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Objectives: To compare the pubertal development, the hormonal profiles and the prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus (T1DM)., Methods: Data were collected from 96 obese adolescent girls and 78 adolescent girls with T1DM at Tanner stage IV or V, whose ages ranged between 11.9 and 17.9 years., Results: High prevalence of hirsutism and menstrual disorder was found in the obese adolescent girls (36.5 and 42% respectively) and the adolescent girls with T1DM (21 and 44% respectively). The obese girls were significantly younger at pubarche, thelarche and menarche than the girls with T1DM. Hirsutism in the obese girls and those with T1DM was associated with hyperandrogenaemia and a raised free androgen index (FAI). When the cause of the raised FAI was investigated in both the groups of girls with hirsutism, the raised FAI in the obese girls was due to low serum sex hormone-binding globulin (SHBG) levels. In contrast, the raised FAI of the girls with T1DM and hirsutism was due to hyperandrogenaemia. Menstrual disorders in the T1DM girls were associated also with hyperandrogenaemia unlike obese girls., Conclusions: Hirsutism and menstrual disorders are common in obese adolescent girls and adolescent girls with T1DM. Although hyperandrogenaemia is present in both groups of girls, the androgenic profiles of the two groups differ. The hyperandrogenaemia in the obese girls is primarily due to their decreased serum SHBG levels, whereas the hyperandrogenaemia in the girls with T1DM is due to their increased androgen production.

Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points., Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants., Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children., Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement., Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

SIM1 (single-minded 1) haploinsufficiency is responsible for obesity in both humans and mice, but the contribution of frequent DNA variation to polygenic obesity is unknown. Sequencing of all exons, exon/intron boundaries, 870 base pairs (bp) of the putative promoter, and 1,095 bp of the 3'UTR of SIM1 gene in 143 obese children and 24 control adults identified 13 common variants. After analysis of the linkage disequilibrium (LD) structure, association study of eight variants was performed in 1,275 obese children and severely obese adults, in 1,395 control subjects, and in 578 obesity-selected pedigrees. A nominal evidence of association was found for the nonsynonymous variant P352T C/A (rs3734354) (P = 0.01, OR = 0.81 (0.70-0.95)), the +2,004 TGA -/insT SNP (rs35180395) (P = 0.02, OR = 1.21 (1.02-1.43)), the +2,215A/G TGA SNP (rs9386126) (P = 0.002, OR = 0.81 (0.71-0.93)), and pooled childhood/adult obesity. Even though transmission disequilibrium test (TDT) further supported the association of P352T and +2,004 -/inst T with obesity, none of these nominal associations remained significant after a multiple testing Bonferroni correction. Therefore, our study excludes a major contribution of SIM1 common variants in exons, 5' and 3' UTR regions in polygenic obesity susceptibility in French Europeans.

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults., Competing Interests: The authors have declared that no competing interests exist.

Background/aims: Former definitions of metabolic syndrome (MS) in children have been adapted from adult MS definitions using age-related thresholds for each biochemical component, whereas the International Diabetes Federation (IDF) definition is based on absolute values. We compared the IDF childhood MS definition (IDF-MS) to the adapted National Cholesterol Education Program (adapted-NCEP) definition in overweight children., Methods: 300 overweight and obese children were included with a median age of 11 years and BMI SDS of +4.7., Results: Below 10 years of age, the frequency of MS according to the adapted-NCEP-MS definition was 18.6%, and 86.1% had abdominal obesity. In children aged 10 to <16 years (n = 214), the frequency of IDF-MS was 8.9% compared to 14.5% by adapted-NCEP. IDF-MS children had a larger waist circumference, and higher triglycerides, fasting insulin and tended to be older than the intermediate severity group of children with MS only according to adapted-NCEP. Children with MS only according to adapted-NCEP (IDF-MS negative), differed from non-MS children in systolic blood pressure, triglycerides and high-density lipoprotein cholesterol., Conclusions: The recent IDF-MS criterion in children represents a more severe definition and appears to identify a group of children with higher fasting insulin than the adapted-MS definition which uses age-related thresholds (90th percentile)., (Copyright 2010 S. Karger AG, Basel.)

Background/aims: Obesity is linked to metabolic complications, even in children, but the role of the distribution of adiposity is unclear. We aimed to assess which compartment of fat mass - total (TFM), visceral (VFM) or subcutaneous (SCFM)--is related to metabolic complications in overweight and obese children and adolescents., Design: Analyses were conducted in 159 overweight or obese children and adolescents (median body mass index 4.0 SD). TFM was measured by dual-energy x-ray absorptiometry. Distribution of abdominal fat was assessed by MRI. Insulin resistance (IR) was determined using a homeostatic model assessment. The definition of metabolic syndrome (MS) was derived from National Cholesterol Education Program ATP III., Results: A parental history of obesity was positively and significantly associated with fat content of the three compartments (TFM: beta = 2.22; VFM: beta = 0.17; SCFM: beta = 0.12, respectively). VFM was also associated with gender (beta = -0.29) and ethnicity (beta = -0.54). TFM was a significant and independent determinant of IR (beta = 0.02) whereas IR and VFM only were significantly related to MS (OR = 3.55 and 3.66 respectively)., Conclusion: Our data indicate that even in overweight children VFM was influenced by several factors such as sex and ethnicity and that a relationship was evidenced between the amount of VFM and MS., (Copyright 2008 S. Karger AG, Basel.)

Context: The melanin-concentrating hormone receptor 2 (MCHR2) is a G protein-coupled receptor for melanin-concentrating hormone, a neuropeptide that plays an important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity., Objective: The aim of this study was to investigate the association between MCHR2 variation and human obesity., Design: Case control and family-based studies were performed., Participants: A total of 141 obese children and 24 nonobese adult subjects was sequenced, and case-control analyses were conducted using 628 severely obese children and 1,401 controls., Results: There were 11 single nucleotide polymorphisms (SNPs) identified. We showed nominal association among -38,245 ATG A/G SNP (P = 0.03; 95% confidence interval 1.02-1.34; odds ratio 1.17), A76A T/C SNP (P = 0.03; 95% confidence interval 0.58-0.97; odds ratio 0.75), and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an overtransmission to obese children of the at risk T allele (59.0%; P = 0.01), especially in children with most severe forms of obesity (Z score of body mass index > 4) (67.0%; P = 0.003). The A76A at risk T allele was also associated with overeating during meals (P = 0.02) in an additional group of 102 nonobese children. None of the MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (P = 0.06) and higher hunger (P = 0.09) was found. This variant was not associated with childhood obesity in an independent case-control study, including 1,573 subjects (P = 0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus., Conclusion: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood.

The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.

Aims/hypothesis: Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity., Subjects and Methods: The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n=161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n=1,163)., Results: Significant association was found for a 5' variant (rs6857715) in the NPY2R gene with both severe adult obesity (p=0.002) and childhood obesity (p=0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n=928) vs the control subjects (n=938) (p=0.0004, odds ratio=1.3, 95% CI 1.1-1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p=0.005, recessive model p=0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p=0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family., Conclusions/interpretation: These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further.

Objective: To estimate the frequency of the metabolic syndrome (MS) and of the insulin resistance syndrome (IRS) in overweight or obese French children and to determine the risk factors., Design, Patients and Methods: A total of 308 overweight and obese children [166 girls, 142 boys, aged 7-17 years; median body mass index (BMI) 4.7 standard deviation (SD) (Q1-Q3: 3.9-5.8) adjusted for age and sex] were included. The frequency of the MS was assessed with the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria and the frequency of the IRS with World Health Organization (WHO) criteria., Results: The overall frequency of MS and IRS was 15.9% and 42.5%, respectively. The most common component, after abdominal obesity (95.8%) and IR (71.8%), was elevated systolic blood pressure (28.6%). The frequency of glucose tolerance disorders was low (3.6%). The frequency of MS was independently influenced by homeostatic model assessment (HOMA) (P = 0.06) and waist-to-hip ratio (P = 0.09), whereas the frequency of IRS was influenced by adiposity (degree of obesity: P = 0.02; waist-to-hip ratio: P = 0.05), puberty (P = 0.05) and mother's BMI (P = 0.01). Ethnicity had no effect on either MS or IRS., Conclusions: Metabolic complications and IR are frequent in overweight and obese children whereas the frequency of glucose tolerance disorders is very low. IRS is more prevalent than MS, indicating a major role of IR, which could precede the other metabolic complications in obese children. IRS is a relevant marker for the risk of type 2 diabetes (T2D) and cardiovascular complications in obese European children.

Context: Type 2 diabetes (T2D) in obese children is an emerging problem, including in Europe. Its presentation at diagnosis very often differs from that in adults., Objective: The objective of this study was to investigate the relative contributions of the two components of T2D, insulin resistance and insulin secretion, early in the history of the disease in adolescents., Patients and Methods: Six obese adolescents with T2D were included 2 months to 4.3 yr after diagnosis (five girls and one boy; median age, 15.4 yr; median body mass index, 4.4 sd). Peripheral and hepatic insulin sensitivity was evaluated with euglycemic hyperinsulinemic (40 mU/m(2).min) clamp. First-phase insulin release was evaluated after iv glucose stimulation. A graded iv glucose infusion and an arginine test were performed to measure insulin secretion., Results: All patients showed decreased peripheral glucose uptake to the same extent. Five patients showed hepatic insulin resistance. First-phase insulin release was very low in two patients. Three patients showed an exaggerated insulin response under graded glucose infusion and preserved secretion under arginine stimulation. Three other patients, with elevated fasting plasma glucose levels, demonstrated a very low insulin response under glucose stimulation and a low insulin response under arginine stimulation., Conclusions: These data emphasize that together with marked insulin resistance, the failure of beta-cell function is a major component in the course of T2D in childhood.

The aim of this study was to investigate the ontogeny of serum leptin concentrations during the second half of gestation and at birth in small for gestational age and normal fetuses and newborns. Serum leptin concentrations were measured in arterial cord blood of fetuses (n = 79) and newborns (n = 132), with or without intrauterine growth retardation, at 18-42 weeks gestation. Serum leptin was detectable in fetal cord blood in all subjects as early as 18 weeks gestation. Leptin levels dramatically increased after 34 weeks gestation. In newborns, serum leptin concentrations were positively correlated with body weight (P < 0.001) and body mass index (P < 0.001). Newborns with intrauterine growth retardation had significantly lower serum leptin values (P < 0.001) than those with normal growth, and leptin levels were only positively correlated with body mass index (P < 0.001). These results suggest that the development of adipose tissue and the accumulation of fat mass are the major determinants of fetal and neonatal serum leptin levels. In addition, a gender difference, with higher leptin concentrations in female fetuses, was observed during the last weeks of gestation and was confirmed at birth regardless of growth status, suggesting that a sexual dimorphism already exists in utero.

Presents an abstract of the article "Coding SNPs in the Human Leptin Receptor Gene Contribute to Severe Obesity in French Caucasian Adults," by Una Fairbrother, A. J. Walley, C. Boyle, M. Tauber, B. Jouret, D. Jaquet, C. Levy-Marchal, M. A. Charles, J. Weill, P. Froguel and A. I. F. Blakemore.