Abstract| Volume 16, ISSUE 9, SUPPLEMENT , S175, September 2010

Insulin Resistance Suppresses Cardiac Autophagy Through the AMPK/mTOR Pathway in Type 2 Diabetes

      Backgroud: Autophagy has been shown to be regulated by insulin signaling in various cell types, however, its role in cardiac insulin signaling remains unclear. OBJECTIVE: To clarify insulin-mediated activation of mTOR signaling may regulates cardiac autophagy and the role of cardiac insulin resistance in metabolic remodeling in the diabetic heart. Methods and Results: LC3-turnover assay revealed that LC3-I/II ratio was increased and immunoblots of autophagic markers p62 and beclin1 consistently increased in the diabetic heart. mTOR phosphorylation level was enhanced and the AMPK (Th172) and Akt (Ser473) phosphorylation levels were reduced. Insulin enhanced tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt in cultured cardiomyocyte. Isoprotelenol treatment decreased both of the IRS-1/Akt phosphorylation. Insulin-treated cardiomyocyte exhibited increase in the ratio of LC3-I/II level as well as p62 and beclin1, those which were augmented in the presence of in vitro cardiac insulin resistance induced by isoproterenol. Isoproterenol decreased AMPK phosphorylation level, however, there was no effect on Akt phospholation. AICAR and rapamycin restored the inhibitory effect of insulin on autophagy. Both AICAR and rapamycin enhanced LC3 punctae formationin cardiomyocyte, however, TUNEL staining revealed that AICAR simultaneously augmented apoptotic cell death and rapamycin had little effect on cardiac apoptosis. Conclusion: Insulin resistance impairs AMPK activity, leading to pathological activation of mTOR, leading to inhibition of cardiac autophagy.
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