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

• Applicant: Dr. Christian Riehle
• Subject Area: Endocrinology, Diabetology, Metabolism ; Anatomy and Physiology ; Biochemistry
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233893572

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor E. Dale Abel, Ph.D.