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Objective: In adults, type 2 diabetes (T2DM) is characterized with progressive deterioration in insulin secretion. Data are scanty in youth. We investigated prospectively the change in β-cell function and in insulin sensitivity in youth with T2DM., Research Design and Methods: Six adolescents with T2DM [hemoglobin A1c (HbA1c) 6.6 ± 1.0%] underwent evaluation of hepatic glucose production (HGP; [6,6-²H₂] glucose), insulin-stimulated glucose disposal (Rd; hyperinsulinemic-euglycemic clamp), first- and second-phase insulin/C-peptide secretion (hyperglycemic clamp), body composition dual energy X-ray absorptiometry (DEXA), and abdominal adiposity (computed tomography) within 3 yr of the diagnosis of diabetes and after 12-16 months of follow-up., Results: Weight, body mass index (37.1 ± 6.9), HbA1c (6.3 ± 0.7%), HGP (2.8 ± 1.2 mg/kg/min), and Rd (4.9 ± 3.4 mg/kg/min) did not change significantly from baseline. However, first-phase insulin and C-peptide declined (152.6 ± 261.2 vs. 75.9 ± 108.5 μU/mL, p = 0.028; 8.0 ± 6.3 vs. 5.9 ± 4.4 ng/mL, p = 0.048, respectively) with no significant change in second-phase insulin/C-peptide. The rate of decline in β-cell function was ∼20% per year., Conclusions: After a median duration of 20 months of diabetes, youth with T2DM manifest a rapid decline in β-cell function with no significant changes in peripheral or hepatic insulin sensitivity. Interventions to retard this deterioration in β-cell function should be investigated., (© 2012 John Wiley & Sons A/S.)

Objectives: To determine if the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL) and non-HDL cholesterol concentration could identify youth with small dense low-density lipoprotein (LDL)., Study Design: One hundred forty-one (75 black and 66 white) overweight adolescents (9 to <18 years) had a fasting measurement of plasma lipids and LDL particle concentrations and size. Receiver operating characteristic curves were used to indicate the ability of different TG/HDL ratios and non-HDL cholesterol concentrations to identify overweight youth with atherogenic LDL concentration and size., Results: Youth with a TG/HDL ratio of ≥3 vs <3 had higher concentrations of small dense LDL (1279.5 ± 60.1 vs 841.8 ± 24.2 nmol/L, P < .001) and smaller LDL particle size (20.3 ± 0.1 vs 21.2 ± 0.1 nm, P < .001). In receiver operating characteristic analyses a TG/HDL cut-point of 3 best predicted LDL concentration in white youth, and 2.5 in black youth. Non-HDL cholesterol cut-point of 120 mg/dL and 145 mg/dL predicted LDL particle concentration in white and in black youth, respectively. TG/HDL ratio with body mass index or waist circumference explained 71% and 79% of the variance, respectively, in total small LDL., Conclusions: TG/HDL ratio and non-HDL cholesterol can identify overweight youth with atherogenic LDL particles. These easily obtained clinical lipid markers, in combination with body mass index and waist circumference, could be cost effective, in observational or interventional studies, for screening and follow-up of youth at heightened risk for atherogenic LDL., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Context: In longitudinal studies of adults, elevated amino acid (AA) concentrations predicted future type 2 diabetes mellitus (T2DM)., Objective: The aim of the present investigation was to examine whether increased plasma AA concentrations are associated with impaired β-cell function relative to insulin sensitivity [i.e. disposition index (DI)], a predictor of T2DM development., Design, Setting, and Participants: Metabolomic analysis for fasting plasma AAs was performed by tandem mass spectrometry in 139 normal-weight and obese adolescents with and without dysglycemia. First-phase insulin secretion was evaluated by a hyperglycemic (∼225 mg/dl) clamp and insulin sensitivity by a hyperinsulinemic-euglycemic clamp. DI was calculated as the product of first-phase insulin and insulin sensitivity., Results: DI was positively associated with branched-chain AAs (leucine/isoleucine and valine; r = 0.27 and 0.29, P = 0.001), neutrally transported AAs (phenylalanine and methionine; r = 0.30 and 0.35, P < 0.001), basic AAs (histidine and arginine; r = 0.28 and 0.23, P ≤ 0.007), serine (r = 0.35, P < 0.001), glycine (r = 0.26, P = 0.002), and branched-chain AAs-derived intermediates C3, C4, and C5 acylcarnitine (range r = 0.18-0.19, P ≤ 0.04)., Conclusion: In youth, increased plasma AA concentrations are not associated with a heightened metabolic risk profile for T2DM; rather, they are positively associated with β-cell function relative to insulin sensitivity. These contrasting observations between adults and youth may be a reflection of developmental differences along the lifespan dependent on the combined impact of the aging process together with the impact of progressive obesity.

Objective: Non-diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM., Research Design and Methods: Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of IS and clearance (hyperinsulinemic-euglycemic clamp), first- and second-phase insulin and C-peptide secretion (hyperglycemic clamp); body composition (DEXA); and abdominal adiposity (CT)., Results: AA and AW T2DM had similar HbA1c, diabetes duration, BMI, and % body fat, with lower visceral fat in AAs (p = 0.013). While insulin-stimulated glucose disposal was similar in AA and AW (7.5 ± 1.0 vs. 7.3 ± 0.9 mg/kg FFM/min), IS tended to be lower (2.5 ± 0.4 vs. 3.8 ± 0.6 mg/kg FFM/min per µU/mL, p = 0.081). First-phase insulin (175.7 ± 52.9 vs. 66.6 ± 10.8 µU/mL, p = 0.01) and second-phase insulin (236.2 ± 40.7 vs. 105.1 ± 17.9 µU/mL, p = 0.008), and first-phase C-peptide (8.2 ± 1.2 vs. 5.0 ± 0.3 ng/mL, p = 0.02) and second-phase C-peptide (10.8 ± 0.9 vs. 7.6 ± 0.6 ng/mL, p = 0.012) were higher in AA. β-Cell function relative to IS was higher in AA vs. AW (259.5 ± 35.3 vs. 168.8 ± 25.1 mg/kg FFM/min, p = 0.043)., Conclusions: Racial differences in insulin secretion can be demonstrated with the clamp technique in obese adolescents with T2DM. Similar to non-diabetic youth, AA adolescents with T2DM compared with their AW counterparts have an upregulated β-cell function relative to IS, the reasons for which remain to be investigated., (© 2011 John Wiley & Sons A/S.)

Objective: To explore associations between measures of obstructive sleep apnea (OSA) and sleep quality, anthropometrics, and neurocognitive functioning in severely obese adolescents., Study Design: This was a cross-sectional pilot study performed at an academic medical center in 37 severely obese (body mass index [BMI] >97th percentile) adolescents. Study evaluations included polysomnography, BMI, waist circumference, and standardized neurocognitive tests to assess memory, executive functioning, psychomotor efficiency, academic achievement, and an approximation of full-scale IQ. Outcome data were evaluated categorically, based on clinical criteria for the diagnosis of OSA, and continuously to quantify associations between sleep parameters, anthropometrics, and neurocognitive test results., Results: Sleep fragmentation and poorer sleep quality were associated with reduced psychomotor efficiency, poorer memory recall, and lower scores on standardized academic tests. Having evidence of OSA was associated with lower math scores, but not with other neurocognitive measures. BMI and waist circumference were negatively associated with oxygen saturation., Conclusion: Our pilot study findings suggest that sleep fragmentation and poorer sleep quality have implications for neurocognitive functioning in obese adolescents. The epidemic of childhood obesity has dire implications, not only for increasing cardiometabolic pathology, but also for possibly promoting less readily apparent neurologic alterations associated with poor sleep quality., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Study Objective: Little is known about racial differences in androgen levels among obese children. The objective of this pilot study was to compare basal and stimulated androgen levels in a cross-sectional sample of obese black and white pubertal females. STUDY DESIGN, SETTING, AND PARTICIPANTS: This was cross-sectional study of obese (body mass index ≥ 95th percentile) but otherwise healthy female adolescents (10 black and 12 white; age range 8.8-13.9 y) who underwent adrenocorticotropic hormone stimulation testing at an academic medical center as part of a protocol for the study of obesity-related conditions., Main Outcome Measures: Basal and stimulated androgen levels., Results: White and black participants were similar with regard to pubertal stage, body mass index, percentage body fat, and fasting glucose and insulin levels. Black girls had lower stimulated levels of 17-hydroxyprogesterone, and the differences between basal and stimulated levels of 17-hydroxyprogesterone and androstenedione were lower in black girls. Body mass index was negatively correlated with stimulated cortisol in blacks only (r = -0.69, P = .03)., Conclusion: There appear to be race-related differences in stimulated androgen levels in obese adolescent females. These differences deserve further study, as measurements of androgen levels are commonly used in clinical practice and research., (Copyright © 2012 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Evidence supports the importance of parental involvement for youth's ability to manage weight. This study utilized the stages of change (SOC) model to assess readiness to change weight control behaviors as well as the predictive value of SOC in determining BMI outcomes in forty adolescent-parent dyads (mean adolescent age = 15 ± 1.84 (13-20), BMI = 37 ± 8.60; 70% white) participating in a weight management intervention for adolescent females with polycystic ovary syndrome (PCOS). Adolescents and parents completed a questionnaire assessing their SOC for the following four weight control domains: increasing dietary portion control, increasing fruit and vegetable consumption, decreasing dietary fat, and increasing usual physical activity. Linear regression analyses indicated that adolescent change in total SOC from baseline to treatment completion was not predictive of adolescent change in BMI from baseline to treatment completion. However, parent change in total SOC from baseline to treatment completion was predictive of adolescent change in BMI, (t(24) = 2.15, p = 0.043). Findings support future research which carefully assesses adolescent and parent SOC and potentially develops interventions targeting adolescent and parental readiness to adopt healthy lifestyle goals.

Objective: The aim of the study was to examine the relationship between vitamin D status, total and abdominal adiposity, and lipids in black and white children., Methods: Plasma 25-hydroxyvitamin D [25(OH)D], adiposity [body mass index (BMI), percentage of total body fat, visceral adipose tissue (VAT), sc adipose tissue (SAT)], and fasting lipids were assessed in healthy obese and nonobese 8- to 18-yr-old black and white children., Results: We studied 237 children (mean ± sd age, 12.7 ± 2.2 yr; 47% black, 47% obese, and 43% male). Mean 25(OH)D concentration for the entire cohort was 19.4 ± 7.4 ng/ml. The majority of the children were vitamin D deficient [25(OH)D < 20 ng/ml; 73% blacks, 40% whites]. Plasma 25(OH)D was associated inversely with BMI, BMI percentile, percentage of total body fat, VAT, and SAT and positively with HDL cholesterol in the entire cohort. VAT was higher in vitamin D-deficient whites, and SAT was higher in vitamin D-deficient blacks compared with their respective vitamin D-nondeficient counterparts. Race, season, pubertal status, and VAT were independent significant predictors of 25(OH)D status., Conclusions: In black and white youth examined together, lower levels of 25(OH)D are associated with higher adiposity measures and lower HDL. Furthermore, vitamin D deficiency is associated with higher VAT in whites and greater SAT in blacks. Besides therapeutic interventions to correct the high rates of vitamin D deficiency in youth, benefits of vitamin D optimization on adiposity measures and lipid profile need to be explored.

Objective: It is unknown whether measurement site of visceral adipose tissue (VAT) influences the relationship between VAT and associated health risk in youth and if so, whether ethnic differences exist in this relationship. We examined the influence of the measurement site of VAT on the relationships between VAT and metabolic syndrome (MetS) in African-American (AA) and American-White (AW) youth., Subjects: Healthy AA (n = 54) and AW (n = 54) children and adolescents (age: 8-18 yr; BMI: 15.3-42.5 kg/m(2))., Measurements: VAT mass was derived using a series of five transverse images measured by magnetic resonance imaging, extending from 5 cm below to 15 cm above L4-L5. MetS was defined using a modified IDF criteria., Results: In AA, VAT measure at 5 cm above L4-L5 (R(2) = 0.93) was most strongly (p < 0.05) correlated with VAT mass and was a significantly (p < 0.05) stronger correlate as compared to L4-L5 (R(2) = 0.84). In AW, VAT measures at 5 cm (R(2) = 0.93) and 10 cm (R(2) = 0.93) above L4-L5 were most strongly (p < 0.05) correlated with VAT mass; however, these were not stronger correlates as compared to L4-L5 (R(2) = 0.91). In AW, all VAT measures were significantly (p < 0.05) associated with an increased odds ratio (OR) for prevalent MetS, wherein the VAT mass [OR = 5.32(1.9-15.0)] and VAT at L4-L5[OR = 5.99(1.9-18.4)] were most strongly associated with MetS. In contrast, only VAT at 10 cm above L4-L5 [OR = 4.39 (1.1-18.1)] was significantly (p < 0.05) associated with MetS in AA., Conclusion: In AA and AW youth, the measurement site for VAT has impact on the estimation of total VAT and the magnitude of the association with obesity-related health risks., (© 2010 John Wiley & Sons A/S.)

Sleep-disordered breathing is associated with obesity, insulin resistance, and the metabolic syndrome in adults. Similar data in children is limited and conflicting. This pilot study examined the relationships between sleep-disordered breathing, visceral adiposity, and cardiometabolic risk factors in obese adolescents. Twenty obese (body mass index ≥ 95(th) percentile), otherwise healthy adolescents (age 14.9 ± 2 years) underwent polysomnogram studies, fasting lipid profile and oral glucose tolerance tests, and measures of body composition (dual-energy X-ray absorptiometry) and visceral adiposity (abdominal computed tomography). The severity of sleep-disordered breathing (as measured by apnea-hypopnea index) was positively associated with visceral adipose tissue (r = 0.73, p < 0.001) but not with other measures of body composition. After controlling for body mass index, the severity of sleep-disordered breathing was positively associated with markers of insulin resistance (homeostasis model assessment and fasting insulin). Further study to allow for critical assessment of the relationships between sleep-disordered breathing and cardiometabolic risk factors in obese youth remains necessary.

Objective: Large waist circumference (WC) is associated with cardiovascular disease and type 2 diabetes. The present study determined differences in lipoprotein particle size and subclass concentration and markers of vascular smooth muscle function in children using WC percentile cutoffs., Research Design and Methods: Participants were 182 children (87 black, 92 female) aged 8-<18 yr. Each participant had a measurement of WC and a fasting blood draw for the measurement of lipoprotein particle concentration and size and circulating biomarkers of endothelial function. Participants were divided into age-, sex-, and ethnicity-specific WC percentiles of below 75th, 75th to 90th, and at least 90th percentiles, and differences in lipoproteins and vascular smooth muscle markers were compared among groups., Results: Children in the 90th percentile or higher for WC had significantly smaller low-density lipoprotein and high-density lipoprotein size than children with WC below this percentile. For lipoprotein concentration, small low-density lipoprotein and large very low density lipoprotein and chylomicrons were lower, and large high density lipoprotein concentrations were higher in children whose WC was below the 75th percentile compared with those with WC in the 90th percentile or higher. Concentrations of the vascular smooth muscle biomarkers, intercellular adhesion molecule-1, and E-selectin were significantly higher in children with WC in the 90th percentile or higher than in children below the 75th percentile., Conclusion: Youths with WC in the 90th percentile or higher have an atherogenic lipoprotein profile with increased concentrations of biomarkers of vascular smooth muscle dysfunction. Given that atherosclerosis begins in childhood, such evidence suggests that these children should be targeted for interventions to reduce adiposity at an early age.

Objective: To examine sex-specific black/white differences in lipoprotein profile and the role of visceral adiposity and to assess the relationship between insulin sensitivity and lipoprotein profiles in each group., Research Design and Methods: Fasting lipoprotein particle size and concentration and visceral adipose tissue (VAT) were determined in 226 children (117 black, 101 male) aged 8 to <18 years. The relationship between lipoproteins and insulin sensitivity was evaluated in a subset of 194 children (100 black, 88 male) who underwent a hyperinsulinemic-euglycemic clamp., Results: Black male children had smaller VLDL and black female children had larger HDL size than their white counterparts. Overall, blacks had larger LDL size with no sex-specific race differences. After adjusting for VAT and sex, only VLDL size and concentrations remained significantly favorable in blacks. Analysis of lipoprotein particle size and concentration across insulin sensitivity quartiles revealed that in both racial groups, the most insulin-resistant children had higher concentrations of small dense LDL, small HDL, and large VLDL and smaller LDL and HDL sizes than their more insulin-sensitive counterparts., Conclusions: The previously reported favorable lipoprotein profiles in black versus white children is partly due to race differences in VAT. In both groups, however, the most insulin-resistant youths have a high-risk atherogenic profile of small dense LDL, small HDL, and large VLDL, akin to the atherogenic lipoprotein pattern in adults with coronary artery disease.

Objective: We evaluated the efficacy of family-based, behavioral weight control in the management of severe pediatric obesity., Methods: Participants were 192 children 8.0 to 12.0 years of age (mean +/- SD: 10.2 +/- 1.2 years). The average BMI percentile for age and gender was 99.18 (SD: 0.72). Families were assigned randomly to the intervention or usual care. Assessments were conducted at baseline, 6 months, 12 months, and 18 months. The primary outcome was percent overweight (percent over the median BMI for age and gender). Changes in blood pressure, body composition, waist circumference, and health-related quality of life also were evaluated. Finally, we examined factors associated with changes in child percent overweight, particularly session attendance., Results: Intervention was associated with significant decreases in child percent overweight, relative to usual care, at 6 months. Intent-to-treat analyses documented that intervention was associated with a 7.58% decrease in child percent overweight at 6 months, compared with a 0.66% decrease with usual care, but differences were not significant at 12 or 18 months. Small significant improvements in medical outcomes were observed at 6 and 12 months. Children who attended > or =75% of intervention sessions maintained decreases in percent overweight through 18 months. Lower baseline percent overweight, better attendance, higher income, and greater parent BMI reduction were associated with significantly greater reductions in child percent overweight at 6 months among intervention participants., Conclusions: Intervention was associated with significant short-term reductions in obesity and improvements in medical parameters and conferred longer-term weight change benefits for children who attended > or =75% of sessions.

Objective: African American youth have lower insulin sensitivity than their Caucasian peers, but the metabolic pathways responsible for this difference remain unknown. Free fatty acids (FFAs) are associated with insulin resistance through the Randle cycle. The present investigation determined whether elevating FFA is more deleterious to insulin sensitivity in African American than in Caucasian adolescents., Research Design and Methods: Insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp) was evaluated in 22 African American and 21 Caucasian adolescents on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid., Results: During intralipid infusion, fasting insulin and C-peptide concentrations increased while fasting glucose and basal glucose turnover did not change in either group. Insulin sensitivity decreased similarly in African American (normal saline 7.65 +/- 0.61 vs. intralipid 5.15 +/- 0.52 micromol x kg(-1) x min(-1) per pmol/l) and Caucasian subjects (normal saline 8.97 +/- 0.85 vs. intralipid 5.96 +/- 0.56 micromol x kg(-1) x min(-1) per pmol/l) (P < 0.001)., Conclusions: African American and Caucasian adolescents respond to FFA elevation similarly through increased fasting insulin secretion to maintain fasting glucose homeostasis and reduced peripheral glucose uptake and insulin resistance. Thus, African American adolescents are not more susceptible to FFA-induced insulin resistance than Caucasian youth.

Introduction: The prevalence of obesity is higher in Blacks with racial divergence in adiposity in girls starting during adolescence. Our hypothesis is that in Black children, puberty associated increase in fat oxidation is diminished and could play a role in predisposing to fat accretion triggered during puberty. Thus, we examined the relationships between race, pubertal development, and postabsorptive fat oxidation in youth., Subjects and Methods: This was a cross-sectional design of healthy Black (n=50) and white (n=51) youth. Resting metabolic rate (RMR) and substrate oxidation rate were measured after an overnight fast with indirect calorimetry. Body composition was measured by dual-energy x-ray absorptiometry., Results and Discussion: Within each race, RMR (kcal/kg fat free mass.min) was lower (puberty effect; P<0.05) in the pubertal vs. prepubertal group independent of gender. In girls, RMR was lower (race effect; P<0.05) in Blacks vs. whites. In girls but not boys, Blacks had lower (race effect; P=0.033) fat oxidation (micromol/kg fat free mass.min) compared with whites independent of pubertal status. Furthermore, the difference in fat oxidation between the prepubertal vs. pubertal groups tended to be greater (puberty x race interaction; P=0.089) in white girls (3.7+/-0.5 vs. 6.5+/-0.5) than in Black girls (3.4+/-0.6 vs. 4.5+/-0.5). These data suggest that the lower fat oxidation and RMR during puberty in Black girls could be a risk factor predisposing to obesity. This metabolic phenotype could potentially explain the divergence in adiposity in Black girls during adolescence against the backdrop of an obesogenic environment.

Objective: African-American (AA) children are hyperinsulinemic and insulin resistant compared with American white (AW) children. Previously, we demonstrated that insulin secretion relative to insulin sensitivity was approximately 75% higher in AA compared with AW children, suggesting that hyperinsulinemia in AA children is not merely a compensatory response to lower insulin sensitivity. The aim of the present investigation was to assess whether glucose-stimulated insulin response is higher in AA versus AW adolescents who have comparable in vivo insulin sensitivity., Research Design and Methods: The hyperinsulinemic-euglycemic and hyperglycemic clamp techniques were utilized to assess first- and second-phase insulin secretion. Insulin secretion relative to insulin sensitivity was calculated as the glucose disposition index., Results: AA adolescents compared with their AW peers with comparable insulin sensitivity and body composition had higher first-phase insulin concentrations., Conclusions: The quantitative relationship between insulin sensitivity and first-phase insulin appears to differ among AA and AW adolescents.

Objective: We examined the influence of race and gender on abdominal adipose tissue (AT) distribution for a given anthropometric measure including waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height (W/Ht) in youth., Methods and Procedures: Subjects included healthy 62 black and 98 white youth. A single transverse image of the abdomen (L4-L5) was obtained using computed tomography., Results: For a given BMI, there was a significant (P<0.05) main effect of race and sex on the relationship between BMI and WC, such that boys and whites had a higher WC than girls and blacks. There was a significant (P<0.05) main effect and interaction effect of gender on the relationship between WC and visceral AT, such that boys had a higher visceral AT than girls, and the difference was magnified with increasing WC. For a given WC, black boys and girls had higher abdominal subcutaneous AT (SAT) than white peers, wherein the magnitude of the difference is increased with increasing WC. For a given W/Ht, black boys had significantly (P<0.05) lower visceral AT than white boys, but with no difference in girls. Black boys and girls had higher SAT than white peers, wherein the magnitude of the difference is increased with increasing W/Ht., Discussion: Our findings demonstrate a significant race and gender differential in the abdominal AT distribution for a given BMI, WC, WHR, and W/Ht. Future studies should take these differences into consideration when developing race- and gender-specific anthropometric cut-offs for obesity and obesity-related health risks in youth.

Context: Cross-sectional observations show an inverse relationship between pubertal increase in GH and insulin sensitivity, suggesting that pubertal insulin resistance may be mediated by GH., Objective: Our objective was to assess longitudinally the effects of short-term GH supplementation in adolescent males with non-GH-deficient idiopathic short stature (ISS) on body composition, substrate metabolism, and insulin sensitivity. Children with ISS were studied to simulate the pubertal increase in GH secretion., Participants and Setting: Eight males with ISS (10.8-16.5 yr) were recruited from pediatric endocrinology clinics at an academic medical center., Study Design: Participants were evaluated in the General Clinical Research Center before and after 4 months of GH supplementation (0.3 mg/kg.wk). Body composition was assessed with dual-energy x-ray absorptiometry. Whole-body glucose, protein, and fat turnover were measured using stable isotopes. In vivo insulin action was assessed during a 3-h hyperinsulinemic (40 mU/m(2).min) euglycemic clamp., Results: GH supplementation led to 1) increase in hepatic glucose production and fasting insulin levels, 2) increase in lean body mass and decrease in fat mass, and 3) improvement in cardiovascular lipid risk profile. Plasma IGF-I levels correlated positively with insulin levels., Conclusions: Four months of GH supplementation in adolescent males with ISS is associated with significant body composition changes and hepatic insulin resistance.

The purpose of this study was to determine whether cardiorespiratory fitness (CRF) is associated with lower abdominal adiposity in youth. Subjects included healthy 61 African-American and 52 white children and adolescents (age: 8-17 years). Body composition was measured by dual-energy X-ray absorptiometry and computed tomography. CRF (VO(2max)) was assessed using a graded maximal treadmill test. CRF was inversely related (P<0.05) to total adiposity, waist circumference, and visceral and abdominal subcutaneous adipose tissue (AT) independent of race. These findings remained significant (P<0.05) after adjusting for age, gender and pubertal status. Multiple regression analyses revealed that CRF is an independent contributor (P<0.05) of waist circumference, and visceral and abdominal subcutaneous AT after accounting for age, pubertal status, gender and body mass index percentile. Our observation suggest that in youth, CRF is associated with lower visceral and abdominal subcutaneous AT, and reinforces the notion that youth should engage in regular physical activity to improve aerobic fitness and reduce abdominal adiposity.

Parallel to the increase in obesity worldwide, there has been a rise in the prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. The etiology of T2DM in youth, similar to adults, is multifactorial including genetic and environmental factors, among them obesity, sedentary lifestyle, family history of the disease, high-risk ethnicity and insulin resistance phenotype playing major roles. Treatment of T2DM should not have a glucocentric approach; it should rather target improving glycemia, dyslipidemia, hypertension, weight management and the prevention of short- and long-term complications. Prevention strategies, especially in high-risk groups, should focus on environmental change involving participation of families, schools, the food and entertainment industries and governmental agencies. Presently, limited pharmacotherapeutic options need to be expanded both for childhood T2DM and obesity. The coming decades will prove very challenging for healthcare providers battling socioeconomic waves conducive to obesity and T2DM. Evidence-based research and clinical experience in pediatrics, possibly modeled after adult trials, need to be developed if this public health threat is to be contained., (Copyright (c) 2007 S. Karger AG, Basel.)

Cross-sectional studies have shown that 1) adolescents are insulin resistant compared with prepubertal children and adults, 2) pubertal insulin resistance is likely mediated by growth hormone (GH), and 3) pubertal insulin resistance is associated with increased fat oxidation and decreased glucose oxidation. The aim of this study was to assess the validity of these cross-sectional observations by performing a longitudinal study in normal children during the prepubertal and pubertal periods. Nine healthy, normal weight, prepubertal children underwent hyperinsulinemic-euglycemic and hyperglycemic clamp studies for evaluation of insulin sensitivity and insulin secretion. Children had repeat evaluations during puberty. Consistent with cross-sectional observations, this longitudinal study demonstrated that during puberty: 1) insulin sensitivity decreased by approximately 50%, 2) the decrease in insulin sensitivity was compensated by a doubling in insulin secretion, and 3) the decrease in insulin sensitivity was independent of changes in percentage of body fat. Puberty was associated with increased total body lipolysis and decreased glucose oxidation. A novel observation is the demonstration of approximately 50% decrease in adiponectin levels at the pubertal time point. These metabolic changes are proposed to be partially mediated by increased GH secretion and are consistent with the Randle cycle of competition between glucose and fat oxidation.

Objectives: To examine whether waist circumference (WC) predicts blood pressure (BP) and lipid components of the metabolic syndrome independent of body mass index (BMI) percentile in youths., Study Design: The study group comprised 70 African-American youths and 97 Caucasian youths. Outcome measures included BP, lipid profile, and abdominal adipose tissue (AT)., Results: Both BMI percentile and WC were significantly (P < .05) associated with daytime and nighttime systolic and diastolic BP, triglycerides (TG), high-density lipoprotein (HDL), and TG/HDL ratio independent of race. In African-Americans and Caucasians, WC remained a significant (P < .05) correlate of daytime (r = .50 and .59, respectively) and nighttime (r = .49 and .62, respectively) systolic BP, and in Caucasians, TG, HDL, TG/HDL, and very-low-density lipoprotein after controlling for BMI percentile. After accounting for age, sex, and race, the addition of WC to BMI percentile increased the variance (R(2)) in systolic BP by 15% (P < .05). The inclusion of WC with BMI percentile explained an additional 3% and 7% of the variance in TG and HDL, respectively (P < .05)., Conclusions: The prediction of childhood obesity-related health risks is significantly improved by the inclusion of WC in addition to BMI percentile. This observation supports the notion that WC should be included in the evaluation of childhood obesity along with BMI percentile to identify those at increased health risks due to excess abdominal fat.

Context: Markers to identify overweight youth with insulin resistance are of clinical importance., Objective: To determine if markers of dyslipidemia could identify overweight adolescents with insulin resistance. SETTING, PARTICIPANTS, AND STUDY DESIGN: We retrospectively examined the association between markers of dyslipidemia and insulin resistance in 35 overweight [body mass index (BMI) of > or =95th percentile], white adolescents [mean age 13.5 +/- (SD) 1.6 yr] who had participated in hyperinsulinemic-euglycemic clamp studies to evaluate insulin action. Total body fat was measured by dual-energy X-ray absorptiometry and abdominal fat with computed tomography. Using receiver-operating curves, cut-points for triglyceride (TG)/high-density lipoprotein (HDL) and TG level to identify overweight individuals in the lowest tertile for insulin sensitivity were determined., Main Outcome Measure: Difference in the values for insulin sensitivity among the groups., Results: Of the markers examined (TG, TG/HDL, adiponectin, measures of adiposity and fasting insulin), fasting insulin was the strongest correlate of insulin sensitivity (r = 0.87, p < 0.001). Youth with TG/HDL level > or =3 had lower insulin sensitivity (50% lower median values, p < 0.01) and higher visceral fat (p < 0.05) despite BMI comparable to that of youth with TG/HDL level <3. Youth with TG/HDL > or =3 had a sensitivity of 61% and specificity of 82% for identifying participants with the greatest degree of insulin resistance., Conclusions: TG and TG/HDL are easily obtained markers associated with insulin resistance. Further research is needed to determine if a constellation of clinical findings, such as components of the metabolic syndrome along with other metabolic markers including adiponectin, better predicts insulin resistance in overweight youth.

Objective: We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African-American (n = 65) and white (n = 57) youth., Research Methods and Procedures: IS and beta-cell function were evaluated by a 3-hour hyperinsulinemic-euglycemic and a 2-hour hyperglycemic (12.5 mM) clamp, respectively. Total fat was measured by DXA and abdominal fat with computed tomography. CRF (peak volume of oxygen) was measured using a graded maximal treadmill test., Results: Independent of race, CRF was inversely (p < 0.05) related to total and abdominal fat, fasting insulin and first phase insulin secretion, and positively (p < 0.05) related to IS. When subjects were categorized into low (< or = 50th) and high (> 50th) CRF groups, IS was significantly (p < 0.05) higher in the high compared with the low CRF group independently of race. Furthermore, first and second phase insulin secretion were lower (p < 0.05) in the high CRF group in comparison with the low CRF group in both races. However, in multiple regression analyses CRF was not (p > 0.05) an independent predictor of IS and acute insulin secretion after accounting for total adiposity., Discussion: Our findings demonstrate that low CRF is associated with decreased IS compensated by higher insulin secretion in both African-American and white youth. However, this relationship disappears after adjusting for differences in adiposity, suggesting that the association between fitness and IS is mediated, at least in part, through fatness.

Objective: Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics., Research Design and Methods: We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels., Results: OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity., Conclusion: The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.

Objective: Obesity is often associated with insulin resistance and the components of the metabolic syndrome. However, wide variations in insulin sensitivity are noted in obese youth. It is not clear if greater insulin resistance confers a higher risk of cardiovascular comorbidities and risk for type 2 diabetes., Research Design and Methods: We investigated physical and metabolic features of 54 obese adolescents. Subsequently, we pair matched 17 moderately insulin-resistant (MIR group) to 17 severely insulin-resistant (SIR group) youth based on cut points for insulin sensitivity (MIR group insulin sensitivity within 2 SDs and SIR group <2 SDs of normal-weight adolescent values). We evaluated differences in body composition (dual-energy X-ray absorptiometry), abdominal fat (computed tomography scan), cardiorespiratory fitness (CRF) (Vo(2max) on a treadmill), insulin sensitivity and secretion (hyperinsulinemic-euglycemic and hyperglycemic clamps), substrate utilization (indirect calorimetry), and fasting adiponectin and lipid profile., Results: SIR youth had higher visceral adiposity (78.3 +/- 6.9 vs. 60.3 +/- 6.9 cm(2), P = 0.017) and waist-to-hip ratio (0.91 +/- 0.01 vs. 0.86 +/- 0.02, P = 0.026) and lower HDL (1.0 +/- 0.03 vs. 1.16 +/- 0.06 mmol/l, P = 0.015) than pair-matched MIR subjects. There was a tendency for adiponectin (6.1 +/- 0.5 vs. 8.6 +/- 1.1 microg/ml, P = 0.079) and CRF (49.9 +/- 3.2 vs. 55.2 +/- 3.5 ml x min(-1) x kg(-1) fat-free mass, P = 0.09) to be lower in SIR subjects. SIR youth also had an impaired balance between insulin sensitivity and beta-cell compensation with a lower glucose disposition index., Conclusions: Despite similar BMI, the degree of insulin resistance impacts the risk for obesity-related metabolic comorbidities. The SIR youth are at greater risk for type 2 diabetes and cardiovascular disease.

Objectives: We examined how well waist circumference (WC) reflects total and abdominal fat and whether WC predicts insulin resistance independent of body mass index (BMI) percentile in youths., Study Design: Body composition was measured by dual-energy x-ray absorptiometry and abdominal adiposity by computed tomography. Insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp., Results: Both BMI percentile and WC were significantly associated (P < .01) with total and abdominal fat and insulin sensitivity. WC remained a significant (P < .01) correlate of total and abdominal fat and insulin sensitivity after controlling for BMI percentile. By contrast, BMI percentile did not remain a significant correlate of visceral fat and markers of insulin resistance after controlling for WC. Without exception, WC explained a greater variance in abdominal fat and metabolic profiles than did BMI percentile., Conclusions: Our findings suggest that the prediction of health risks associated with obesity in youths is improved by the additional inclusion of WC measure to the BMI percentile. Such observations would reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk due to excess abdominal fat.

Background: A range of allometric coefficients have been proposed in describing the maximal oxygen uptake (VO2max): body mass relation in children using weight-bearing ergometry. However, a wide deviation in the allometric coefficients for VO2max may be apparent when selected pediatric cohorts are studied in conjunction with clinical intervention for growth abnormalities., Aim: The purpose of this study was to determine the allometric coefficients for VO2max after short-term pharmacologically induced growth in pre- and early pubescent children., Subjects and Methods: The treatment group consisted of nine subjects with non-growth hormone (GH)-deficient short stature and one with GH-deficient short stature (mean age: 13.7+/-1.7 years). Ten pre- and early pubescent children matched for age, height, weight, VO2max and body mass index (BMI) were controls. The treatment group were evaluated before (Pre-GH) and after (Post-GH) 4 months of subcutaneous GH therapy (0.05 mgkg(-1)day(-1) x 6 days week(-1))., Results: The mean ontogenetic coefficient for the treatment group was 1.50+/-0.20 and for the control group was 0.77+/-0.34. The mean allometric coefficient for body mass relative to VO2max was significantly higher in the treatment group compared with the control group (p<0.05). Height, weight, fat free mass (FFM), VO2max indexed to body mass (mLkg(-1)min(-1)) and FFM (mLkgFFM(-1)min(-1)) increased (p<0.05) with GH therapy. GH therapy also increased insulin-like growth factor-I (IGF-I) and served as a biochemical marker of GH therapy (p<0.05). The control group had no significant differences in all the variables tested (p<0.05)., Conclusion: The scaling for oxygen uptake (VO2) for body mass varies with GH treatment and the increase in VO2max that commonly occurs in conjunction with physical growth in the pre-and early pubescent individual may be linked to an increase in FFM and linear size.

The purpose of this investigation was to determine whether maximal oxygen consumption (VO2max) differed between clinically obese black and white children and if a difference existed to determine whether it was related to hematological profiles and/or physical activity/inactivity levels. Twenty-three black and 21 white adolescents were matched for age, BMI, and Tanner stage (II-V). Body composition was determined by DEXA and CT scan. Daily physical activity/inactivity was assessed by questionnaire. VO2max was assessed using the Bruce treadmill protocol. Black participants had significantly lower VO2max and VO2maxFFM values when compared with white adolescents (26.1 +/- 4.2 versus 29.9 +/- 3.1 mL . kg(-1) . min(-1); 48.3 +/- 8.8 versus 55.6 +/- 5.2 mL . kgFFM(-1) . min(-1), respectively). Black adolescents also had significantly lower Hb concentrations ([Hb]) than white children (12.7 +/- 1.3 versus 13.4 +/- 0.7 g/dL). Black adolescents were more physically inactive than their white peers. VO2max correlated with [Hb] for the combined groups. Obese black adolescents had lower VO2max compared with white children and this difference was explained, in part, by the lower [Hb] observed in the black participants. Further investigations should study Hb flow rate (a function of [Hb] . maximal cardiac output) and physical activity/inactivity patterns in obese black and white children as it relates to VO2max.

Until recently, the majority of cases of diabetes mellitus among children and adolescents were immune-mediated type 1a diabetes. Obesity has led to a dramatic increase in the incidence of type 2 diabetes (T2DM) among children and adolescents over the past 2 decades. Obesity is strongly associated with insulin resistance, which, when coupled with relative insulin deficiency, leads to the development of overt T2DM. Children and adolescents with T2DM may experience the microvascular and macrovascular complications of this disease at younger ages than individuals who develop diabetes in adulthood, including atherosclerotic cardiovascular disease, stroke, myocardial infarction, and sudden death; renal insufficiency and chronic renal failure; limb-threatening neuropathy and vasculopathy; and retinopathy leading to blindness. Health care professionals are advised to perform the appropriate screening in children at risk for T2DM, diagnose the condition as early as possible, and provide rigorous management of the disease.

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.

The marked increase in conditions associated with insulin resistance in youth, including obesity, polycystic ovary syndrome, type 2 diabetes mellitus etc., has prompted the need to assess insulin sensitivity in this age group. Even though insulin resistance plays an important role in disorders of glucose metabolism and other pathological conditions, both insulin sensitivity and insulin secretion should be determined for a comprehensive evaluation of glucose homeostasis disorders. Insulin sensitivity and secretion are intricately coupled with a delicate feedback mechanism governing their relationship. This article will delineate our paediatric experience with the clamp technique, the hyperinsulinaemic-euglycaemic clamp in assessing in vivo insulin sensitivity, and the hyperglycaemic clamp in assessing insulin secretion., (Copyright (c) 2005 S. Karger AG, Basel.)

Objective: Family history of type 2 diabetes is a major risk factor for type 2 diabetes in youth, which is increasing. This investigation aimed to evaluate the impact of family history of type 2 diabetes on insulin secretion relative to insulin sensitivity in healthy children. beta-Cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity x first-phase insulin secretion, termed glucose disposition index (GDI)., Research Design and Methods: A total of 28 healthy white children (12 boys and 16 girls; 12.1 +/- 0.5 years of age) with a positive family history of type 2 diabetes and 26 healthy white children (13 boys and 13 girls; 11.5 +/- 0.4 years of age) with a negative family history of type 2 diabetes underwent a 3-h 40 mU.m(-2).min(-1) hyperinsulinemic-euglycemic clamp to assess insulin sensitivity and clearance and a 2-h hyperglycemic clamp to assess insulin secretion. Body composition and visceral adiposity were evaluated with dual-energy X-ray absorptiometry and computed tomography at the L4-L5 intervertebral space., Results: Insulin sensitivity was lower in children with a family history of type 2 diabetes versus children without a family history (8.8 +/- 0.9 vs. 12.2 +/- 1.1 micromol.kg(-1).min(-1) per pmol/l, P = 0.02). Similarly, insulin clearance was lower. First- and second-phase insulin levels were not different between groups with and without a positive family history. The GDI was lower in youth with versus youth without a positive family history (4.1 +/- 0.3 vs. 5.2 +/- 0.5 mmol.kg(-1).min(-1), P = 0.039). IGF binding protein-1 (IGFBP-1) was 60% lower in youth with versus youth without the positive family history., Conclusions: These results demonstrate that family history of type 2 diabetes in white children is associated with decreased insulin sensitivity and clearance, decreased IGFBP-1, and an impaired relationship between insulin action and beta-cell compensation. Detection of these alterations in hormonal and metabolic parameters in children with a positive family history suggests that at least some of the determinants of GDI are genetic/heritable.

The purpose of this investigation was to determine whether maximal oxygen consumption (VO2max) differed between two selected groups of black and white children and whether a difference existed to determine whether it was related to hematologic profiles, body composition, and/or physical activity/inactivity level. Forty-five prepubertal and 42 pubertal, clinically normal black and white children participated. Dual-energy x-ray absorptiometry was used to determine body composition. A computed tomography scan of the abdomen was used to determine visceral adipose tissue and s.c. adipose tissue. Daily physical activity/inactivity was assessed by questionnaire. Black prepubertal and pubertal children had lower VO2max values when compared with white children (28.8 +/- 7.8 versus 35.0 +/- 6.5 mL . kg(-1) . min(-1), p < 0.01; 33.7 +/- 6.4 versus 40.4 +/- 10.2 mL . kg(-1) . min(-1), p < 0.05; respectively). Black prepubertal and pubertal children had lower Hb concentrations ([Hb]) and hematocrits than white children (prepubertal: 12.1 +/- 0.5 versus 12.8 +/- 0.9 g/dL, p < 0.001; 35.6 +/- 1.4 versus 37.4 +/- 2.3%, p < 0.01, respectively; pubertal: 13.0 +/- 0.9 versus 13.6 +/- 0.7 g/dL, p < 0.05; 37.7 +/- 2.5 versus 39.5 +/- 2.1%, p < 0.05, respectively). In conclusion, these findings indicate that black prepubertal and pubertal children had lower VO2max when compared with their white peers matched for age, pubertal stage, and body mass index. This difference in VO2max could be attributed at least in part to comparatively lower [Hb] and more sedentary lifestyle in the black children. Further investigations should study Hb flow rate (a function of [Hb] x maximal cardiac output) in black and white children as it relates to VO2max.

Background: Accurate estimation of children's resting energy expenditure (REE) is important for planning dietary therapy., Objective: Our objective was to compare the utility of 5 REE prediction equations in a diverse sample of young children., Design: REE was obtained in 502 black and white girls and boys aged 6-11 y by using indirect calorimetry at 4 US sites. Measured REE and REE predicted from the equations were compared., Results: None of the equations provided both accurate and unbiased estimates of REE. Two new sets of sex-specific equations including race as a factor were generated and evaluated. One set used easily measured variables-females: REE = 0.046 x weight - 4.492 x 1/height(2) - 0.151 x race + 5.841; males: REE = 0.037 x weight - 4.67 x 1/height(2) - 0.159 x race + 6.792-and accounted for 72% and 69%, respectively, of REE variance. The other set used body-composition variables-females: REE = 0.101 x fat-free mass + 0.025 x fat mass + 0.293 x height(3) - 0.185 x race + 1.643; males: REE = 0.078 x fat-free mass + 0.026 x fat mass - 2.646 x 1/height(2) - 0.244 x race + 4.8-and accounted for 75% and 71%, respectively, of REE variance. When split by race and adiposity, the small bias generated could be corrected to within 0.25 MJ (60 kcal) of the mean measured value., Conclusion: Sex-specific equations must take race into account to predict REE adequately in children.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

Objective: The aim of this study was to compare the prevalence of being overweight in black and white children and adolescents at onset of insulin-treated diabetes during two time periods: 1979-1989 (period I) and 1990-1998 (period II)., Research Design and Methods: All black children <19 years of age diagnosed with diabetes and treated with insulin at onset admitted to the Children's Hospital of Pittsburgh between January 1979 and December 1998 were matched with white children by sex, age at onset, and year of diagnosis. Data were obtained from a review of medical records. Overweight was defined as BMI >or=85th percentile for age and sex. Islet cell autoantibodies were measured., Results: The prevalence of being overweight increased from 12.6% (period I) to 36.8% (period II) (P = 0.0003); in whites from 2.9 to 16.6% (P = 0.04) and in blacks from 22 to 55% (P = 0.001); and in the age-group <11 years from 7.3 to 22.2% (P = 0.04) and age 11-18 years from 20 to 50% (P = 0.006). In children with at least one antibody, the prevalence of being overweight increased from 5.1 to 24.4% (P = 0.001). In the multivariate logistic regression, period of diagnosis (period II), race (black), age at onset (>or=11 years old), and absence of autoimmunity were associated with being overweight., Conclusions: At onset of the disease, the prevalence of being overweight has tripled from the 1980s to the 1990s, following the trend in the general population. Weight gain may be an accelerating factor for onset of insulin-treated diabetes and may have contributed to the increased incidence of diabetes in youth seen in some populations.

Objective: We have previously reported differences in the prevalence of beta-cell autoantibodies (AAs) in black and white children with insulin-treated diabetes, suggesting that the disease pathogenesis may be more heterogeneous among racial groups than previously thought. To further explore this issue, we compared clinical, biochemical, and autoimmune characteristics at disease diagnosis and follow-up treatment in an expanded number of black and white children with and without the presence of AAs., Research Design and Methods: The study cohort of 130 black children and adolescents, aged <19 years, diagnosed with diabetes and treated with insulin at time of diagnosis (January 1979 to December 1998) were matched with an equal number of white children by age at onset, sex, and year of diagnosis., Results: The black children had a higher prevalence of obesity (43 vs. 11%) and acanthosis nigricans (21 vs. 1%) than white children and a lower prevalence of AAs. Compared with black children who had AAs, those with no AAs were older and had a higher prevalence of obesity, acanthosis nigricans, and parental diabetes. However, one of four of the black children with AAs was obese and/or had acanthosis nigricans. Among white children, the absence of AAs was not associated with any differences in terms of obesity or acanthosis nigricans compared with those with AAs. Similar to their black counterparts, white children without antibodies were older and had a higher prevalence of parental diabetes. Although treatment with an insulin sensitizer was used, insulin therapy was rarely discontinued on follow-up., Conclusions: These pediatric subjects, irrespective of autoimmunity, often showed characteristics associated with type 2 diabetes. These characteristics were more frequently displayed in black than in white children. Our data suggest that childhood diabetes may constitute a spectrum of pathogenic mechanisms that may overlap, including those typically associated with both type 1 and type 2 diabetes. This finding could have therapeutic implications.

The incidence of type 2 diabetes mellitus in children is increasing with the increasing prevalence of obesity, particularly in African-American children. We hypothesized that African-American obese adolescents are more insulin resistant than their white peers, but have lower insulin secretion, thus increasing their risk of type 2 diabetes mellitus. The present study investigated insulin sensitivity and secretion, visceral adiposity (VAT), and cardiovascular disease (CVD) risk profile in black obese adolescents (BOA) vs. white obese adolescents (WOA). Twenty-four BOA and 26 WOA underwent a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity, a hyperglycemic clamp to determine insulin secretion, dual energy x-ray absorptiometry for body composition and computed tomography scan at L4-L5 to measure VAT and sc abdominal adipose tissue. Fasting lipid and automated blood pressure measurements were obtained. The WOA and BOA groups were divided into low VAT and high VAT groups. BOA compared with WOA of similar body mass index and percent body fat had less visceral adiposity, lower hepatic glucose production, and lower lipid levels. Visceral adiposity was associated with lower insulin sensitivity in both groups [low vs. high VAT; BOA, 2.9 +/- 0.4 vs. 1.7 +/- 0.2 micromol/kg x min per pmol/liter (P = 0.016); WOA, 2.6 +/- 0.5 vs. 1.5 +/- 0.1 (P = 0.032)]. However, this was compensated by higher insulin secretion in whites (low VAT, 934.8 +/- 121.8; high VAT, 1590.6 +/- 232.8 pmol/liter; P = 0.037), but not in blacks (low VAT, 1398.9 +/- 214.0; high VAT, 1423.7 +/- 108.7 pmol/liter). Glucose disposition index (insulin sensitivity x first phase insulin) was lower in high VAT vs. low VAT BOA, but not in WOA. In each racial group, high VAT groups had elevation of systolic and diastolic blood pressure, but dyslipidemia was worse in WOA with high VAT. In conclusion, a given level of body mass index confers different metabolic risks for WOA vs. BOA. Although differences in fat patterning may help explain the more atherogenic risk profile in whites, the cause of the more diabetogenic insulin sensitivity/secretion profile in blacks remains unknown and needs to be investigated further.

Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17alpha, the rate-limiting enzyme in androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tolerance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fifteen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/m(2).min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion. After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose tolerance. Total and free T decreased [1.5 +/- 0.2 vs. 1.0 +/- 0.1 nmol/liter (P = 0.022) and 41.3 +/- 8.3 vs. 22.2 +/- 2.1 pmol/liter (P = 0.028), respectively]. Insulin-stimulated glucose disposal increased (21.5 +/- 2.2 vs. 25.0 +/- 2.2 micromol/kg.min; P = 0.041). Fasting insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimulated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment [2.8 +/- 0.4 vs. 1.7 +/- 0.3 nmol/liter (P = 0.014), 7.0 +/- 0.6 vs. 5.3 +/- 0.5 nmol/liter (P = 0.011), and 30.4 +/- 3.7 vs. 25.7 +/- 4.2 nmol/liter (P = 0.054)]. Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008). In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, placebo-controlled studies will determine whether insulin-sensitizing therapy corrects not only ovarian hyperandrogenism but also functional adrenal hyperandrogenism in adolescents with PCOS.

Type 2 diabetes mellitus (DM) has historically been considered an adult disease. However, the incidence of type 2 DM has increased dramatically in pediatric populations in recent years. This increase parallels the recent rise in childhood obesity and has been greatest among minority adolescents. Differences between African-American and white American youths are discussed, including risk factor differences that may help to account for the overwhelming number of African-American children with type 2 DM as compared with white children. African-American youths have higher rates of insulinemia, obesity, family history, and acanthosis nigricans than their white counterparts. In addition, despite similar declines in insulin action during puberty, there is no compensatory increase in insulin secretion in African-American children, contrary to the observation in white children. These differences are likely to have a genetic basis modulated by environmental and lifestyle influences. Treatment of type 2 DM should focus on identifying individuals at risk and instituting lifestyle changes to reduce the risk and stem the development of DM.

Type 2 diabetes has been increasing in children, mostly affecting minority populations at around the age of puberty. Despite a multitude of studies demonstrating pubertal insulin resistance/hyperinsulinemia in white children, data are almost non-existent in African-American children. The aim of the present study was to investigate the impact of puberty on glucose metabolism, insulin sensitivity and secretion in African-American children. Twenty prepubertal and 16 pubertal African-American subjects participated. All underwent a 3-h hyperinsulinemic (40 mU/m(2)/min) euglycemic clamp to determine insulin-stimulated glucose disposal, and a 2-h hyperglycemic (12.5 mmol/L) clamp to assess first- and second-phase insulin secretion. Body composition was assessed by dual energy X-ray absorptiometry (DEXA) and visceral and subcutaneous abdominal adiposity with computed tomography (CT) scan at L4-L5. Total glucose disposal, glucose oxidation and non-oxidative glucose disposal were significantly lower in the pubertal group compared with the prepubertal one (53.8 +/- 3.9 vs. 72.2 +/- 5.0 micromol/kg/min, p = 0.009; 23.3 +/- 1.1 vs. 31.6 +/- 1.7 micromol/kg/min, p = 0.001; and 30.0 +/- 3.3 vs. 40.5 +/- 3.9 micromol/kg/min, p = 0.049, respectively). Insulin sensitivity was approximately 30% lower in the adolescents compared with the prepubertal children. However, first- and second-phase insulin secretions were not different between the two groups (971.4 +/- 180.6 vs. 1044.0 +/- 191.4 pmol/L and 999.6 +/- 159.6 vs. 955.8 +/- 142.2 pmol/L, respectively). In conclusion, despite approximately 30% lower insulin sensitivity in African-American adolescents compared with prepubertal children, insulin secretion is not higher. This is in contrast to published findings in white children in whom insulin secretion is higher during puberty. These racial differences in physiologic adaptation to puberty could play a role in the higher prevalence of type 2 diabetes in African-American children at the time of puberty.

Puberty is characterized by temporary insulin resistance, which subsides with the completion of pubertal development. This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal children. Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. Previously, we demonstrated that T treatment in adolescents with delayed puberty was not associated with the deterioration of insulin action. The present investigation evaluated the effects of 4 months of dihydrotestosterone administration (50 mg im every 2 wk) on body composition, glucose, fat, and protein metabolism, and insulin sensitivity. Ten adolescents with delayed puberty were evaluated before and after 4 months of DHT administration. Body composition was assessed by dual energy x-ray absorptiometry. Insulin-stimulated glucose metabolism was measured during a 3-h hyperinsulinemic (40 mU/m(2).min)-euglycemic clamp procedure. Lipolysis and proteolysis were evaluated by stable isotopes of [(2)H(5)]glycerol and [1-(13)C]leucine. After 4 months of dihydrotestosterone treatment, height, weight, and fat free mass increased and percentage of body fat decreased. IGF-I and nocturnal GH levels did not change. There was no significant change in insulin-stimulated glucose metabolism (57.2 +/- 3.9 vs. 58.3 +/- 3.9 micromol/kg.min). Total body proteolysis and lipolysis did not change. In summary, based on the present and past studies, we conclude that during puberty insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids in boys.

The roles of insulin resistance and insulin secretion in the pathogenesis of glucose intolerance in polycystic ovary syndrome (PCOS) were evaluated in 11 adolescents with impaired glucose tolerance (IGT) and 10 with normal glucose tolerance (NGT). Hepatic glucose production and insulin-stimulated glucose disposal were measured using [6,6-(2)H(2)]glucose and a 3-h hyperinsulinemic (80 mu/m(2).min)-euglycemic clamp. First and second phase insulin secretions were evaluated during a hyperglycemic clamp. Automated blood pressure measurements were made to assess the nocturnal change in blood pressure. Hepatic glucose production was significantly higher in IGT vs. NGT. Insulin-stimulated glucose disposal was not different between the two groups. The first phase insulin level was lower in IGT (207.9 +/- 21.0 vs. 357.0 +/- 62.9 muu/mL; P = 0.025; 1247 +/- 126 vs. 2142 +/- 377 pmol/L) without a difference in second phase insulin. The glucose disposition index (product of insulin sensitivity x first phase insulin) was lower in IGT vs. NGT (278 +/- 40 vs. 567 +/- 119 mg/kg.min; P = 0.023; 1546 +/- 223 vs. 3249 +/- 663 micromol/kg.min). The glucose disposition index correlated inversely with OGTT glucose concentrations at 30, 60, and 120 min. Adolescents with PCOS-IGT lacked the normal nocturnal decline in blood pressure. We conclude that in obese adolescents with PCOS, glucose intolerance is associated with 1) decreased first phase insulin secretion, 2) decreased glucose disposition index, and 3) increased hepatic glucose production. These metabolic abnormalities are precursors of type 2 diabetes and are present early in the course of PCOS. Furthermore, the absence of nocturnal dipping in blood pressure may herald the early expression of cardiovascular disease risk in these adolescents.

Type 2 diabetes mellitus (DM) has been considered rare in the pediatric population. However, over the last decade, there has been a disturbing upswing in the rate of diagnosis of type 2 DM in the pediatric age group, mirroring the increasing rates of obesity in childhood. The pathophysiology of type 2 DM discussed in this article focuses on the delicate balance between insulin sensitivity and insulin secretion. The risk factors for youth-onset type 2 DM are presented, with careful evaluation of their impact on insulin sensitivity versus insulin secretion.

Type 2 diabetes mellitus is a disease of adults and has been considered rare in the pediatric population. Over the last decade, however, there has been a disturbing trend of increasing cases of type 2 diabetes in children, particularly adolescents, and with a greater proportion of minority children being affected. This article reviews the clinical characteristics of youth with type 2 diabetes, presents the risk factors associated with insulin resistance and type 2 diabetes, discusses treatment options, and projects future directions in research. The ultimate goal is to raise awareness of this challenging entity among healthcare professionals.