Identifying the genes for insulin resistance in Japanese population.

1、我们通过对基因敲除小鼠和培养细胞的分析，研究了胰岛素信号转导的机制，发现PKClambda可能是PI3K的下游效应分子。我们发现在肝脏中缺乏PKClambda的小鼠(L-lambdaKO小鼠)表现出胰岛素敏感性增加，甘油三酯含量降低，肝脏中SREBP-1c基因表达减少。恢复PKClambda在肝脏中的表达纠正了这些动物的代谢异常。因此，肝脏PKClambda是肝脏脂质含量和全身胰岛素敏感性的决定因素。我们发现，肝脏特异性STAT-3缺陷的小鼠表现出与肝脏糖异生基因表达增加相关的胰岛素抵抗。这些小鼠肝脏STAT-3表达的恢复纠正了代谢异常和肝脏糖异生基因表达的变化。一种成分活性形式的…的肝脏特异性表达更多的FSTAT-3显著降低糖尿病小鼠的血糖、血浆胰岛素浓度和肝脏糖异生基因的表达。因此，肝脏STAT-3信号对正常血糖稳态是必不可少的，并可能为糖尿病提供新的治疗靶点。此外，我们还展示了PI3-激酶、PDK-1、SREBP-1和p27；；kip1&gt；在胰岛素信号和葡萄糖代谢中的作用。2、我们进行了病例对照关联研究，以确定2型糖尿病的易感基因。我们已经证明解偶联蛋白1(UCP1)基因的-112A和C多态(Rs10011540)与日本人的2型糖尿病相关。此外，我们还研究了该基因多态性对临床特征的影响，包括磁共振波谱测量的心肌细胞内脂肪含量(IMCL)和肝脏脂肪含量(HLC)。在携带-112c等位基因(风险等位基因)的患者中，胰岛素抵抗(HOMA-IR)和HLC的稳态模型评估显著更高。这些结果表明，-112c等位基因引起的胰岛素抵抗影响2型糖尿病的易感性。较少

1, We have investigated the mechanism of insulin signaling by analyzing knockout mice and cultured cells.PKClambda is implicated as a downstream effector of PI3K in insulin action. We showed that mice that lack PKClambda specifically in the liver (L-lambdaKO mice) exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the SREBP-1c gene in the liver Restoration of PKClambda expression in the liver of L-lambdaKO mice corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.We showed that mice with liver-specific deficiency in STAT-3 show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Liver-specific expression of a constitutively active form o … More f STAT-3 markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signalling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes.Moreover we have shown the roles of PI3-kinase, PDK-1, SREBP-1 and p27^<kip1> for insulin signaling and glucose metabolism.2, We have performed case-control association studies to identify susceptibility genes for type 2 diabetes mellitus. We have shown the-112A > C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) is associated with type 2 diabetes mellitus in Japanese individuals. Furthermore, we investigated the effects of this polymorphism on clinical characteristics including intramyocellular lipid content (IMCL) and hepatic lipid content (HLC) measured by magnetic resonance spectroscopy. Homeostasis model assessment for insulin resistance (HOMA-IR) and HLC were significantly greater in patients with the -112C allele (risk allele). These results suggest insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes. Less