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Myocardial Activation of p38 alpha MAPK Results in Cardiac Insulin Resistance by Chronic Insulin Signaling
Author(s) -
Qi Yajuan,
Dostal Davide,
Guo Shaodong
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.918.8
Subject(s) - insulin resistance , irs2 , insulin , medicine , irs1 , insulin receptor , endocrinology , hyperinsulinemia , type 2 diabetes , insulin receptor substrate , type 2 diabetes mellitus , diabetes mellitus
Diabetic cardiomyopathy is widely present in diabetic patients and the major course of its death is heart failure. The molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark of type 2 diabetes and hyperinsulinemia is characteristics of insulin resistance. However, whether insulin itself is a determinant factor leading to cardiac insulin resistance and dysfunction is uncertain. Our previous studies demonstrated that insulin receptor substrate protein 1 and 2 (IRS2 and IRS2) are major mediators of insulin action. Using rat neonatal cardiomyoctes, we analyzed insulin signaling components, including IRS1, IRS2, PI3Kinase and MAPKinase, and assessed their contribution to insulin action and resistance in regulation metabolic gene expression. We found that acute insulin stimulation for 0.5 hour activated Akt and Foxo1 phosphorylation, while chronic insulin stimulation for 24 hours sustained p38á MAPK activation accompanied with reduction in both IRS1 and IRS2, whereas inhibiting p38á largely rescued the decrease of IRS1 and IRS2 and expression of p38á MAPKinase by adenovirus infection degraded IRS1 and IRS2 proteins. Taken together, these data suggest that chronic insulin exposure can result in insulin resistance, impair energy metabolism, and likely contributes to heart failure in type 2 diabetes, involving in activation of p38á MAPK.