Diagnostic Accuracy of Transient Elastography in Hepatosteatosis in Youth With Obesity.

Context: Steatotic liver disease is common but overlooked in childhood obesity; diagnostic methods are invasive or expensive. Objective: We sought to determine the diagnostic accuracy of vibration-controlled transient elastography (VCTE) compared with magnetic resonance imaging (MRI) in adolescents with obesity and high risk for hepatosteatosis. Methods: Baseline data in 3 clinical trials enrolling adolescents with obesity were included (NCT03919929, NCT03717935, NCT04342390). Liver fat was assessed using MRI fat fraction and VCTE-based controlled attenuation parameter (CAP). Hepatosteatosis was defined as MRI fat fraction ≥5.0%. The area under the receiver-operating characteristic curves (AUROCs) for CAP against MRI was calculated, and optimal CAP using the Youden index for hepatosteatosis diagnosis was determined. Results: Data from 82 adolescents (age 15.6 ± 1.4 years, body mass index 36.5 ± 5.9 kg/m2, 81% female) were included. Fifty youth had hepatosteatosis by MRI (fat fraction 9.3% ; 95% CI 6.7, 14.0), and 32 participants did not have hepatosteatosis (fat fraction 3.1%; 95% CI 2.2, 3.9; P < .001). The hepatosteatosis group had higher mean CAP compared with no hepatosteatosis (293 dB/m; 95% CI 267, 325 vs 267 dB/m; 95% CI 248, 282; P = .0120). A CAP of 281 dB/m had the highest sensitivity (60%) and specificity (74%) with AUROC of 0.649 (95% CI 0.51-0.79; P = .04) in the entire cohort. In a subset of participants with polycystic ovary syndrome (PCOS), a CAP of 306 dB/m had the highest sensitivity (78%) and specificity (52%) and AUROC of 0.678 (95% CI 0.45-0.90; P = .108). Conclusion: CAP of 281 dB/m has modest diagnostic performance for hepatosteatosis compared with MRI in youth with significant obesity. A higher CAP in youth with PCOS suggests that comorbidities might affect optimal CAP in hepatosteatosis diagnosis.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS: Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS: Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.

Hypoglycemia in children and young adults with cystic fibrosis during oral glucose tolerance testing vs. continuous glucose monitoring.

BACKGROUND: Hypoglycemia is common in people with cystic fibrosis (pwCF) during oral glucose tolerance tests (OGTTs) and in the free-living setting, yet its pathophysiology remains unclear. OBJECTIVE: To evaluate hypoglycemia in children and young adults with CF by OGTT and continuous glucose monitoring (CGM). METHODS: A 3-h OGTT was performed in children and young adults with CF and healthy controls (HC). Individuals were classified as experiencing hypoglycemia on OGTT (glucose <70 mg/dL) or not. Insulin, C-peptide, glucose, glucagon, and incretins were measured. CGM was performed for 7 days in the free-living setting. Measures of insulin sensitivity, beta cell function accounting for insulin sensitivity, and insulin clearance were calculated. RESULTS: A total of 57 participants (40 CF and 17 HC) underwent assessment. Rates of hypoglycemia by OGTT were similar in pwCF (53%, 21/40) compared to HC (35%, 6/17), p = 0.23. PwCF compared to HC had higher A1c; on OGTT higher and later glucose peaks, later insulin peaks; and on CGM more glucose variability. CF Hypo+ versus CF Hypo- had higher lung function, higher insulin sensitivity, higher beta cell function accounting for insulin sensitivity, and decreased CGM variability. When comparing CF Hypo+ to HC Hypo+, although rates of hypoglycemia are similar, pwCF had blunted glucagon responses to hypoglycemia. OGTT hypoglycemia was not associated with CGM hypoglycemia in any group. CONCLUSION: Youth with CF have increased insulin sensitivity and impaired glucagon response to hypoglycemia on OGTT. Hypoglycemia on OGTT did not associate with free-living hypoglycemia.

11-Oxygenated Androgen Metabolite Concentrations Are Affected by Pubertal Progression and Obesity.

INTRODUCTION: 11-oxygenated C19 steroids (11-oxyandrogens) have been shown to rise during adrenarche and remain higher throughout adulthood than in early childhood. The patterns of circulating 11-oxyandrogens throughout normal puberty have not yet been described. METHODS: We conducted a secondary analysis of healthy youth participants, both males and females, enrolled in six prior endocrine studies (N = 249). Participants were classified according to Tanner stage and body mass index (BMI). Concentrations of three adrenal-specific 11-oxygenated androgens, 11ß-hydroxyandrostenedione (11OHA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT), were measured in fasting serum samples. RESULTS: 11OHA4 and 11OHT increased modestly between early and late puberty in youth with normal weight (p < 0.05), whereas increases in 11KT did not reach statistical significance (p < 0.06). 11KT levels differed between sexes throughout puberty (p < 0.01), and changes in 11-oxyandrogens were small compared to the marked increases for estradiol in girls or testosterone in boys. The trajectories of 11KT and 11OHA4 changes throughout puberty differed by BMI category (p < 0.05). CONCLUSION: Beyond adrenarche, 11-oxyandrogens continue to rise during pubertal development. The differences in 11KT trajectories in males and females are small compared to changes in testosterone for males and estradiol for females during puberty. Obesity appears to influence the trajectories of 11-oxyandrogens during puberty.

A Pipeline for the Implementation and Visualization of Explainable Machine Learning for Medical Imaging Using Radiomics Features.

Machine learning (ML) models have been shown to predict the presence of clinical factors from medical imaging with remarkable accuracy. However, these complex models can be difficult to interpret and are often criticized as "black boxes". Prediction models that provide no insight into how their predictions are obtained are difficult to trust for making important clinical decisions, such as medical diagnoses or treatment. Explainable machine learning (XML) methods, such as Shapley values, have made it possible to explain the behavior of ML algorithms and to identify which predictors contribute most to a prediction. Incorporating XML methods into medical software tools has the potential to increase trust in ML-powered predictions and aid physicians in making medical decisions. Specifically, in the field of medical imaging analysis the most used methods for explaining deep learning-based model predictions are saliency maps that highlight important areas of an image. However, they do not provide a straightforward interpretation of which qualities of an image area are important. Here, we describe a novel pipeline for XML imaging that uses radiomics data and Shapley values as tools to explain outcome predictions from complex prediction models built with medical imaging with well-defined predictors. We present a visualization of XML imaging results in a clinician-focused dashboard that can be generalized to various settings. We demonstrate the use of this workflow for developing and explaining a prediction model using MRI data from glioma patients to predict a genetic mutation.

Survival prediction models: an introduction to discrete-time modeling.

BACKGROUND: Prediction models for time-to-event outcomes are commonly used in biomedical research to obtain subject-specific probabilities that aid in making important clinical care decisions. There are several regression and machine learning methods for building these models that have been designed or modified to account for the censoring that occurs in time-to-event data. Discrete-time survival models, which have often been overlooked in the literature, provide an alternative approach for predictive modeling in the presence of censoring with limited loss in predictive accuracy. These models can take advantage of the range of nonparametric machine learning classification algorithms and their available software to predict survival outcomes. METHODS: Discrete-time survival models are applied to a person-period data set to predict the hazard of experiencing the failure event in pre-specified time intervals. This framework allows for any binary classification method to be applied to predict these conditional survival probabilities. Using time-dependent performance metrics that account for censoring, we compare the predictions from parametric and machine learning classification approaches applied within the discrete time-to-event framework to those from continuous-time survival prediction models. We outline the process for training and validating discrete-time prediction models, and demonstrate its application using the open-source R statistical programming environment. RESULTS: Using publicly available data sets, we show that some discrete-time prediction models achieve better prediction performance than the continuous-time Cox proportional hazards model. Random survival forests, a machine learning algorithm adapted to survival data, also had improved performance compared to the Cox model, but was sometimes outperformed by the discrete-time approaches. In comparing the binary classification methods in the discrete time-to-event framework, the relative performance of the different methods varied depending on the data set. CONCLUSIONS: We present a guide for developing survival prediction models using discrete-time methods and assessing their predictive performance with the aim of encouraging their use in medical research settings. These methods can be applied to data sets that have continuous time-to-event outcomes and multiple clinical predictors. They can also be extended to accommodate new binary classification algorithms as they become available. We provide R code for fitting discrete-time survival prediction models in a github repository.

11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome.

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 < .006) were lower in those on COCP treatment compared to untreated PCOS. Metformin treatment had no effect on 11-oxyandrogens, although testosterone was lower (P = .01). 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.

Aminoaciduria and metabolic dysregulation during diabetic ketoacidosis: Results from the diabetic kidney alarm (DKA) study.

OBJECTIVE: We examined changes in the excretion of various amino acids and in glycolysis and ketogenesis-related metabolites, during and after diabetic ketoacidosis (DKA) diagnosis, in youth with known or new onset type 1 diabetes (T1D). METHODS: Urine samples were collected from 40 youth with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, blood glucose 451 ± 163 mg/dL) at 3 time points: 0-8 h and 12-24 h after starting an insulin infusion, and 3 months after hospital discharge. Mixed-effects models evaluated the changes in amino acids and other metabolites in the urine. RESULTS: Concentrations of urine histidine, threonine, tryptophan, and leucine per creatinine were highest at 0-8 h (148.8 ± 23.5, 59.5 ± 12.3, 15.4 ± 1.4, and 24.5 ± 2.4% of urine creatinine, respectively), and significantly decreased over 3 months (p = 0.028, p = 0.027, p = 0.019, and p < 0.0001, respectively). Urine histidine, threonine, tryptophan, and leucine per urine creatinine decreased by 10.6 ± 19.2, 0.7 ± 0.9, 1.3 ± 0.9, and 0.5 ± 0.3-fold, respectively, between 0 and 8 h and 3 months. CONCLUSIONS: In our study, DKA was associated with profound aminoaciduria, suggestive of proximal tubular dysfunction analogous to Fanconi syndrome.

Novel clinical algorithm for hypothalamic obesity in youth with brain tumours and factors associated with excess weight gain.

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.

Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury. RESEARCH DESIGN AND METHODS: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age <25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models. RESULTS: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P < 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile 17-470] vs. 27 [13-73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable. CONCLUSIONS: Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

PaIRKAT: A pathway integrated regression-based kernel association test with applications to metabolomics and COPD phenotypes.

High-throughput data such as metabolomics, genomics, transcriptomics, and proteomics have become familiar data types within the "-omics" family. For this work, we focus on subsets that interact with one another and represent these "pathways" as graphs. Observed pathways often have disjoint components, i.e., nodes or sets of nodes (metabolites, etc.) not connected to any other within the pathway, which notably lessens testing power. In this paper we propose the Pathway Integrated Regression-based Kernel Association Test (PaIRKAT), a new kernel machine regression method for incorporating known pathway information into the semi-parametric kernel regression framework. This work extends previous kernel machine approaches. This paper also contributes an application of a graph kernel regularization method for overcoming disconnected pathways. By incorporating a regularized or "smoothed" graph into a score test, PaIRKAT can provide more powerful tests for associations between biological pathways and phenotypes of interest and will be helpful in identifying novel pathways for targeted clinical research. We evaluate this method through several simulation studies and an application to real metabolomics data from the COPDGene study. Our simulation studies illustrate the robustness of this method to incorrect and incomplete pathway knowledge, and the real data analysis shows meaningful improvements of testing power in pathways. PaIRKAT was developed for application to metabolomic pathway data, but the techniques are easily generalizable to other data sources with a graph-like structure.

Tubular injury in diabetic ketoacidosis: Results from the diabetic kidney alarm study.

OBJECTIVE: Glomerular injury is a recognized complication of diabetic ketoacidosis (DKA), yet the tubular lesions are poorly understood. The aim of this prospective study was to evaluate the presence and reversibility of tubular injury during DKA in children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Blood and urine samples were collected from 40 children with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, glucose 451 ± 163 mg/dL) at three timepoints: 0-8 and 12-24 h after starting insulin, and 3 months after discharge. Mixed-effects models evaluated the changes in tubular injury markers over time (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], and interleukin 18 [IL-18]). We also evaluated the relationships among the tubular injury biomarkers, copeptin, a vasopressin surrogate, and serum uric acid (SUA). RESULTS: Serum NGAL, KIM-1, and IL-18 were highest at 0-8 h (306.5 ± 45.9 ng/mL, 128.9 ± 10.1 pg/mL, and 564.3 ± 39.2 pg/mL, respectively) and significantly decreased over 3 months (p = 0.03, p = 0.01, and p < 0.001, respectively). There were strong relationships among increases in copeptin and SUA and rises in tubular injury biomarkers. At 0-8 h, participants with acute kidney injury (AKI) [17%] showed significantly higher concentrations of tubular injury markers, copeptin, and SUA. CONCLUSIONS: DKA was characterized by tubular injury, and the degree of injury associated with elevated copeptin and SUA. Tubular injury biomarkers, copeptin and SUA may be able to predict AKI in DKA.

Two-Year Treatment With Metformin During Puberty Does Not Preserve ß-Cell Function in Youth With Obesity.

CONTEXT: Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the ß-cell. OBJECTIVE: Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory ß-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 ±â€…0.16, P = 0.02), percentage body fat (%body fat; -3.4 ±â€…1.2%, P = 0.06), and waist circumference (-11.3 ±â€…3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ±â€…0.87 × 10-4/min-1/µIU/mL, P = 0.34), AIRg (-259 ±â€…386 µIU/mL, P = 0.51), or DI (508 ±â€…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 ß-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 ß-cell function in youth at risk for type 2 diabetes.

Twelve-month Continuation of the Etonogestrel Implant in Adolescents With Polycystic Ovary Syndrome.

STUDY OBJECTIVE: To identify why adolescents with polycystic ovary syndrome (PCOS) chose the etonogestrel (ENG) contraceptive implant, to determine the 12-month continuation rate, and to characterize factors related to discontinuation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective chart review of adolescents seen at a tertiary care children's hospital between July 1, 2008, and August 30, 2019, with PCOS diagnosis confirmed per National Institutes of Health criteria and ≥12-month ENG follow-up. INTERVENTIONS AND MAIN OUTCOME MEASURES: Demographic characteristics, reasons for ENG insertion and removal, and information on other hormonal/contraceptive therapies were collected. Patients were categorized as ENG continuers (use ≥12 months) or discontinuers (removal at <12 months), and groups were compared. RESULTS: A total of 96 patients met inclusion criteria (age 17.7 ± 2.2 years, body mass index 34.8 ± 8 kg/m2). Reasons for ENG were documented in 74% (51% contraception, 32% ease of use, 15% other, 13% estrogen avoidance). In all, 27% had never been sexually active, and 67% had had prior sexual activity. Treatments prior to ENG placement included 74% combined hormonal contraception, 20% medroxyprogesterone acetate withdrawal, and 17% depot medroxyprogesterone. A total of 77% continued ENG at 12 months. The main reasons for discontinuation were bleeding (41%), concern about weight gain (23%), and mood changes (18%). No preimplantation characteristics were independently predictive of continuation, although 100% of patients with type 2 diabetes (n = 11) continued. Patients who sought additional care, including telephone calls (41% vs 12%, P = .006) and clinic visits (64% vs 20%, P < .001) were more likely to discontinue. CONCLUSIONS: The ENG implant was well tolerated in adolescents with PCOS and similar to published 12-month continuation rates.

Puberty Is Associated with a Rising Hemoglobin A1c, Even in Youth with Normal Weight.

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.

Depression in Girls With Obesity and Polycystic Ovary Syndrome and/or Type 2 Diabetes.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (p<0.0001 for both cutpoints). A higher CES-D score was not associated with severity of hirsutism or acne (p>0.05 for both). CONCLUSIONS: 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.

The Impact of Obesity On Insulin Sensitivity and Secretion During Pubertal Progression: A Longitudinal Study.

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 < 0.001), but DI was similar between the groups. There were no group differences in trajectory of Si, AIRg or DI over time. Leptin, insulin-like growth factor-1, and obesity were most strongly associated with Si and AIRg at all time points. CONCLUSIONS: Obesity significantly impacts Si during puberty, even at the earliest stages. However, in general, obese youth have adequate ß-cell compensation for the significantly reduced Si of puberty. Future studies are needed to better predict the subset of youth who fail to maintain ß-cell compensation during puberty.