Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes.

AIMS/HYPOTHESIS: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. METHODS: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. RESULTS: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10-9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. CONCLUSIONS/INTERPRETATION: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. DATA AVAILABILITY: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).

Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes.

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher ß-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the ß-cell pPS with reduced ß-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Youth-onset type 2 diabetes: translating epidemiology into clinical trials.

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.

How does exposure to overnutrition in utero lead to childhood adiposity? Testing the insulin hypersecretion hypothesis in the EPOCH cohort.

AIMS/HYPOTHESIS: Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children. METHODS: 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. RESULTS: >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). CONCLUSIONS/INTERPRETATION: 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.

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.

Development of type 2 diabetes in adolescent girls with polycystic ovary syndrome and obesity.

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.

High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome.

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.

Normal Hemoglobin A1c Variability in Early Adolescence: Adult Criteria for Prediabetes Should Be Applied with Caution.

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.

Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA.

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.

Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial.

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

A multi-centre quality improvement project to reduce the incidence of obstetric anal sphincter injury (OASI): study protocol.

BACKGROUND: Third and fourth degree perineal tears, or obstetric anal sphincter injuries (OASI), sustained during childbirth can result in anal incontinence and psychosocial problems which require ongoing treatment. Within the English National Health System (NHS) reported rates of OASI have gradually increased. In response, a care bundle was developed incorporating four elements: 1) antenatal information to women, 2) manual perineal protection during all vaginal births, 3) episiotomy to be performed with a 60° mediolateral angle at crowning (when clinically indicated) and 4) perineal examination (including per rectum) after childbirth. Implementation of the OASI Care Bundle is aided by a skills development module and an awareness campaign. The project is a collaboration between two national professional bodies, an NHS hospital trust and an academic institution. METHODS: Implementation of the OASI Care Bundle will be evaluated using a stepped-wedge design. From January 2017 sixteen maternity units across England, Wales and Scotland will participate in the study over a 15-month period, with sequential roll-out of the intervention in four blocks (regions) of four units. The primary clinical outcome is OASI rate. Regression analysis will adjust for differences in organisational characteristics and obstetric risk factors in women who gave birth before and after implementation of the care bundle. Focus group discussions and in-depth interviews with clinicians will evaluate the feasibility of integrating the care bundle into routine practice. Interviews with women will explore the acceptability of the intervention. DISCUSSION: This protocol outlines the evaluation of our quality improvement project which aims to prevent OASI using a bundle of evidence-based interventions that are each widely used in practice. The OASI project aims to 1) standardise practice to prevent OASI in a way that is acceptable to clinicians and women and 2) identify the barriers and enablers associated with upscaling interventions within maternity units. If found to be effective, feasible and acceptable, the OASI Care Bundle will be shared with a range of audiences using the communication channels available to the professional bodies. TRIAL REGISTRATION: The OASI Project was retrospectively registered on the ISCTRN12143325 database date assigned 03/10/2017.

Adolescent's Health Behaviors and Risk for Insulin Resistance: A Review of the Literature.

PURPOSE OF REVIEW: One-third of US adolescents are obese, and related comorbidities exist in this population. Preventing early indicators of these diseases, such as insulin resistance (IR), may impact future morbidity and mortality. Interventions to date have only focused on diet or exercise. Additional targets to prevent disease are needed. This paper reviews the evidence in adolescents examining multiple health behaviors that have been associated with IR. RECENT FINDINGS: Health behaviors (i.e., diet, activity, sleep) have been individually examined as possible contributors to disease, but an understanding of the complex interplay between these behaviors is lacking. A better understanding of how multiple health behaviors contribute to IR in adolescents is needed. Future studies using both advanced statistical methodology and robust measures of each health behavior may facilitate better understanding of the impact of lifestyle factors on IR and guide intervention strategies to reduce the risk of disease.

Alternate glycemic markers reflect glycemic variability in continuous glucose monitoring in youth with prediabetes and type 2 diabetes.

OBJECTIVE: To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D). STUDY DESIGN: Youth with BMI ≥85th%ile, 10-18 years, had collection of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), FA, GA, and 1,5AG and 72 hours of CGM. Participants with HbA1c ≥5.7% were included. Relationships between glycemic markers and CGM variables were determined with Spearman correlation coefficients. Linear models were used to examine the association between alternate markers and CGM measures of glycemic variability-standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)-after controlling for HbA1c. RESULTS: Total n = 56; Median (25th%ile, 75th%ile) age = 14.3 years (12.5, 15.9), 32% male, 64% Hispanic, 20% black, 13% white, HbA1c = 5.9% (5.8, 6.3), FA=211 mmol/L (200, 226), GA= 12% (11%, 12%), and 1,5AG = 22mcg/mL (19, 26). HbA1c correlated with average sensor glucose, AUC, SD, MAGE, and %time > 140 mg/dL. FA and GA correlated with average and peak sensor glucose, %time >140 and >200 mg/dL, and MAGE. GA also correlated with SD and AUC180. 1,5AG correlated with peak glucose, AUC180, SD, and MAGE. After adjusting for HbA1c, all 3 markers independently predicted MAGE; FA and GA independently predicted SD. CONCLUSIONS: Alternate glycemic markers predict glycemic variability as measured by CGM in youth with prediabetes and T2D. After adjusting for HbA1c, these alternate markers continued to predict components of glycemic variability detected by CGM.

Insulin Resistance of Puberty.

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

Testosterone concentration and insulin sensitivity in young men with type 1 and type 2 diabetes.

OBJECTIVE: Reduced testosterone, a recognized comorbidity of reduced insulin sensitivity (IS) and type 2 diabetes (T2D), has also been reported in adult males with type 1 diabetes (T1D). However, there are limited data on how early reduced testosterone occurs, and whether it is related to the reduced IS in T1D. Leptin, a modulator of the HPG-axis, may also influence testosterone in T1D. We hypothesized that IS and leptin would be associated with total testosterone (TT), and free androgen index (FAI) in adolescent males with T1D. METHODS: T1D (n = 35), T2D (n = 13), lean (n = 13) and obese (n = 9) adolescent males had IS measured by hyperinsulinemic-euglycemic clamps (glucose infusion rate [GIR]), in addition to leptin, sex hormone binding globulin (SHBG), TT, and FAI. The cohort was stratified into those with T1D (n = 35) and those without (n = 35). RESULTS: TT and SHBG were lower in T2D boys vs. lean controls, and GIR and leptin correlated with FAI and TT in non-T1D participants. However, despite being insulin resistant, adolescent males with T1D had normal TT and FAI, unrelated to GIR. In T1D, leptin was inversely associated with TT (p = 0.005) and FAI (p = 0.01), independent of puberty, hemoglobin A1c (HbA1c), diabetes duration, body mass index (BMI) z-score and GIR. CONCLUSION: Leptin accounted for a significant proportion of the variability of testosterone in T1D. However, despite reduced IS, there was no association between IS and testosterone in T1D adolescents. These observations suggest that the mechanisms affecting testosterone may differ between adolescent males with and without T1D.

Screening for type 2 diabetes and prediabetes in obese youth: evaluating alternate markers of glycemia - 1,5-anhydroglucitol, fructosamine, and glycated albumin.

Hemoglobin A1c (HbA1c) is increasingly performed over the oral glucose tolerance test (OGTT) as the initial screening test for type 2 diabetes in youth. However, the optimal strategy for identifying type 2 diabetes in youth remains controversial. Alternate glycemic markers have been proposed as potentially useful tools for diabetes screening. We examined the relationships among fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with traditional screening tests, HbA1c and OGTT. Youth 10-18 yrs, BMI ≥85th‰, and HbA1c <7.5% had a single visit with measurement of HbA1c, 1,5-AG, FA, GA, and a standard OGTT. Distributions of FA, GA, and 1,5-AG by HbA1c and 2-hour glucose (2hG) categories were compared. Receiver operating characteristic (ROC)-curves were generated to determine the cut points at which alternate markers maximized sensitivity and specificity for predicting prediabetes and diabetes. One hundred and seventeen, 62% female, 59% Hispanic, 22% White, 17% black, median 14.1 yr, and body mass index (BMI) z-score 2.3 participated. Median values of each alternate marker differed significantly between prediabetes and diabetes HbA1c and 2hG categories (p < 0.017). Only GA medians differed (p = 0.006) between normal and prediabetes HbA1c. Area under the receiver operating characteristic curves (ROC-AUCs) for alternate markers as predictors of prediabetes (0.5-0.66) were low; however, alternate marker ROC-AUCs for identifying diabetes (0.82-0.98) were excellent. Although the alternate markers were poor predictors of prediabetes, they all performed well predicting diabetes by 2hG and HbA1c. Whereas the usefulness of these markers for identifying prediabetes is limited, they may be useful in certain scenarios as second line screening tools for diabetes in overweight/obese youth.