study entry, women who reported a pregnancy during the trial were older (14 yrs. vs. 13.6 yrs., p=0.05) with lower household income (51.5% vs. 37.8% below $25,000, p=0.002) . Primary study outcome, defined as HbA1c >8% or inability to wean from insulin, was similar between the two groups. In Cox regression models adjusted for participant characteristics from study entry including age, race/ethnicity, household income, diabetes duration, HbA1c (>6%) , and BMI, women with a pregnancy had an increased risk of hyperfiltration, 2.76 (1.38-5.49) , p=0.0vs. those without a pregnancy. No differences were observed in rates of retinopathy, neuropathy, or macro- and microalbuminuria in women with vs. without a history of pregnancy. In fully adjusted models, history of pregnancy did not impact echocardiographic measures or arterial stiffness obtained prior to the reported pregnancy versus the measures after the pregnancy. These results suggest that pregnancy increases the risk of hyperfiltration in women with youth-onset T2D, but not other micro or macrovascular complications. Disclosure J.B.Tryggestad: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Chernausek: None. K.Drews: None. E.N.Escaname: None. M.Geffner: Advisory Panel; Novo Nordisk, Pfizer Inc., Research Support; Novo Nordisk. E.M.Isganaitis: Research Support; AstraZeneca, Dexcom, Inc., Insulet Corporation. Funding U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254

To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years.Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups.A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic.The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10−8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10−20; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10−14; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10−12; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10−11; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10−9; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10−8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10−8; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 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.

BACKGROUND: A standardized approach for identifying and treating hypothalamic obesity (HO) in children with hypothalamic tumours is lacking. OBJECTIVES: To describe children with hypothalamic tumours at risk for obesity, assess outcomes of a novel HO clinical algorithm, and identify factors associated with weight gain. METHODS: Retrospective analysis of youth with hypothalamic and suprasellar tumours, seen at a paediatric tertiary care centre from 2010 to 2020. RESULTS: The study cohort (n = 130, 50% female, median age at diagnosis 5 [range 0–17]y) had a median duration of follow up of 5 (0.03–17)y. At last recorded body mass index (BMI) measurement, 34% had obesity, including 17% with severe obesity. Median onset of overweight and obesity after diagnosis was 6.2 (0.3–134) and 8.9 (0.7–65) months, respectively. After algorithm implementation (n = 13), the proportion that had an early dietitian visit (within 6 months) increased from 36% to 54%, (p = 0.498) and weight management referrals increased from 51% to 83% (p = 0.286). Higher BMI z-score at diagnosis was associated with overweight and obesity development (p < 0.001). CONCLUSION: Patients with hypothalamic tumours commonly develop obesity. Use of a clinical algorithm may expedite recognition of HO. Further research is needed to identify predictors of weight gain and to develop effective treatment.

Objective: To assess pregnancy outcomes in young women with youth-onset type 2 diabetes followed in the TODAY study. Research Design and Methods: Pregnancy information (outcome, any maternal or fetal complications) was obtained from the female participants by self-report. Additionally, medical records for the pregnancy and the child’s neonatal course were obtained with data abstracted into standardized forms. Results: Over a maximum of 15 years, 260 pregnancies were reported by 141 women (age 21.5 years ± 3.2 years, BMI 35.6 ± 7.2 kg/m2, diabetes duration 8.1 ± 3.2 years). Contraception use prior to pregnancy reported by 13.5% of the women. Complications were reported by 65% of the women during their pregnancy. Pregnancy loss was observed in 25.3% and preterm birth in 32.6% of pregnancies. HbA1c ≥ 8% was observed in 31.9% of the pregnancies and 35% of the pregnancies were complicated by chronic hypertension. Nephropathy prior to pregnancy was observed in 25% of the women. In the offspring, 7.8% were classified as small for gestational age, 26.8% large for gestational age, and 17.9% in the macrosomic range. Conclusion: Based on observations from the TODAY cohort, young women with pre-gestational, youth-onset type 2 diabetes had very high rates of maternal complications stemming from significant socioeconomic disadvantage. The substantial maternal and infant complications seen in these young moms could potentially be avoided with improved contraception rates and reproductive planning.

Context Polycystic ovary syndrome (PCOS) is common and diagnosis requires an elevated testosterone. The clinical importance of adrenal 11-oxyandrogens in PCOS is unclear. Objective We sought to determine if 11-oxyandrogens 1) better identify PCOS diagnosis compared to testosterone, 2) predict clinical comorbidities of PCOS, and 3) are altered with an combined oral contraceptive pill (COCP) or metformin therapy. Methods Data from 200 adolescent female participants aged 12 to 21 years, most with obesity, enrolled across 6 studies in pediatric endocrinology were included: 70 non-PCOS controls, 115 untreated PCOS, 9 PCOS + obesity treated with COCP, and 6 PCOS + obesity treated with metformin. 11-Hydroxyandrostenedione (11-OHA4), 11-hydroxytestosterone (1-OHT), 11-ketotestosterone (11-KT), and testosterone were measured with liquid chromatography–tandem mass spectrometry. Data between 1) untreated PCOS and controls and 2) untreated PCOS and the 2 treatment groups were compared. Results Untreated girls with PCOS had higher 11-OHA4 (P = .003) and 11-OHT (P = .005) compared to controls, but not 11-KT (P = .745). Elevated 11-OHA4 remained statistically significant after controlling for obesity. Testosterone better predicted PCOS status compared to 11-oxyandrogens (receiver operating characteristic curve analysis: 11-OHA4 area under the curve [AUC] = 0.620, 11-OHT AUC = 0.638; testosterone AUC = 0.840). Among untreated PCOS patients, all 3 11-oxyandrogens correlated with hirsutism severity. 11-KT (P = .039) and testosterone (P Conclusion Although 11-oxyandrogens do not aid in the diagnosis of PCOS, they relate to excess hair growth. COCP treatment may related to 11-KT; however, further work is needed to determine causality, relationship with metabolic outcomes, and the clinical utility of measuring these androgens in PCOS.

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

IntroductionThe pathophysiology of type 2 diabetes (T2D) in youth differs from adults and conventional medical treatment approaches with lifestyle change, metformin, thiazolidinediones or insulin are inadequate. Metabolic bariatric surgery (MBS) improves multiple health outcomes in adults with T2D. Initial small, uncontrolled studies of Roux-en-Y gastric bypass have also suggested beneficial effects in adolescents. Definitive studies in youth with T2D are lacking, especially with the now more common form of MBS, vertical sleeve gastrectomy (VSG). The surgical or medical treatment for paediatric type 2 diabetes (ST2OMP) clinical trial was designed to test the hypothesis that VSG will more effectively reduce hyperglycaemic and diabetes comorbidities than the best currently available medical treatment incorporating state of the art pharmacotherapies. ST2OMP is also designed to better understand the pancreatic and enterohepatic mechanisms by which MBS improves diabetes and its associated comorbidities.Methods and analysisST2OMP is a prospective, open-label, controlled clinical trial that will recruit 90 postpubertal participants, age range 13–19.9 years, with body mass index ≥35 kg/m2or >120% of 95th percentile and youth-onset T2D. The primary outcome is the per cent of youth achieving haemoglobin A1c Ethics and disseminationThe ST2OMP protocol was approved by the Cincinnati Children’s Hospital Medical Center and the University of Colorado Institutional Review Boards. Written informed consent is obtained prior to study enrolment. Study findings will be widely disseminated through peer-reviewed publications and conference presentations.Trial registration numberClinical Trials.GovNCT04128995.

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.

American Diabetes Association adult criteria are used to screen youth for diabetes, but little is known about normal glycemia in youth. In the HEALTHY Study (total n = 8814), hemoglobin A1c was ≥5.7% in 2% of normal weight youth. This suggests need for cautious interpretation of prediabetes hemoglobin A1s in youth.

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies.

OBJECTIVE To compare diabetic kidney disease (DKD) rates over 5 years of follow-up in two cohorts of severely obese adolescents with type 2 diabetes (T2D) undergoing medical or surgical treatment for T2D. RESEARCH DESIGN AND METHODS A secondary analysis was performed of data collected from obese participants of similar age and racial distribution enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) studies. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. Glycemic control, BMI, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and prevalence of hyperfiltration (eGFR ≥135 mL/min/1.73 m2) and elevated UAE (≥30 mg/g) were assessed annually. RESULTS Participants with T2D from Teen-LABS (n = 30, mean ± SD age, 16.9 ± 1.3 years; 70% female; 60% white; BMI 54.4 ± 9.5 kg/m2) and TODAY (n = 63, age 15.3 ± 1.3 years; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. During 5 years of follow-up, hyperfiltration decreased from 21% to 18% in Teen-LABS and increased from 7% to 48% in TODAY. Elevated UAE decreased from 27% to 5% in Teen-LABS and increased from 21% to 43% in TODAY. Adjusting for baseline age, sex, BMI, and HbA1c, TODAY participants had a greater odds of hyperfiltration (odds ratio 15.7 [95% CI 2.6, 94.3]) and elevated UAE (27.3 [4.9, 149.9]) at 5 years of follow-up. CONCLUSIONS Compared with MBS, medical treatment of obese youth with T2D was associated with a higher odds of DKD over 5 years.

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 This report estimates the percent of medically eligible adolescents who are referred for metabolic and bariatric surgery (MBS) evaluation or factors associated with referral. Methods This cross-sectional retrospective review evaluated patients aged 13 to 18 years seen between 2017 and 2019 for demographics, insurance status, body mass index (BMI), obesity-related comorbidities, and compared these data to patients whom had been referred and received MBS. Results Half of the patients (86 411/163137, 53%) between ages of 13 and 18 years identified had BMI documented, of which, 1974 (2.3%) were medically eligible for MBS, 238 (12%) were referred for MBS and 52 (22%) underwent MBS. Females had similar odds of being eligible for MBS [odds ratio (OR) = 1.01, 95% confidence interval (CI) 0.92-1.11, P = .9], but greater odds of referral (OR = 1.58, 95% CI 1.13-2.23, P = .009). Independently, miniorities and patients with public insurance had higher odds of being eligible for MBS, but similar odds of being referred as non-Hispanic white patients. Black patients with public insurance had greater odds of being referred for MBS (OR = 12.22, 95% CI 2.08-235.15, P = .022). Patients' multiple comorbidities had greater odds of being referred for MBS (OR = 2.16, 95% CI 1.29-3.68, P = .004). Conclusions Referral is barrier for patients medically eligible for MBS; however, this barrier is not uniformly faced by all patients.

We explored the longitudinal sequence of metabolic changes linking overnutrition in utero to development of adiposity among initially normal weight children in the EPOCH cohort. This study includes 312 normal weight youth (body mass index [BMI] z Disclosure W. Perng: None. M. M. Kelsey: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. K. A. Sauder: None. D. Dabelea: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068001); Colorado Clinical and Translational Sciences Institute (KL2-TR002534 to W.P.)

Background: Prenatal exposures, including parental nutrition and diabetes (DM) status, are increasingly viewed as risk factors for future cardiometabolic health. There are currently no data on effects of parental DM on disease progression or complications in youth-onset T2D. Aims: To analyze effects of parental history of DM on glycemic outcomes and complications in the TODAY study. Methods: Participants (n=699) aged 10-14 yr with newly diagnosed T2D were enrolled at 14 U.S. centers and followed for up to 15 yr. Subjects had negative islet autoantibodies and BMI >= 85th %. Information about DM diagnosis in mothers of participants was available for 621 participants [Never (MN) =301; During pregnancy (MD) =218; After pregnancy (MA)=102)] and in biological fathers in 519 (No DM=352; Paternal DM=167). Results: Maternal, but not paternal, DM was associated with accelerated loss of glycemic control, defined as HbA1c >8% for over 6 months (p < 0.0001). Participants whose mothers had diabetes had 60% higher risk of loss of glycemic control [MD vs. MN hazard ratio (HR): 1.58 (1.28, 1.95), p < 0.0001; MA vs. MN HR: 1.57 (1.20, 2.04), p = 0.0009]. Similarly, maternal, but not paternal, diabetes was associated with glomerular hyperfiltration [MD vs. MN HR: 1.58 (1.18-2.1), p = 0.0021; MA vs. MN HR: 1.56 (1.08, 2.24), p = 0.0170;], diabetic retinopathy (MD: 50.0%; MA: 59.7%; MN: 41.8%, p=0.0439), and pulse wave velocity indices reflecting heart rate variability, including SD of normal R-R interval [(SDNN), MD: 42 ± 26 ms; MA: 41 ± 26 ms; MN: 54 ± 31 ms; p = 0.0005] and proportion of successive NN intervals greater than 50 ms [(pNN50%), MD: 14.1 ± 19.4; MA: 16.2 ± 21.5; MN: 21.9 ± 23.5; p = 0.0069], after 10 to 15 yr of follow-up. Associations were maintained after adjusting for multiple confounders. Conclusions: Maternal, but not paternal, diabetes is associated with adverse diabetes outcomes and accelerated onset of complications in their offspring with T2D in TODAY. Disclosure E. M. Isganaitis: None. M. A. Van name: None. R. Shah: None. S. Chernausek: None. R. M. Farrell: Stock/Shareholder; Self; Tandem Diabetes Care. M. Geffner: Advisory Panel; Self; Daiichi Sankyo, Novo Nordisk, Pfizer Inc., Consultant; Self; Gilead Sciences, Inc., Other Relationship; Self; Ascendis Pharma A/S, McGraw-Hill, UpToDate, Research Support; Self; Novo Nordisk. J. Keady: None. M. M. Kelsey: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. B. Tesfaldet: None. J. B. Tryggestad: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254)

Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children.We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/mAll participants were normal weight at baseline (BMIZ -0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mmOvernutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia.

OBJECTIVES: In this report, we compare weight loss, comorbidity resolution, nutritional abnormalities, and quality of life between younger and older adolescents after metabolic and bariatric surgery. METHODS: From March 2007 to December 2011, 242 adolescents (≤19 years of age) who underwent bariatric surgery at 5 clinical centers in the United States were enrolled in the prospective, multicenter, long-term outcome study Teen–Longitudinal Assessment of Bariatric Surgery. Outcome data from younger (13–15 years; n = 66) and older (16–19 years; n = 162) study participants were compared. Outcomes included percent BMI change, comorbidity outcomes (hypertension, dyslipidemia, and type 2 diabetes mellitus), nutritional abnormalities, and quality of life over 5 years post surgery. RESULTS: Baseline characteristics, except for age, between the 2 cohorts were similar. No significant differences in frequency of remission of hypertension (P = .84) or dyslipidemia (P = .74) were observed between age groups. Remission of type 2 diabetes mellitus was high in both groups, although statistically higher in older adolescents (relative risk 0.86; P = .046). Weight loss and quality of life were similar in the 2 age groups. Younger adolescents were less likely to develop elevated transferrin (prevalence ratio 0.52; P = .048) and low vitamin D levels (prevalence ratio 0.8; P = .034). CONCLUSIONS: The differences in outcome of metabolic and bariatric surgery between younger and older adolescents were few. These data suggest that younger adolescents with severe obesity should not be denied consideration for surgical therapy on the basis of age alone and that providers should consider adolescents of all ages for surgical therapy for obesity when clinically indicated.

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.

Context Polycystic ovary syndrome (PCOS) is common and associated with metabolic syndrome. In the general population, metabolic disease varies by race and ethnicity. Objective This work aimed to examine in depth the interaction of race and ethnicity with PCOS-related metabolic disease in adolescent youth. Methods A secondary analysis was conducted of data from girls (age 12-21 years) with overweight or obesity (> 90 body mass index [BMI] percentile) and PCOS. Measurements included fasting hormone and metabolic measures, a 2-hour oral glucose tolerance test (OGTT), and magnetic resonance imaging for hepatic fat. Groups were categorized by race or ethnicity. Results Participants included 39 non-Hispanic White (NHW, age 15.7 ± 0.2 years; BMI 97.7 ± 0.2 percentile), 50 Hispanic (HW, 15.2 ± 0.3 years; 97.9 ± 0.3 percentile), and 12 non-Hispanic Black (NHB, 16.0 ± 0.6 years; 98.6 ± 0.4 percentile) adolescents. Hepatic markers of insulin resistance were worse in NHW, including lower sex hormone–binding globulin and higher triglycerides over high-density lipoprotein cholesterol (TGs/HDL-C) ratio (P = .002 overall, HW vs NHB [P = .009] vs NHW [P = 0.020]), although homeostasis model assessment of estimated insulin resistance was worst in NHB (P = .010 overall, NHW vs NHB P = .014). Fasting and 2-hour OGTT glucose were not different between groups, although glycated hemoglobin A1c (HbA1c) was lowest in NHW (overall P Conclusion Adolescents with PCOS appear to show similar racial and ethnic variation to the general population in terms of metabolic disease components.

Objective Hepatic steatosis (HS) is common in adolescents with obesity and polycystic ovary syndrome (PCOS). Gut microbiota are altered in adults with obesity, HS, and PCOS, which may worsen metabolic outcomes, but similar data is lacking in youth. Methods Thirty-four adolescents with PCOS and obesity underwent stool and fasting blood collection, oral glucose tolerance testing, and MRI for hepatic fat fraction (HFF). Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing. Results 50% had HS (N = 17, age 16.2±1.5 years, BMI 38±7 kg/m2, HFF 9.8[6.5, 20.7]%) and 50% did not (N = 17, age 15.8±2.2 years, BMI 35±4 kg/m2, HFF 3.8[2.6, 4.4]%). The groups showed no difference in bacterial α-diversity (richness p = 0.202; evenness p = 0.087; and diversity p = 0.069) or global difference in microbiota (β-diversity). Those with HS had lower % relative abundance (%RA) of Bacteroidetes (p = 0.013), Bacteroidaceae (p = 0.009), Porphyromonadaceae (p = 0.011), and Ruminococcaceae (p = 0.008), and higher Firmicutes:Bacteroidetes (F:B) ratio (47.8% vs. 4.3%, p = 0.018) and Streptococcaceae (p = 0.034). Bacterial taxa including phyla F:B ratio, Bacteroidetes, and family Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae correlated with metabolic markers. Conclusions Obese adolescents with PCOS and HS have differences in composition of gut microbiota, which correlate with metabolic markers, suggesting a modifying role of gut microbiota in HS and PCOS.

Globally, the proportion of new diagnoses of youth-onset diabetes represented by type 2 diabetes is increasing, and youth with type 2 diabetes commonly have complications and comorbidities, as well as a higher rate of mortality. In this review, we summarise what is known about the natural progression of youth-onset type 2 diabetes from published clinical trials and large-scale prospective epidemiological studies. It is important to note that the robust pathophysiological and treatment data specifically related to individuals with a diabetes onset at ≤20 years of age largely hails from the USA. Youth-onset type 2 diabetes is characterised by pathophysiological heterogeneity and inadequate glycaemic control, highlighting the need for new treatment approaches and innovative study designs in populations of varied genetic and cultural backgrounds.

Clinical providers may underestimate the role of management of diseases that can occur with obesity, termed co-morbid conditions, distinct from disease that arise as a result of obesity, co-morbidities. Many of these conditions are associated with iatrogenic weight gain, and can interfere with weight loss outcomes in children and adolescents with obesity. Management of co-morbid conditions, and thoughtful selection of medications associated with weight neutrality or weight loss may increase the effectiveness of obesity treatment strategies. The aim of this commentary is to summarize the literature and discuss considerations for obesity treatment in the context of the more complicated patient, which often requires strategic management of co-morbid conditions and minimizing iatrogenic weight gain.

Context Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. Objective This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. Design and Setting A multi-institutional case series is presented from tertiary pediatric oncology centers. Patients Patients included children with pituitary blastoma. Interventions Genetic testing, surgery, oncologic therapy, endocrine support are reported. Outcome Measures Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. Results Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. Conclusions Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Our objective was to explore the longitudinal trajectory of hemoglobin A1c (HbA1c) in well-characterized youth (n = 84) with normal weight and obesity during puberty. HbA1c rose from early puberty to Tanner stage 5, even in healthy, normal weight youth, revealing important implications for defining normal glycemia and prediabetes in adolescents.

Background Cardiovascular disease (CVD) remains the leading cause of mortality in type 2 diabetes (T2D). Better interventions are needed to mitigate the high lifetime risk for CVD in youth T2D. Objective To compare 30-year risk for CVD events in 2 cohorts of adolescents with T2D and severe obesity undergoing medical or surgical treatment of T2D. Setting Longitudinal multicenter studies at University hospitals. Methods A secondary analysis of data collected from the participants with T2D enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 30) and participants of similar age and racial distribution from the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY, n = 63) studies was performed. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. A 30-year CVD event score developed by the Framingham Heart Study was the primary outcome, assessed at baseline (preoperatively for Teen-LABS), 1 year, and 5 years of follow-up. Results Participants with T2D from Teen-LABS (n = 30; mean ± SD age = 16.9 ± 1.3 yr; 70% female; 60% white; body mass index (BMI) = 54.4 ± 9.5 kg/m2) and TODAY (n = 63; 15.3 ± 1.3 yr; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. The likelihood of CVD events was higher in Teen-LABS versus TODAY at baseline (17.66 [1.59] versus 12.11 [.79]%, adjusted P = .002). One year after MBS, event risk was significantly lower in Teen-LABS versus TODAY (6.79 [1.33] versus 13.64 [0.96]%, adjusted P Conclusion Despite higher pretreatment risk for CVD events, treatment with MBS resulted in a reduction in estimated CVD event risks, whereas medical therapy associated with an increase in risk among adolescents with T2D and severe obesity.

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.

Background As severe obesity continues to rise among youth, metabolic and bariatric surgery (MBS) will increasingly be used as a treatment of choice for durable weight loss and improvement of obesity-related complications. MBS for youth with intellectual and developmental disabilities (IDD) and for preadolescents has raised ethical questions. Objectives The purpose of this article is to present the creation and application of an ethical framework that supports why MBS should be considered in pediatrics based on the principle of justice without automatic exclusions. This framework also provides a guide for how to conduct a robust, ethically grounded evaluation of pediatric patients presenting for MBS in general, and among subpopulations including youth with IDD and preadolescents. Setting Academic medical center, United States. Methods An ethical framework was developed and applied through a collaboration between an MBS center at a children’s hospital and the institution’s ethics consult service. Results Application of the ethical framework to address 4 core ethical questions is illustrated using 2 hypothetical cases: 1 that highlights an adolescent with IDD and 1 that highlights a preadolescent. Conclusions We have demonstrated the application of a novel, overarching framework to conduct the ethical evaluation of youth presenting for MBS. This framework resulted from a collaboration between MBS and ethics consult teams and has the potential to be used as a prototype for other youth-focused MBS programs. Next steps include prospective data collection to test the framework and determine its validity in the target population.

Objective: Traumatic events, including abuse, neglect, and other dangerous/shocking experiences, are commonly observed in adolescents with T2D. Research has shown there is a link between trauma and poorer health outcomes, yet, the extent to which trauma increases risk for developing T2D is not well understood. Trauma may heighten T2D risk through LOC eating, which can arise to cope with negative emotions. Our aim was to evaluate the links of trauma and LOC eating with T2D risk in adolescent girls with obesity. Methods: Participants (n=65, mean±SD 15.2±1.6y) were girls at-risk for T2D based on BMI ≥85%ile, ≥1 family member with T2D, and elevated depression (Center for Epidemiologic Studies Depression [CES-D] score ≥21). Trauma history (presence vs. absence) was assessed with the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, and LOC eating (presence vs. absence) with the Eating Disorder Examination. T2D risk was assessed as HbA1c and Matsuda Whole Body Insulin Sensitivity Index (WBISI), derived from a 7-sample 2-hr OGTT. ANCOVA tested differences in HbA1c and WBISI by trauma and LOC, controlling for age, BMIz, race/ethnicity, and depression. Results: Trauma history was endorsed in 40.6% and LOC eating in 36.4% of girls. Girls with and without a trauma history reported similar rates of LOC (36.4% vs. 37.5%, p=.93). Girls with trauma had higher HbA1c (5.7±0.06%) vs. those with no trauma (5.5±0.05%, p=0.04), with no difference in WBISI (p=0.32). Girls with LOC had worse WBISI vs. those with no LOC (3.0±0.53 vs. 4.8±0.40, p Conclusions: Trauma history and LOC eating were unrelated to each other, but each related to different aspects of elevated T2D risk. Attention to both factors may warrant consideration in intervening to lessen T2D risk in teens with obesity and elevated depression. Disclosure V. Jimenez: None. A.M. Hilkin: None. M.M. Verros: None. E.L. Clark: None. M. Casamassima: None. R.L. Miller: None. L. Pyle: None. M.M. Kelsey: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. L.B. Shomaker: None.

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: Sleeve gastrectomy is the most commonly performed weight loss surgery in adolescents with moderate-to-severe obesity. While studies in adults have reported on the deleterious effects of gastric bypass surgery on bone structure and strength estimates, data are lacking for the impact of sleeve gastrectomy on these measures in adolescents. Objective: To evaluate the impact of sleeve gastrectomy on bone outcomes in adolescents and young adults over 12 months using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT). Participants and Methods: We enrolled 33 youth 14-22 years old with moderate to severe obesity; 17 underwent sleeve gastrectomy and 16 were followed without surgery. DXA was used to assess areal bone mineral density (aBMD). HRpQCT was used to assess bone geometry, microarchitecture and volumetric BMD (vBMD) and finite element analysis to assess strength estimates (stiffness and failure load) at the distal tibia and distal radius at baseline and 12 months. 25(OH) vitamin D (25OHD) levels were obtained at baseline and follow-up. Results: The surgical group lost 28.2% of total body weight compared to 1.4% in the non-surgical group. The groups did not differ for changes in 25OHD levels (P=0.181). After controlling for age and sex, compared to the non-surgical group, the surgical group had reductions in aBMD Z-scores at the femoral neck and total hip (p≤ 0.0005). At the distal tibia, there were reductions in cortical thickness and trabecular number, and increases in trabecular separation and cortical vBMD, without changes in strength estimates in the surgical group vs. controls (p≤0.043). Changes were less marked at the distal radius. While sleeve gastrectomy resulted in deleterious effects on most bone parameters, there was an increase in cortical vBMD at both sites, possibly from a decrease in cortical porosity. Most differences were attenuated after adjusting for changes in BMI over 12 months. Conclusions: Over 12 months, weight loss associated with sleeve gastrectomy in adolescents had deleterious effects on areal BMD, bone geometry and trabecular microarchitecture at weight-bearing sites. However, strength estimates did not decrease, possibly because of a simultaneous increase in cortical volumetric BMD. Additional research is necessary to determine the relative contribution(s) of weight loss and the metabolic effects of surgery, and whether the observed effects on bone stabilize or progress over time.