In vivo role of Rho-kinase in glucose metabolism

描述（由申请人提供）：胰岛素急性刺激外周组织葡萄糖摄取和代谢的能力对正常的葡萄糖稳态至关重要。抵抗胰岛素的这种作用是2型糖尿病和肥胖的主要致病特征。虽然许多胰岛素信号传导的近端步骤已被确定，但胰岛素维持葡萄糖稳态的分子机制仍不清楚。我们最近的研究表明rho激酶是胰岛素作用和葡萄糖稳态的重要介质。我们发现rho激酶通过IRS-1丝氨酸磷酸化在培养的脂肪细胞和肌肉细胞中调节胰岛素刺激的葡萄糖转运和信号传导，建立了调节葡萄糖转运和胰岛素信号传导的新机制。在这个应用中，我们将进一步定义rho激酶在体内调节葡萄糖转运和胰岛素敏感性中的生理作用，使用遗传方法。在Aim 1中，我们将开发转基因小鼠，其中rho激酶过表达是通过Cre重组酶共表达有条件地调节组织的。我们将通过与脂联素Cre重组酶转基因小鼠杂交产生脂肪特异性rho激酶转基因小鼠。在Aim 2中，我们将研究rho激酶在脂肪细胞中选择性表达对体内全身胰岛素敏感性、葡萄糖稳态和瘦的影响。这些研究将有助于更好地理解葡萄糖稳态调节的机制，并可能为糖尿病和肥胖症的治疗提供新的靶点。胰岛素抵抗是2型糖尿病的主要危险因素，其原因尚不完全清楚。初步数据显示，抑制rho激酶功能导致胰岛素反应降低，导致胰岛素抵抗。本研究的目的是确定rho激酶在调节葡萄糖稳态和胰岛素敏感性中的生理意义。这些实验可能会导致确定新的糖尿病药物的潜在目标。

DESCRIPTION (provided by applicant): Insulin's ability to acutely stimulate glucose uptake and metabolism in peripheral tissues is essential for normal glucose homeostasis. Resistance to this effect of insulin is a major pathogenic feature of type 2 diabetes and obesity. Although many of the proximal steps in insulin signaling have been identified, the molecular mechanism(s) for insulin action to maintain glucose homeostasis are still unclear. Our recent study suggests that Rho-kinase is an important mediator of insulin action and glucose homeostasis. We found that Rho-kinase regulates insulin-stimulated glucose transport and signaling via IRS-1 serine phosphorylation in cultured adipocytes and muscle cells, establishing a novel mechanism for the regulation of glucose transport and insulin signaling. In this application, we will further define the physiological role of Rho-kinase in the regulation of glucose transport and insulin sensitivity in vivo, using genetic approaches. In Aim 1, we will develop transgenic mice in which Rho-kinase overexpression is conditionally regulated tissue specifically by Cre recombinase co-expression. We will generate adipose-specific Rho-kinase transgenic mice by breeding with the adiponectin Cre recombinase transgenic mice. In Aim 2, we will examine the effects of Rho-kinase expression selectively in adipocytes on whole-body insulin sensitivity, glucose homeostasis, and leanness in vivo. These studies will provide a better understanding of the mechanisms for regulation of glucose homeostasis, and may offer a novel target for the treatment of diabetes and obesity. Insulin resistance is a major risk factor for type 2 diabetes, and the cause of this is not fully understood. Preliminary data show that inhibition of Rho-kinase function results in a decreased insulin response, leading to insulin resistance. The goal of the study is to determine the physiological significance of Rho-kinase in the regulation of glucose homeostasis and insulin sensitivity. These experiments could lead to the identification of a potential target for new diabetes drugs.