Expression of wild-type and mutant S20G hIAPP in physiologic knock-in mouse models fails to induce islet amyloid formation, but induces mild glucose intolerance.

UNLABELLED: Aims/Introduction: Human islet polypeptide S20G mutation (hIAPP(S20G)) is associated with earlier onset type 2 diabetes and increased amyloidogenicity and cytotoxicity in vitro vs wild-type hIAPP (hIAPP(WT)), suggesting that amyloidogenesis may be pathogenic for type 2 diabetes. We compared the contributions of hIAPP(S20G) and hIAPP(WT) toward intra islet amyloid formation and development of type 2 diabetes in a unique physiologic knock-in mouse model. MATERIALS AND METHODS: We replaced the mouse IAPP gene (M allele) with hIAPP(WT) (W allele) and hIAPP(S20G) (G allele) via homologous recombination and backbred transgenic mice against C57Bl/6 strain 5 generations to minimize genetic variation. Mice (3 month old) were maintained on control (CD) or high fat diet (HFD) for 15 months and studied at 3 month intervals by oral glucose tolerance testing (OGTT) and pancreas histology to assess glucose homeostastis, amyloidogeneisis, islet mass, ß cell replication, and apoptosis. RESULTS: IAPP blood levels were indistinguishable in all mice. WW and GW mice maintained on both diets lacked intraislet amyloid at all ages. On both diets relative to MM controls WW and GW mice exhibit glucose intolerance (P < 0.008) with no differences in insulin secretion. However, GW mice secreted significantly more insulin (P < 0.03 that WW mice on both diets throughout the study. By 12 months on the high fat diet all mice increased their ß cell mass about 3-fold and were indistinguishable. CONCLUSIONS: Physiologic expression of hIAPP(WT) and hIAPP(S20G) in C57Bl/6 mice produces mild glucose intolerance with inappropriately normal insulin secretion that is independent of intraislet amyloid formation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00166.x, 2011).

Revised optimal cut-off point of waist circumference for the diagnosis of metabolic syndrome in Japanese women and the influence of height.

AIM: We reevaluated waist circumference as a diagnostic criterion of metabolic syndrome (MetS) in Japanese. METHODS: We enrolled 5,571 subjects (3,148 men and 2,423 women) who had health check-ups in our center. The criterion was reevaluated using the positive predictive value of a receiver-operating characteristics (ROC) curve at 10 different hypothesized lengths of waist circumference with or without a cluster of risk factors. We also drew ROC curves based on the atherosclerotic findings of clinical examinations. RESULTS: Based on the ROC curves, the optimal waist circumference cut-off was 85 cm in men and 80 cm in women. Using this 80 cm cut-off point in women, misdiagnosis rates of MetS were lowered (-19.1--56.6%) compared to the cut-off point currently in use. Integrating the influence of height, namely by using a waist-to-height(2) ratio, misdiagnosis rates in shorter populations were decreased in both men and women. CONCLUSION: These data suggested an optimal waist circumference cut-off to improve the diagnostic probability of MetS in Japanese women of 80 cm, as well as the utility of an easily detected anthropometric index such as a waist-to-height (cm x 100/cm) or waist-to-height(2) (cm x 10,000/cm(2)) ratio, determined as 51 in men and 52 in women, or 30 in men and 33 in women, respectively.

Mutations in the beta1 adrenergic receptor gene and massive obesity in Japanese.

Catecholamines strongly promote lipolysis and thermogenesis, and play a central role in the regulation of body fat content. The beta1 adrenergic receptor (BAR-1) is a major mediator of catecholamine-induced lipolysis and thermogenesis. To explore whether mutations in the BAR-1 gene contribute to morbid obesity in Japanese, we scanned for mutations in the coding sequence of the gene in 50 morbid obese [body mass index (BMI)>==35.0kg/m(2); 99.7th percentile] Japanese subjects. Direct DNA sequencing was performed following polymerase chain reaction (PCR) amplification. Two common polymorphisms, Gly49Arg and Arg389Ser, were detected in these subjects. The frequencies of these polymorphisms, as determined by PCR-restriction fragment length polymorphism (RFLP) analysis, showed no significant difference between 180 severely obese subjects (BMI>==30.0kg/m(2); 97th percentile) and 132 control (BMI<25.0kg/m(2)) subjects. This study represents the first investigations of genetic variations of BAR-1 in relationship to morbid obesity and suggests mutations in the BAR-1 coding sequence is not likely a major cause of morbid obesity at least in Japanese.