Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons.

beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative beta-cell volume, and increased relative alpha-cell volume and hyperglucagonemia. These results strongly support the concept that IA and beta-cell apoptosis in concert with alpha-cell proliferation and hypertrophy are key determinants of islets of Langerhans "dysfunctional remodeling" and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R(2) = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.

Leptin receptor gene K656N polymorphism is associated with low body fat levels and elevated high-density cholesterol levels in Mexican children and adolescents.

INTRODUCTION: This study evaluated the association between obesity and the K109R, Q223R, and K656N polymorphisms of the leptin receptor (LEPR) locus. Such polymorphisms cause changes in the extracellular extreme of the LEPR gene product and appear to be related to signal transduction toward the cell. SUBJECTS AND METHODS: A total of 128 participants between 6 and 17 years of age from a Mexican Mestizo population were included in the study. Individuals were classified as overweight-obese (n = 76) and normal (n = 52), based on anthropomorphic measurements. The K109R, Q223R, and K656N polymorphisms of the LEPR were determined by the size of restriction fragments obtained from polymorphic fragment amplification (polymerase chain reaction-restriction fragment length polymorphism) obtained from genomic DNA. Allele frequency was compared using the chi-square test. Odds ratio was calculated to determine allele obesity risk factor. RESULTS: Variant allele frequency was 109R = 0.35, 223R = 0.49, and 656N = 0.11 for the K109R, Q223R, and K656N polymorphisms, respectively. No statistically significant association with obesity was found in any of the alleles. The N allele of the K656N polymorphism was associated with nonobesity markers, such as high concentrations of high-density lipoproteins, normal body mass index, less thickness of skinfolds, and body perimeters. None of the alleles studied were shown to be obesity risk factors. CONCLUSIONS: Our results suggest that there is no association between the K109R, Q223R, and K656N polymorphisms of the LEPR gene with obesity, and none of the alleles of the LEPR gene K109R, Q223R, and K656N polymorphisms are an obesity risk factor.