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Metabolic and bariatric surgery is the most effective weight loss treatment for severe obesity. The number of adolescents undergoing sleeve gastrectomy is increasing. We investigated changes in body composition in adolescents undergoing sleeve gastrectomy 12-26 weeks post-operatively using whole-body magnetic resonance imaging (WB-MRI).This prospective cohort study assessed changes in adipose tissue compartments (ie, visceral, subcutaneous, and intermuscular) and muscle in 18 obese adolescents, ages 14-19, 89% female, with body mass index z -score of 2.6 ± 0.25 (range 2.16-3.2). All underwent WB-MRI 1.5-17 weeks pre-operatively and 12-26 weeks post-operatively.Pre- and post-operative WB-MRI showed decreases in all adipose tissue compartments, as well as decreased skeletal muscle and liver fat fraction ( P0.0001). The post-operative percentage loss of adipose tissue in subcutaneous, visceral, and intermuscular compartments (89.0%, 5.8%, 5.2%, respectively) was similar to the pre-operative percentages of corresponding adipose tissue compartments (90.5%, 5.0%, 4.5%, respectively). Of note, participants with obstructive sleep apnea had significantly higher pre-operative volume of subcutaneous and intermuscular adipose tissue than participants without obstructive sleep apnea ( P = 0.003).We found, contrary to what is reported to occur in adults, that pre-operative percentage loss of adipose tissue in subcutaneous, visceral, and intermuscular compartments was similar to the post-operative percentage loss of corresponding adipose tissue compartments in adolescents 12-26 weeks after sleeve gastrectomy.

Perhaps the most unexpected development in pediatric endocrinology in the past 50 years has been the recognition of obesity as an endocrine/metabolic disorder rather than a life choice or moral failing. The history of obesity research is disjointed, having followed two separate paths in the 20th century, based on two independent yet overlapping paradigms. Proponents of the “Energy Storage” hypothesis point to data implicating monogenetic disorders, the ventromedial hypothalamus, insulin, cortisol, and the adipocyte itself in the pathogenesis of obesity. Alternatively, proponents of the “Energy Balance” hypothesis point to data implicating increased caloric intake, decreased caloric expenditure, gastrointestinal hormones, and microbiome changes as being critical for obesity. These two separate lines of research merged somewhat with the discovery of leptin in 1994, as leptin established a major hormonal role in weight control. Leptin has explained some of the dichotomy and has proved essential in understanding the importance of developmental programming and epigenetics. However, the mystery of leptin resistance remains unsolved. Despite all our collective knowledge, we appear no closer in solving the obesity puzzle today than we were 50 years ago.

Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants inBSNhave previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants inBSNare associated with higher BMI with log10-p value of 11.78 in the UK biobank cohort. The association was replicated in the All of Us whole genome sequencing data. Additionally, we have identified two individuals (one of whom has ade novovariant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity at Columbia University. Like the individuals identified in the UKBB and All of us Cohorts, these individuals have no history of neurobehavioral or cognitive disability. Heterozygosity for pLoFBSNvariants constitutes a new etiology for obesity.

Type 2 diabetes mellitus is a complex and under-treated disorder closely intertwined with obesity. Adolescents with severe obesity and type 2 diabetes have a more aggressive disease compared to adults, with a rapid decline in pancreatic β cell function and increased incidence of comorbidities. Given the relative paucity of pharmacotherapies, bariatric surgery has become increasingly used as a therapeutic option. However, subsets of this population have sub-optimal outcomes with either inadequate weight loss or little improvement in disease. Predicting which patients will benefit from surgery is a difficult task and detailed physiological characteristics of patients who do not respond to treatment are generally unknown. Identifying physiological predictors of surgical response therefore has the potential to reveal both novel phenotypes of disease as well as therapeutic targets. We leverage data assimilation paired with mechanistic models of glucose metabolism to estimate pre-operative physiological states of bariatric surgery patients, thereby identifying latent phenotypes of impaired glucose metabolism. Specifically, maximal insulin secretion capacity, σ, and insulin sensitivity, SI, differentiate aberrations in glucose metabolism underlying an individual’s disease. Using multivariable logistic regression, we combine clinical data with data assimilation to predict post-operative glycemic outcomes at 12 months. Models using data assimilation sans insulin had comparable performance to models using oral glucose tolerance test glucose and insulin. Our best performing models used data assimilation and had an area under the receiver operating characteristic curve of 0.77 (95% confidence interval 0.7665, 0.7734) and mean average precision of 0.6258 (0.6206, 0.6311). We show that data assimilation extracts knowledge from mechanistic models of glucose metabolism to infer future glycemic states from limited clinical data. This method can provide a pathway to predict long-term, post-surgical glycemic states by estimating the contributions of insulin resistance and limitations of insulin secretion to pre-operative glucose metabolism.

IntroductionThe known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation with other known risk measures.Materials and MethodsThe study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11–15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected.ResultsThe subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score ConclusionIGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified.

Introduction: There is a paucity of data exploring the effect of baseline metabolic factors on weight loss success following laparoscopic sleeve gastrectomy (LSG) in adolescents. This study aimed to identify if there is a relationship between abnormal baseline metabolic characteristics including Metabolic Syndrome (MeS), elevated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), impaired glucose tolerance, and liver function in adolescents presenting for LSG and subsequent weight loss. METHODS: This was a retrospective study at the Center for Adolescent Bariatric Surgery. Subjects were recruited from 2010-2021. Patients with diabetes, identified by fasting blood glucose ≥ 125 mg/dl, 2-hour blood glucose ≥ 200 mg/dl, or HbA1c ≥ 6.5%, were excluded. Anthropometric measurements, fasting triglycerides, HDL, glucose, ALT, HbA1c, and oral glucose tolerance test results were collected pre-surgery and at 6 and/or 12 months post-surgery. Subjects were classified as having childhood MeS using de Ferranti et. al. [1] criteria. Successful weight loss was defined by a change in BMI of at least -11.49 kg/m 2 in the 6-month group and -13. 05 kg/m 2 in the 12-month group. ALT > 22 mg/dl for females and > 26 mg/dl for males, HbA1c ≥ 5.7%, and HOMA-IR > 2.7 were considered abnormal. Chi-squared or Fisher's analyses were performed using RStudio [2], calculating the presence of a relationship between abnormal metabolic factors pre-surgery and subsequent weight loss at 6 and 12 months. A p-value of NOTES: *ACB and ASF are co-first authors. Presentation: No date and time listed

Severe obesity is often associated with co-morbid conditions such as diabetes mellitus, hypertension, and obstructive sleep apnea. Successful weight loss can result in remission of these conditions. The authors retrospectively examined the co-morbidity profiles of pre-operative gastric sleeve adult patients from the MBSAQIP database with subjects from our adolescent bariatric program. Five conditions were compared: hypertension (HTN), type 2 diabetes mellitus (T2DM), dyslipidemia (DL), obstructive sleep apnea (OSA), and gastroesophageal reflux disease (GERD). Patients were matched by gender and body mass index (BMI). The prevalence of each condition was statistically more significant in the adult cohort. Successful weight loss at an earlier age may reduce the prevalence of these co-morbid conditions.

Laparoscopic adjustable gastric banding (LAGB) is used to treat obesity in adults. Less is known about long-term results of the procedure in adolescents. To evaluate LAGB 5-year outcomes in teenagers with severe obesity. Children’s hospital, USA. Adolescents (14–18 years) underwent LAGB in an FDA-approved observational clinical trial. Outcomes including anthropometric measurements, comorbid conditions, complications, and band retention were collected through 60 months. One hundred thirty-seven subjects underwent LAGB (94 female, 43 male; 43% white, 37% Hispanic, 17% black; 4% other). Mean age and body mass index (BMI) pre-operatively were 17.0 + 1.2 years and 48.3 + 8.2 kg/m2, respectively. Comorbidities were present in 71%. Maximum weight loss occurred by 36 months (mean % excess weight loss (EWL) 40.6 + 35.2, mean % excess BMI loss (EBMIL) 41.6 + 34.9) and was maintained through 5 years for most subjects. There were no significant differences in weight loss by gender. Twenty-three (18%) of 127 adolescents reporting at 60 months achieved 50% excess weight loss. Postoperative heartburn and emesis occurred in 70% and 32%, respectively. Complications requiring additional surgery occurred 80 times in 63 patients. Thirty-three (26%) of 127 subjects contacted at 5 years had undergone band removal. In this study, fewer than 20% of adolescents with severe obesity lost > 50% of their excess weight following LAGB. Nearly 50% of patients required additional surgery. With reports of success following sleeve gastrectomy and gastric bypass, we believe that LAGB is not a preferred choice to treat adolescents with obesity.

Objective To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. Methods Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with an optional exercise intervention. Results Groups were demographically and anthropometrically similar. The intervention resulted in significant reductions in indices of adiposity (ΔBMI z-scores [-0.035 ± 0.014; p = 0.01], Δ% body fat [-0.5 ± 0.2; p

Introduction: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders that affects females of reproductive age. The characteristic features of PCOS individually have opposing effects on bone mineral density (BMD); however, their cumulative effect on BMD has not been clearly defined. Adolescence and young adulthood span a crucial period in achieving peak bone mass. Thus, a better understanding of the impact of PCOS on BMD in this age group is needed. Objectives: To determine whether BMD is different between young females with PCOS and controls and to identify factors that influence BMD in this population. Methods: Data from four cross-sectional studies with a total of 170 females aged 12–25 years with PCOS (n = 123) and controls (n = 47) with a wide range of BMIs (18.7–53.4 kg/m2) were analyzed. Participants had fasting glucose, insulin, and free and total testosterone concentrations measured. HOMA-IR was calculated. Whole-body BMD was assessed by dual-energy X-ray absorptiometry. Multiple regression analysis for predicting BMD included PCOS status, menstrual age, obesity, HOMA-IR, and free testosterone. Results: HOMA-IR and total and free testosterone were significantly higher in PCOS compared to controls but there was no difference in BMD z-score between PCOS (0.8 ± 1.0) and controls (0.6 ± 1.0) (p = 0.36). Obesity (p = 0.03) and HOMA-IR (p = 0.02) were associated with BMD z-score. Conclusions: Obesity status and insulin resistance, but not PCOS status, were each independently associated with BMD in adolescents and young women who spanned a wide range of BMIs.

Introduction: Although growth hormone (GH) is essential for attainment of peak bone mass, bone health in prepubertal children with GH deficiency is not routinely evaluated. The objective of this study was to evaluate bone microarchitecture in GH-deficient (GHD) boys using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: Fifteen control and fifteen GHD, GH naïve pre-pubertal boys were recruited for a case-control study at a major academic center. Subjects with panhypopituitarism, chromosomal pathology, chronic steroids, or stimulant use were excluded. Volumetric bone mineral density (vBMD; total, cortical, and trabecular), bone geometry (total, cortical and trabecular cross-sectional area, cortical perimeter), bone microarchitecture, and estimated bone strength of the distal radius and tibia were assessed by HR-pQCT. Areal BMD and body composition were assessed by DXA. Insulin-like growth factor 1 (IGF-1), osteocalcin, C telopeptide, and P1NP levels were measured. Results: GHD subjects had a significantly smaller cortical perimeter of the distal radius compared to controls (p < 0.001), with the difference in cortical perimeter persisting after adjusting for height z score, age, lean mass, and 25-hydroxyvitamin D level (p < 0.05).No significant differences were found in vBMD. No significant differences were found in microarchitecture, estimated strength, areal BMD, body composition, or bone turnover markers. Analysis showed significant positive correlations between IGF-1 levels and cortical parameters. Discussion/Conclusions: Prepubertal GHD boys had deficits in bone geometry not evident with DXA. Larger prospective/longitudinal HR-pQCT studies are needed to determine the extent of these deficits, the need for routine bone evaluation, and the timing of GH replacement for prevention or restoration of these deficits.

Introduction: Recent studies have shown 11-oxygenated androgens (11oAs) are the dominant androgens in premature adrenarche (PA). Our objective was to compare 11oAs and conventional androgens in a well-defined cohort of children with PA or premature pubarche (PP) and correlate these androgens with metabolic markers. Methods: A prospective cross-sectional study was conducted at a university hospital. Fasting early morning serum steroids (including 11oAs) and metabolic biomarkers were compared and their correlations determined in children ages 3–8 years (F) or 3–9 years (M) with PA or PP (5 M and 15 F) and healthy controls (3 M and 8 F). Results: There were no differences between PA, PP, and controls or between PA and PP subgroups for sex, BMI z-score, or criteria for childhood metabolic syndrome. Dehydroepiandrosterone sulfate (DHEAS) was elevated only in the PA subgroup, as defined. 11oAs were elevated versus controls in PA and PP although no differences in 11oAs were noted between PA and PP. Within the case cohort, there was high correlation of T and A4 with 11-ketotestosterone and 11β-hydroxyandrostenedione. While lipids did not differ, median insulin and HOMA-IR were higher but not statistically different in PA and PP. Conclusions: PA and PP differ only by DHEAS and not by 11oAs or insulin sensitivity, consistent with 11oAs – rather than DHEAS – mediating the phenotypic changes of pubarche. Case correlations suggest association of 11oAs with T and A4. These data are the first to report the early morning steroid profiles including 11oAs in a well-defined group of PA, PP, and healthy children.

25-hydroxy vitamin D (25 OHD) deficiency and secondary hyperparathyroidism have been seen after metabolic and bariatric surgery, but data are lacking on the bone health outcomes of adolescent sleeve gastrectomy (SG). The purpose of this study was to examine bone-related nutrition after SG, compared to laparoscopic adjustable gastric band (LAGB), and trend bone turnover markers following SG. This is an observational study of 197 adolescents who underwent LAGB (n = 98) or SG (n = 99). Bone health labs were collected at baseline and 6 and/or 12 months after LAGB or SG, with additional analysis of bone turnover markers in the SG group. Calcium and 25 OHD levels increased at 6 and 12 months after LAGB and SG, with no difference between the surgeries. Parathyroid hormone levels decreased only in the SG group. SG patients had increased osteocalcin and carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX) at 6 and 12 months post-SG, although CTX decreased between 6 and 12 months. Excess weight loss at 6 months predicted the rise in CTX, but the changes in osteocalcin and CTX could not be attributed to 25 OHD deficiency, hypocalcemia or hyperparathyroidism. Patients had improved 25 OHD levels post-surgery, which may be secondary to stringent vitamin supplementation guidelines. However, there were marked increases in bone turnover markers following SG. More studies are needed to evaluate the effects of SG on adolescent bone health and to correlate the early changes in bone turnover with bone mineral density and fracture risk.

Premature adrenarche (PA), the early onset of pubic hair and/or axillary hair/odor in children, is associated with elevated adrenal androgens and precursors in the absence of gonadotropin-dependent puberty. Laboratory data in PA classically demonstrate increased DHEAS, T, and A4 levels that correlate with pubic hair development. In premature pubarche (PP), the clinical presentation occurs in the absence of elevated DHEAS, T, and A4. PA is associated with insulin resistance and progression to metabolic syndrome (MetS) and PCOS; it is unclear which of these children are at risk for metabolic abnormalities. Adrenally-derived 11-oxygenated C19 steroids (11oAs) have comparable androgenic potency to T and DHT and are elevated in disorders of androgen excess. We sought to characterize the 11oA profiles of children with PA/PP and controls and to correlate them with traditional androgens and metabolic markers, including criteria for childhood MetS. A prospective cross-sectional study was performed of subjects with PA or PP (5 M, 14 F) and controls (2 M, 6 F) ages 3 – 8 yrs (F) or 3 – 9 yrs (M). Children with precocious puberty, steroid use, or recent illness were excluded. Fasting early morning serum was collected, a complete physical exam was performed, and BP and waist circumference were measured; a bone age was obtained only in PA/PP subjects. 11oAs (11OHT, 11KT, 11OHA4, 11KA4) were analyzed by LC-MS. Subjects were divided into PA (DHEAS ≥ 50 µg/dL, n=10) or PP (DHEAS < 50 µg/dL, n=9) for sub-analysis. There were no significant differences in sex, race/ethnicity, BMI z-score, preterm gestation, birth weight, family history, or clinical criteria for childhood MetS. T, A4, DHT, DHEAS, and all 11oAs were significantly higher in PA/PP subjects. While lipids did not differ, insulin and HOMA-IR were higher in PA/PP vs. controls {insulin Mdn = 8.2 (IQR 3.5 – 10.0) vs. 2.0 (2.0 – 3.3) µIU/mL, p < 0.03; HOMA-IR Mdn = 1.8 (IQR 0.8 – 2.1) vs. 0.4 (0.4 – 0.8), p < 0.03}. In a sub-analysis of PA vs. PP, there were no differences in baseline characteristics or metabolic markers. DHEAS was elevated in PA vs. PP {Mdn = 95 (IQR 73 – 111) vs. 42 (36 – 46) µg/dL, p < 0.00003}, although no differences were noted in 11oA levels. Correlations of androgens and their precursors suggested best correlation of 11KT and 11OHA4 with T (ρ=0.87; ρ=0.87) and A4 (ρ=0.87; ρ=0.88). There was moderate correlation of 11KT and 11OHT with insulin (ρ=0.47; ρ=0.51) and HOMA-IR (ρ=0.43; ρ=0.47). We conclude that PA and PP differ only by DHEAS (by definition) and not by insulin sensitivity or 11oA, consistent with 11oA – rather than DHEAS – mediating the phenotypic changes of pubarche. These pilot data are the first to report the early morning steroid metabolite levels including 11oAs in a phenotypically and metabolically well-defined group of PA, PP, and age-matched male and female controls. The relationships between PA, PP, risk for MetS, and 11oA warrant further study.

Severe obesity is often associated with co-morbid conditions such as diabetes mellitus, hypertension, and obstructive sleep apnea. Successful weight loss can result in remission of these conditions. The authors retrospectively examined the co-morbidity profiles of pre-operative gastric sleeve adult patients from the MBSAQIP database with subjects from our adolescent bariatric program. Five conditions were compared: hypertension (HTN), type 2 diabetes mellitus (T2DM), dyslipidemia (DL), obstructive sleep apnea (OSA), and gastroesophageal reflux disease (GERD). Patients were matched by gender and body mass index (BMI). The prevalence of each condition was statistically more significant in the adult cohort. Successful weight loss at an earlier age may reduce the prevalence of these co-morbid conditions.

Limited data are available on the characteristics of adolescents with obesity who seek bariatric surgery. Existing data suggest that adolescent surgery candidates have a higher body mass index (BMI) than comparison adolescents with obesity, but the limited findings regarding psychosocial functioning are mixed. This study aimed to compare BMI and psychosocial functioning among adolescent bariatric surgery candidates, outpatient medical-treatment-seeking adolescents with obesity (receiving lifestyle modification), and adolescents in the normal-weight range. All adolescents completed self-report measures of impulsivity, delay discounting, depression, anxiety, stress, eating pathology, family functioning and quality of life, and had their height and weight measured. Adolescent surgical candidates had higher BMIs than both comparison groups. Surgical candidates did not differ from medical-treatment-seeking adolescents with obesity on any measure of psychosocial functioning, but both groups of adolescents with obesity reported greater anxiety and eating pathology and poorer quality of life than normal-weight adolescents. Quality of life no longer differed across groups after controlling for BMI, suggesting that it is highly related to weight status. Adolescents with obesity may experience greater anxiety, eating pathology, and quality of life impairments than their peers in the normal-weight range regardless of whether they are seeking surgery or outpatient medical treatment. Clinical implications and directions for future research are discussed.

Anemia following bariatric surgery is a known complication. To prevent nutrient deficiencies, adolescents require multivitamin/mineral supplementation following bariatric surgery. The purpose of this study was to investigate if routine multivitamin/mineral supplementation is sufficient to prevent anemia in adolescents undergoing bariatric surgery, particularly sleeve gastrectomy (SG), a procedure that may induce nutrient malabsorption.We conducted a retrospective review of pediatric patients who underwent SG (34 patients) and laparoscopic adjustable gastric banding (LAGB) (141 patients) (January 2006 through December 2013). We examined anemia marker levels (iron, ferritin, folate, BFollowing SG, folate levels decreased 3 and 6 months postsurgery but returned to baseline levels at 12 months. Furthermore, the SG group demonstrated lower folate levels compared with LAGB at 3 and 6 months. BWhile anemia did not occur in any patients while on recommended routine supplementation, folate levels were significantly reduced following SG and were lower in SG compared with LAGB patients. Additional folate supplementation seemed to improve folate levels, which highlights the importance of ongoing surveillance by primary care providers and the need for additional folate supplementation following SG.

Background/Aims: To delineate the relationship of polycystic ovary syndrome (PCOS), obesity, and hyperandrogenism (HA) with glucose and insulin dynamics in adolescents across a broad body mass index (BMI). Methods: Seventy-four PCOS subjects (aged 16 years) and 82 controls (aged 16 years) were evaluated by an oral glucose tolerance test. Subjects were categorized by BMI: normal weight (21 ± 0.4), overweight/obesity (OO; 33 ± 1.0), and severe obesity (SO; 48 ± 1.4). Indices of glucose and insulin dynamics were determined. Multiple linear regression analysis was used to evaluate the contribution of PCOS, HA, and BMI to these indices. Results: BMI was significantly associated with systolic and diastolic blood pressure and insulin resistance. A significant interaction between BMI and PCOS and indices of post-glucose load was observed. The mean difference in peak glucose, early glucose response, area under the curve for glucose, and glucose effectiveness (SgIo) between PCOS and control subjects was significantly different between OO and SO. In PCOS subjects, testosterone was positively associated with BMI, fasting insulin, early insulin response, and diastolic blood pressure, and negatively associated with SgIo. Conclusions: Abnormal glucose dynamics in adolescents with PCOS is mainly due to SO. The combination of PCOS and SO has a synergistic effect on glucose dynamics when compared to all other groups.

Background: Polycystic ovary syndrome (PCOS) is a prevalent disease that impacts approximately 4-8% of the United States population. Bariatric surgery has been found to not only treat obesity but also reverse the symptoms associated with PCOS. The aim of this study was to investigate in adolescent girls with PCOS changes in glucose-insulin dynamics after significant weight loss and to determine how hyperandrogenism is influenced. We hypothesized that girls with PCOS would demonstrate improvements in glucose-insulin dynamics and hyperandrogenism after bariatric surgery. Methods: This study was a retrospective analysis of a longitudinal dataset with participants divided into two groups: 1) girls without PCOS (Ctrls), and 2) girls with PCOS (PCOS), as defined by the NIH criteria. Primary outcomes were HOMA-IR, Matsuda index, and oral disposition index (ODI) after oral glucose tolerance test. Data were analyzed by T-tests comparison of parameters at baseline, and changes in parameters at 6 and 12 months post-surgery between groups with p50ng/dl and/or free testosterone >5.3 pg/ml) with regular menses. The remaining 29 had regular menses and normal androgen levels but were grouped with the 14 without irregular periods as the control group. Surgery occurred at a mean age of 16.9± 1.1yr. At 6m, 61 were available for analysis (25 with PCOS, and 36 Ctrl) while at 12m, 41 were available (11 with PCOS, 29 Ctrls). At baseline HOMA-IR was significantly higher in PCOS patients (3.6±2.3) compared to controls (2.51±1.71), p

Introduction: The Homeostasis Model Assessment of insulin resistance (HOMA-IR) is a validated surrogate measure of insulin sensitivity and beta-cell function for epidemiological studies. Insulin resistance is closely associated with obesity and shares dysmetabolic state with other cardiometabolic risk factors. The aim of this study was to analyze the change in HOMA-IR levels in US youth from 1999 to 2018. Methods: Serial cross-sectional data of fasting insulin and glucose levels measured in youth aged 12 to 18 years enrolled in National Health and Nutrition Examination Surveys representative of US population from 1999 to 2018 were used. Two-year survey cycles were combined to derive 4-year survey periods, and NHANES recommended adjustments were made for glucose and insulin levels for forward conversion to 2017–18 instrument levels. Median HOMA-IR was compared across the survey periods in subgroups by age, gender, race/ethnicity and levels of obesity. Association of HOMA-IR with selected cardiometabolic risk factors was assessed. Change of HOMA-IR levels were analyzed using design adjusted multivariable regression models, association of HOMA-IR with cardiometabolic risk factors was assessed and percentiles were derived. Results: In an analysis of 5,541 youth, the unadjusted median HOMA-IR increased from 1.83 (95% CI 1.77–1.89) in 1999-02 to 2.41 (95% CI 2.29–2.54) in 2007–10 and has remained in this range till 2015–18. Youth with obesity (Body mass index > 95th percentile or waist circumference > 90th percentile), female gender, those of Hispanic and Black origin, and those aged 12–16 years had higher levels of HOMA-IR (p 1, the HOMA-IR levels were higher in boys compared to girls. The addition of total body fat from DXA scans in the model, when available, explained the variance related to gender, but not the interaction between gender and WCZ. No change was observed in the higher levels of HOMA-IR by ethnicity when high sensitivity CRP level as a measure of inflammation was added to the model. There was a positive association of HOMA-IR with triglycerides (29 %/unit, 95% CI 25–33), non-HDL cholesterol (8 %/unit, 95% CI 6–10), systolic blood pressure (2% /unit, 95% CI 1–2) and alanine transferase (11 %/unit, 95% CI 8–14) while controlling for age, sex, race/ethnicity, obesity and survey period. In youth with BMI between 5-85th percentile, HOMA-IR decreased with increase in age from 12 to 18 years. Conclusions: HOMA-IR levels in US youth have increased since 1999-02 and may herald future cardiometabolic risks.

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell–derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p–/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p–/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p–/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH–releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m2) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 2) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 μIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=−0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

47,XXY (Klinefelter Syndrome) is associated with a spectrum of complex clinical needs that are associated with variable physical, neurocognitive and psychosocial aspects. For patients and families affected by this sex chromosome trisomy, navigation of health care services is difficult due to lack of 47,XXY awareness among many health care providers and little evidence to support endocrine and additional treatment plans. While endocrine management of androgen deficiency has been the mainstay of treatment for patients from puberty through adulthood, testosterone replacement, alone, fails to mitigate many symptoms and issues. Prior to the onset of puberty, boys with 47,XXY often do not receive interdisciplinary evaluations and treatment. Since multiple health and ancillary therapeutic services are required for the management of 47,XXY, patients and families often experience disjointed and uncoordinated care. We discuss complexities of caring for patients with 47,XXY and the benefit of integrating advanced practice nursing and medical perspectives to improve care delivery.

Background Elevated levels of alanine aminotransferase (ALT) are associated with obesity and are often a consequence of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to assess the relationship between ALT and risk factors for adiposity-related co-morbidities in a diverse population of middle school children. Methods We measured height, weight, body fatness (bioelectrical impedance), waist circumference, insulin sensitivity, phase 1 insulin release (acute insulin response following intravenous glucose), beta-cell function (acute insulin response corrected for insulin sensitivity), ALT, lipid profiles, and circulating concentrations of interleukin-6 (IL-6), C-reactive protein, adiponectin, and tumor necrosis factor-α (TNF-α) in a multi-ethnic/racial population of 106 middle school students (aged 11–14 years, 45 female) of varying body mass indexes (BMI). Results Alanine aminotransferase was significantly correlated with BMI, % body fat, fat mass, waist circumference, fasting insulin, insulin resistance, triglycerides, and was inversely correlated with high-density lipoprotein cholesterol in children, even though all values of ALT were “normal” (range of 4.0–33.0 U/L). ALT was significantly higher in males than females even when corrected for body fatness. Significant correlations with lipids and insulin resistance persisted even when adjusted for age, gender, and body fatness. Conclusion Even within the normative range, ALT levels were significantly correlated with anthropomorphic and biochemical risk factors for adiposity-related co-morbidities in youth. Therefore, because ALT is correlated with dyslipidemia, insulin resistance, and central fat distribution, it might also serve as a marker of risk for adiposity-related co-morbidities beyond NAFLD. 摘要 背景： 丙氨酸氨基转移酶（alanine aminotransferase，ALT）水平升高与肥胖相关，这通常是非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）的结果。这项研究的目的是在不同的中学儿童人群中评估ALT与肥胖相关合并症危险因素之间的关系。 方法： 我们在106名体重指数（BMI）不同的多种族/人种中学生人群（年龄为11–14岁，有45名女性）中测量了身高、体重、体脂（生物电阻抗）、腰围、胰岛素敏感性、1相胰岛素释放（静脉注射葡萄糖后的急性胰岛素反应）、β-细胞功能（校正胰岛素敏感性后的急性胰岛素反应）、ALT、血脂谱、循环中的白细胞介素-6（IL-6）、C-反应蛋白、脂联素以及肿瘤坏死因子-α（TNF-α）浓度。 结果： 在儿童中，ALT与BMI、体脂百分比、脂肪含量、腰围、空腹胰岛素、胰岛素抵抗、甘油三酯显著相关，并且与高密度脂蛋白胆固醇负相关，即使所有的ALT值都是“正常的”（范围为4.0–33.0 U/L）。即便校正体脂后，男性ALT仍显著高于女性。血脂与胰岛素抵抗之间存在显著的相关性，即便在校正年龄、性别与体脂之后。 结论： 在年轻人中，即使ALT水平处在标准范围，它仍然与肥胖相关合并症的人体测量学以及生化危险因素显著相关。因此，由于ALT与血脂异常、胰岛素抵抗以及中心性脂肪分布相关，所以除了NAFLD之外它还可以作为一个肥胖相关合并症风险的标志物。

Objective To describe gonadal dysfunction and evaluate polycystic ovary syndrome (PCOS) and its association with metabolic syndrome (MeS) among girls in a morbidly obese adolescent population. Design In a cross-sectional study of 174 girls, height, weight, waist circumference, Tanner stage, reproductive hormones, carbohydrate and lipid markers, drug use, and menstrual history were obtained at baseline. Exclusion criteria were menarcheal age Setting University medical center outpatient clinic. Patient(s) Ninety-eight girls ages 13–19.6 years, Tanner 5, average body mass index of 46.6 kg/m2, menarche at 11.4 years, and average menarcheal age of 5 years. Intervention(s) None. Main Outcome Measure(s) Polycystic ovary syndrome and MeS. Result(s) Ninety-eight girls were divided into four groups: PCOS by National Institutes of Health criteria (PCOSN, n = 24), irregular menses only (n = 25), elevated T (≥55 ng/dL) only (n = 6), and obese controls (n = 43). Metabolic syndrome by modified Cook criteria affected 32 girls or 33% overall: 6 of 24 PCOSN, 7 of 25 irregular menses only, 4 of 6 elevated T only, and 15 of 43 obese controls. Polycystic ovary syndrome by National Institutes of Health criteria and its individual components were not associated with MeS after adjusting for body mass index. Conclusion(s) Unlike obese adults, PCOSN and its individual components were not associated with MeS in the untreated morbidly obese adolescent population.

Objective To determine the frequency of Melanocortin4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations. Design and Methods In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12 month postoperative data available for analysis. Results MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although non-significant, %EWL compared to 52 non-matched controls at 12 months postoperatively (48.6% vs. 23.4%; p

Aim: To compare our recent findings in a cohort of 77 nonmosaic XXY infants

Klinefelter syndrome (KS) is the most common sex chromosome disorder and a major cause of male infertility. In adult patients, serum inhibin B and anti-Mullerian-hormone (AMH) are undetectable, testosterone secretion is often impaired, and the tubules are depleted of germ cells. Before puberty, inhibin B, AMH, and testosterone levels are within the normal range.Sertoli and Leydig cell secretions, including insulin-like peptide-3 (INSL3), were evaluated in infants with nonmosaic XXY karyotype to assess testicular function soon after birth.The study was conducted in four University Pediatric Departments from the United States and France.Sixty-eight prenatally diagnosed infants aged 2-750 d were enrolled.Serum FSH, LH, inhibin B, AMH, and INSL3 were measured by immunoassay, and testosterone was measured by tandem mass-spectrometry.In infants with KS, INSL3 levels transiently increased at 2-3 months of age and were significantly correlated with testosterone (Spearman r = 0.57) and LH (Spearman r = 0.73) levels. They did not differ from controls. Testosterone levels were within the normal range, but most of them were below the median of controls. Inhibin B and AMH levels were also within normal range. Inhibin B was correlated with FSH (Spearman r = 0.49). AMH was not correlated with FSH or testosterone. FSH levels were above normal in 25% of patients, despite normal inhibin B levels.In infants with KS, Leydig cells are normally sensitive to the LH proliferative effect. In contrast, the Sertoli cell sensitivity to FSH is questionable, which may be prophetic of the postpubertal Sertoli cell resistance to FSH.

Aim: To review the evidence base for providing testosterone therapy in the infant and prepubertal child with Klinefelter syndrome (KS). Methods: Major databases were searched to identify articles that addressed the role of testosterone in the development of the male foetus with and without KS and that characterized testicular function in infants with KS. Results: Infants with KS have been shown to have an increased frequency of clinical features consistent with deficient testosterone production. However, there are conflicting results regarding whether testosterone levels are low or normal. No direct data address the outcome of therapy in the prepubertal child. Conclusion: There is an absence of data that directly address the risks and benefits of testosterone therapy in prepubertal children with KS outside of the entity of microphallus. At this time, there is no other documented benefit for testosterone therapy in these children.

Allogenic hematopoietic cell transplantation (alloHCT) is currently the only curative treatment option for patients with sickle cell disease. Alemtuzumab is a monoclonal antibody directed against CD52 positive cells used in myeloablative conditioning regimens for alloHCT. Its use has been associated with development of autoimmune disease in adult patients with rheumatologic conditions. We report on three cases of new onset autoimmune thyroid disease after alloHCT treatment with alemtuzumab in pediatric patients with sickle cell disease.

CME EDUCATIONAL OBJECTIVES 1. Discuss the comorbidities commonly encountered in childhood obesity. 2. Review the evaluations suggested for the comorbidities associated with childhood obesity. 3. Evaluate management suggestions for each of the comorbidities discussed.

Bisphosphonates are currently used in the treatment of osteoporosis (postmenopausal and steroid-induced), hypercalcemia of malignancy, Paget's disease of bone, multiple myeloma, and skeletally related events associated with metastatic bone disease in breast, prostate, lung, and other cancers. There are, however, numerous other conditions where a decrease in bone remodeling by bisphosphonates might aid in disease management. The focus of this review will be to discuss a select group of conditions for which bisphosphonate therapy may be efficacious. In this review we present several cases where bisphosphonates have been used as a primary or adjunctive treatment for giant cell lesions of the jaws. Use of bisphosphonate therapy for giant cell tumors of the appendicular skeleton, pediatric osteogenesis imperfecta, fibrous dysplasia, Gaucher's disease, and osteomyelitis will be discussed. Finally, we will review previous in vivo studies on the use of bisphosphonates to augment integration and to treat osteolysis surrounding failing orthopedic implants.

Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity.Conclusions: We recommend defining overweight as body mass index (BMI) in at least the 85th percentile but < the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.

Objective Congenital lipoid adrenal hyperplasia is an autosomal recessive condition due to mutations in Steroidogenic Acute Regulatory Protein (StAR) associated with the inability to synthesize all adrenal and gonadal steroids, resulting in adrenal insufficiency and failure to develop male genitalia in affected 46,XY individuals. We used two independent methods of prenatal diagnosis for CLAH. Method CLAH was diagnosed prenatally by measuring amniotic fluid estriol, adrenal, and gonadal hormone levels, and by mutation analysis for the c.201–202 delCT mutation in StAR. Results Prenatal testing diagnosed one affected and three unaffected fetuses in two families at risk for CLAH. Conclusion Prenatal testing for CLAH is effective, and targeted molecular genetic analysis should be considered in Palestinian families with a fetus with discordant 46,XY karyotype and female genitalia on ultrasound, and low maternal serum estriol. Copyright © 2007 John Wiley & Sons, Ltd.

Congenital lipoid adrenal hyperplasia (CLAH), caused by mutations in steroidogenic acute regulatory protein (StAR), is most frequent in Japanese and Palestinians. We report eight Palestinians from four unrelated families with CLAH.The objective of the study was to identify the mutation(s) in StAR, correlate genotype with phenotype, and determine whether the common mutation represents a founder mutation.Clinical, histopathological, and molecular genetic characterization was performed in these eight patients.All affected individuals (three XY, five XX) presented neonatally with undetectable adrenocortical hormones and are responding to replacement therapy. Only two sisters had neurodevelopmental deficits. Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells. Significantly, already at 1 yr of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of StAR revealed homozygosity for c.201_202delCT mutation in all eight cases, causing premature termination of the StAR protein. This mutation was confirmed to be a founder mutation using both an intragenic microsatellite and several single nucleotide polymorphism markers. Screening of 100 normal Jerusalem Palestinians detected no carriers of this mutation.CLAH is rare in the general Palestinian population. In most Palestinian cases, a founder c.201_202delCT mutation in StAR is the cause. The observed early neonatal presentation may reflect the major StAR protein truncation caused by this mutation. A crucial role for StAR in the central nervous system was not supported with normal neurological examinations in six of eight cases. Finally, we advocate early gonadectomy in XY CLAH cases, given the early onset of neoplastic changes observed histologically.

Objectives To characterize associations among psychosocial well-being, physical phenotype, and sex hormones in a sample of youth with Klinefelter syndrome (KS). We hypothesized that KS physical traits (phenotype) are associated with adverse psychosocial health measures and that testosterone levels are associated with adverse psychosocial health. Study design Forty-three boys with KS (ages 8-18 years) participated in a cross-sectional study. Participants underwent physical examination, hormone analyses, and psychosocial health questionnaires. Results Using an investigator-developed Klinefelter Phenotype Index Scale, the number of KS physical traits ranged from 1-13 (mean 5.1 ± 1.9). Pubertal boys presented with more KS traits compared with prepubertal boys (5.6 vs 4.2, P = .01). Boys diagnosed prenatally had a milder phenotype compared with those diagnosed postnatally. Gonadotropins were elevated without androgen deficiency in 45%. Psychosocial health scores indicated adverse quality of life (QOL) (67%), low self-esteem (38%), poor self-concept (26%), and risk for depression (16%) without a difference between pubertal groups. Linear regression showed that 22% of the variance in QOL ( P = .0001) was explained by phenotype. Testosterone level was not associated with psychosocial health measures. Conclusions Depending on the degree of phenotypic abnormality, boys with KS may be at risk for impaired QOL. Testosterone levels were not shown to influence psychosocial health. The Klinefelter Phenotype Index Scale may be a useful tool to characterize KS features in boys.

Objective Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control and cardiometabolic risk factors in adults with type 2 diabetes mellitus, but pediatric data is sparse. Research design and methods This is the first report to describe the effects of GLP-1 receptor agonist Exenatide on metabolic risk and weight in adolescents with morbid obesity (BMI>35kg/m2) and type 2 diabetes in the first 6 months after treatment initiation. Two patients with morbid obesity who failed conventional therapy with insulin glargine and Metformin were treated with the addition of Exenatide. Metabolic parameters were obtained at 3 and 6 months post intervention. Results Improvements in cardiometabolic risk factors, such as fasting glucose and triglyceride levels, as well as HbA1c, were reached at 6 months compared to baseline. Conclusions Our cases highlight the therapeutic potential of exenatide for adolescent patients with morbid obesity and type 2 diabetes.

Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management decisions as the pathologic changes can both mimic or lead to thyroid cancer.Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy.Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic.These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients.

Context: Risk factors for type 2 diabetes mellitus (T2DM) include obesity, family history, dyslipidemia, a proinflammatory state, impaired insulin secretory capacity, and insulin resistance. Objective: The aim of this study was to examine the effects of a 3to 4-month school-based intervention consisting of health, nutrition, andexerciseclassesplusanaerobicexerciseprogramondiabetesrisk. Design: This study was a randomized before/after controlled trial. Methods: Seventy-three eighth-grade students in a predominantly Hispanic New York City public school were divided into a control group (studied twice without receiving the intervention) and an experimental group (studied before and after the intervention). Outcome Measures: We measured body fatness (bioelectrical impedance), insulin sensitivity, -cell function (insulin release in response to an iv glucose load corrected for insulin sensitivity), lipid profiles, and circulating concentrations of IL-6, C-reactive protein, adiponectin, and TNF-. Results: Participation in the intervention was associated with significantreductionsinbodyfatness,insulinresistance,andcirculating concentrations of C-reactive protein and IL-6, irrespective of somatotype on enrollment. Conclusion: Short-term school-based health, nutrition, and exercise intervention is beneficial to all students and affects multiple diabetes risk factors. (J Clin Endocrinol Metab 92: 504–508, 2007)

The prevalence of type 2 diabetes mellitus (T2DM) among adolescents has increased 5- to 10-fold over the past decade. T2DM results from pancreatic beta-cell dysfunction and insulin resistance. Using rapid iv glucose tolerance testing, we examined beta-cell function and insulin resistance in 72 predominantly Latino eighth grade students (41 males and 31 females; mean +/- sem age, 13.6 +/- 0.1 yr). Thirty-six percent of the children had body mass indexes above the 85th percentile for age and gender, and 50% had a first- or second-degree relative with T2DM. Overweight children were five times more likely to be in the highest quartile for insulin resistance. Children with a family history of T2DM were five times more likely to be in the lowest quartile for insulin secretory capacity, 4.5 times more likely to be in the lowest quartile for glucose disposal, and three times more likely to be in the lowest quartile for insulin resistance. These findings are consistent with a model for the physiology of T2DM in which a familial beta-cell dysfunction is unmasked by increasing insulin resistance secondary to overweight in this predominantly Latino population.