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

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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.