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The regulation of insulin targeted cell proliferation and differentiation in the insulin resistance ; the role of expression of glucose transporters

胰岛素抵抗中胰岛素靶向细胞增殖和分化的调节；

基本信息

批准号：
11671132
负责人：
SATOH Shinobu
金额：
$ 0.9万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

We studied the regulation of insulin targeted cell proliferation and differentiation in the insulin resistance ; the role of expression of glucose transporter. To investigate the role of IRS-1 in endocrine pancreatic function, we have performed in vivo experiments of islet function in mice with knockout mutations in Insulin Receptor Substrate (IRS)-1 (IRS-1-/-), as well as in vitro studies on isolated islets. We found that immunostaining for GLUT2 was remarkably reduced in the beta-cells of IRS-1-/- islets. In pancreatic beta-cells, two types of granules can be distinguished by electron microscopy : mature granules with a dense core and immature granules with lightly stained content. The proportion of light granules in IRS-1-/- islets was increased and that of dark granules decreased in comparison with wild-type islets. These studies indicate that IRS-1 deficiency leads to reduced GLUT2 expression and insulin response to glucose. Thus, IRS-1 plays unique roles in beta-cell development and function. Heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.

我们研究了胰岛素靶向细胞增殖和分化在胰岛素抵抗中的调控;葡萄糖转运蛋白的表达在胰岛素抵抗中的作用。为了研究IRS-1在胰腺内分泌功能中的作用，我们在胰岛素受体底物（IRS）-1（IRS-1-/-）基因敲除突变的小鼠中进行了胰岛功能的体内实验，以及对分离胰岛的体外研究。我们发现IRS-1-/-胰岛β细胞中GLUT 2的免疫染色显著减少。在胰腺β细胞中，可以通过电子显微镜区分两种类型的颗粒：具有致密核心的成熟颗粒和具有轻度染色内容物的未成熟颗粒。与野生型胰岛相比，IRS-1-/-胰岛中浅色颗粒的比例增加，深色颗粒的比例减少。这些研究表明，IRS-1缺乏导致GLUT 2表达和胰岛素对葡萄糖的反应降低。因此，IRS-1在β细胞发育和功能中发挥着独特的作用。杂合型PPAR γ缺陷小鼠在高脂饮食条件下，由于脂肪细胞肥大而不发生胰岛素抵抗。这些表型通过PPARgamma激动剂处理而消除。杂合子PPAR γ缺陷小鼠表现出过度表达和过度分泌的瘦素，尽管较小的脂肪细胞和减少的脂肪质量，这可以解释这些表型至少部分。这项研究揭示了一个迄今为止无法预测的作用，在高脂饮食诱导的肥胖由于脂肪细胞肥大和胰岛素抵抗，这需要两个等位基因的过氧化物酶体增殖物激活物受体γ。