Identification of Mechanisms by which Insulin Receptor Substrates (IRS) Regulate Cardiomyocyte Metabolism and Survival

在2型糖尿病患者中进行严格代谢控制的临床试验，包括强化胰岛素治疗，增加了死亡率和主要心血管事件的数量。我们之前在一个压力过载模型中表明，高胰岛素血症本身激活了心脏中的胰岛素信号级联，从而加速了细胞死亡和心力衰竭。胰岛素和IGF-1信号是由胰岛素受体底物（IRS） 1和2介导的。我们的初步研究确定了irs -异构体对心脏代谢和生长的特异性贡献。在压力过载的情况下，irs1缺失具有有益的影响，而IRS2缺失则是有害的。这项建议将阐明其基本机制。此外，虽然心肌细胞特异性缺失IRS1或IRS2的小鼠存活正常，但两种IRS亚型的缺失导致心力衰竭死亡率增加。同样，心肌细胞特异性缺失胰岛素（IR）和IGF-1受体的小鼠死于心力衰竭。除了IR和IGF-1受体外，IRS蛋白还与细胞因子受体和整合素相连。因此，我们建议研究IR/IGF-1受体依赖性和独立机制，这些机制有助于irs1 /2缺陷心脏的心力衰竭。总之，这些研究将为压力过载条件下胰岛素信号的IRS亚型特异性调节提供新的见解，并剖析心肌细胞中由IRS1和IRS2转导的上游信号。

Clinical trials of tight metabolic control in subjects with type 2 diabetes, which involve intensive insulin therapy increased mortality and the number of major cardiovascular events. We have previously shown in a model of pressure overload that hyperinsulinemia per se activates the insulin signaling cascade in the heart and thereby accelerates cell death and heart failure. Insulin and IGF-1 signaling is mediated by insulin receptor substrates (IRS) 1 and 2. Our preliminary studies identified an IRS-isoform specific contribution to cardiac metabolism and growth. In the presence of pressure overload, IRS1-deletion had beneficial effects whereas absence of IRS2 was detrimental. The underlying mechanisms will to be elucidated in this proposal. Furthermore, while mice with cardiomyocyte-specific deletion of either IRS1 or IRS2 had normal survival, knockdown of both IRS isoforms resulted in increased mortality due to heart failure. Similarly, mice with a combined cardiomyocyte-specific deletion of both insulin (IR) and IGF-1 receptors died from heart failure. In addition to IR and IGF-1 receptors, IRS proteins are linked to cytokine receptors and integrins. Therefore, we propose to investigate IR/IGF-1 receptor dependent and independent mechanisms that contribute to heart failure in IRS1/2-deficient hearts. Together, these studies will provide new insight into the IRS isoform-specific modulation of insulin signaling under conditions of pressure overload and dissect the upstream signals that are transduced by IRS1 and IRS2 in cardiomyocytes.