Ghrelin is a novel growth hormone؊releasing peptide isolated from human and rat stomach that induces weight gain by increasing food intake and reducing fat utilization. Although recent data indicate that ghrelin is downregulated in human adult obesity, the characteristics of human obesity are heterogeneous, especially in children and adolescents, and depend on the distribution of subcutaneous and visceral fat tissue. We measured fasting plasma ghrelin concentrations by radioimmunoassay in 49 obese Japanese children and adolescents (38 boys and 11 girls; mean age 10.2 ؎ 2.8 years; BMI 28.0 ؎ 4.5 kg/m 2 , percent overweight 56.0 ؎ 20.7%), and analyzed associations of their ghrelin concentrations with their body composition, insulin resistance, and adipocytokine concentrations. Fasting plasma ghrelin levels were negatively correlated with BMI and waist circumference, but not with percent overweight or percent body fat, whereas fasting leptin levels were positively correlated with all of the following parameters: BMI, waist circumference, percent overweight, and percent body fat. Plasma ghrelin levels were negatively correlated with fasting immunoreactive insulin, homeostasis model assessment insulin resistance index, and quantitative insulin sensitivity check index values. There was no correlation between plasma ghrelin and leptin, but ghrelin was negatively correlated with the PAI-1 concentrations. The results suggest that the downregulation of ghrelin secretion may be a consequence of higher insulin resistance associated with visceral fat accumulation and elevated PAI-1 concentrations, and not a consequence of total body fat accumulation associated with elevated leptin concentrations.

Objective: Childhood onset Graves’ disease (GD) has been documented to be clinically distinct from adult onset GD, and an association with the genes encoding HLA and CTLA-4 (cytotoxic T lymphocyte antigen-4) has been reported in both Caucasian and Japanese adult GD patients. The aim of this study was to determine whether HLA-DR, -DQ and CTLA-4 are associated with childhood onset GD in Japanese individuals. Methods: We investigated the genotype of HLA class II (DRB1, DQB1) and the A/G transition polymorphism of CTLA-4 exon 1 position 49 in 43 GD patients and in healthy controls for comparison. The CTLA-4 alleles were identified by the polymerase chain reaction (PCR) of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with Ita1. Results: The frequency of both HLA-DRB1*0405 and DQB1*0401 was increased in the patient group (DRB1*0405: 26.7%, p < 0.001; DQB1*0401: 25.6%, p < 0.005) compared with the controls. Patients with GD had a significantly lower frequency of the AA genotype of CTLA-4 than the controls, but there was no difference in allele frequency between the G and A allele. Conclusions: the association of HLA-DRB1 and DQB1 genotype with susceptibility to childhood onset GD differs from that in adult onset GD, whereas the association between CTLA-4 gene polymorphism and childhood onset GD is similar to that in adult onset GD in Japanese individuals, but the association is weak.

The CTLA4 gene might confer a susceptibility to childhood-onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high-risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.

We demonstrate that AN is a useful clinical marker for the severity of obesity associated with a high BMI, and that B2ADR Gly16 and B3ADR Arg64 are associated synergistically with AN in obese children and adolescents.

Acanthosis nigricans (AN) is a skin lesion characterized by thickening and obvious darkening of the keratin layer of the skin. It has been demonstrated to be associated with hyperinsulinemia, and is used as an empirical marker for elevated risk of type 2 diabetes. The prevalence of school children with simple obesity in Japan has recently increased to over 10%. We investigated the clinical characteristics of AN-positive and AN-negative subjects, and compared 105 obese children (64 males and 41 females) with regard to sex, percentage overweight, age distribution, duration of obesity, standard deviation score (SDS) of height, liver function, birth weight, and family history of diabetes mellitus. Forty-one (27 males, 14 females) (39.0%) of the 105 subjects had AN on the neck and/or in the axilla. There was a significant difference between the AN-positive and AN-negative groups in age (p<0.05), percentage overweight (p <0.0005), duration of obesity (p<0.03), and serum ALT level as a marker of fatty liver (p<0.01). The prevalence of AN was significantly higher in older subjects (≥8 years) and in subjects with higher levels of percentage overweight (≥50%). There was no significant difference in birth weight or family history of diabetes mellitus between the AN-positive and AN-negative groups. It is a very important to determine the frequency with which AN-positive obese subjects develop overt diabetes later in life.