Abstract 177: Insulin Resistance and Mechanisms of Heart Failure
A major cause of death in patients with type 2 diabetes is cardiac failure and the molecular mechanism that links diabetes to cardiomyopathy remains unclear. Insulin resistance is a hallmark of type 2 diabetes and intensive insulin therapy on the patients with type 2 diabetes increases the risks of cardiovascular dysfunction. Thus, understanding the mechanisms of insulin actions and resistance, related to cardiac dysfunction, will be critical for development of new strategies treating heart failure in type 2 diabetes. Insulin receptor substrate 1, & 2 (IRS1, IRS2) are major components in insulin signaling pathway regulating metabolism and survival. Here we hypothesized that (1) loss of IRS1 and IRS2 causes heart failure; (2) hyperinsulinemia contributes to loss of IRS1 and IRS2 in type 2 diabetes and promotes cardiac dysfunction; and (3) underlying mechanisms are involved in protein kinase activation. H-DKO mice (Heart Double IRS1 and IRS2 Knock-Out) and L(Liver)-DKO mice were generated using Cre/Loxp system. Cardiac function and ATP content were measured by echocardiograms and ATP assay kit. Protein and gene expressions were detected through western-blot and Q-PCR. Primary cultures of neonatal rat ventricular cardiomyocytes (NRVMs) were prepared from Sprague-Dawley rats with enzymatic method. H-DKO mice reduced ventricular mass, developed cardiac fibrosis and failure, and diminished Akt→Foxo1 signaling accompanied by impaired cardiac metabolic gene expression patterns and reduced ATP content. L-DKO mice decreased cardiac expression of IRS1 and IRS2 proteins with insulin resistance, disrupting cardiac energy metabolism, leading to heart failure and activation of p38α MAPK (p38). Using NRVMs, we demonstrated that hyperinsulinemia degraded IRS1 and IRS2, resulting in insulin resistance and impaired insulin action through activation of p38. In conclusion, myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38 during Insulin resistance, revealing a fundamental mechanism of heart failure during insulin resistance and/or type 2 Diabetes Mellitus.
- © 2013 by American Heart Association, Inc.