451-P: SGLT2 Inhibitor Protects Cardiomyocytes against Palmitate-Induced Lipotoxicity by Increasing Activation of AMPK and Lipid Oxidations

Aim: This study was designed to evaluate the effects of SGLT2 inhibitor on palmitate-induced lipotoxicity of cardiomyocytes and the underlying mechanism involved with palmitate. Methods: We checked SGLT2 expression in muscle cells, including H9C2. H9C2 cells were palmitate treated with/without SGLT2 inhibitor. Then, insulin resistance was measured, 2-NBDG uptake, and immunoblotting using insulin signaling pathway antibodies. Inflammation and cardiac metabolism were analyzed several related genes. Cardiomyocyte apoptosis was also detected using DNA fragmentations assay and immunoblotting using cleaved caspase 3. Results: Low doses of palmitates evoked lipotoxicity in cardiomyocytes. Treatment of SGLT2 inhibitor dramatically reduced palmitate-induced expression levels of inflammatory cytokines. Immunoblotting analysis showed treatment of cardiomyocytes, with SGLT2 inhibitor, recovered impaired insulin signaling, such as phospho-IR and phospho-AKT, but total IR and AKT did not change. SGLT2 inhibitor also restored insulin-stimulated glucose uptake, which was destroyed by lipotoxicity. Treatment with SGLT2 inhibitor decreased the level of ER stress markers as well as inflammatory signaling markers. In particular, SGLT2 inhibitor stimulated phosphorylation of AMPK and fatty acid beta-oxidation. Cardiomyocyte exposure to high doses of palmitates evoked apoptotic features such as caspase 3 activation and DNA fragmentations. But pretreatment of SGLT2 inhibitor significantly protected palmitate-induced apoptotic features. Conclusions: This data suggests SGLT2 inhibitors protect palmitate-induced cardiomyocytes inflammation, impaired cardiac metabolism, insulin resistance, and cardiomyocyte apoptosis. Therefore, attempts to use treatment of SGLT2 inhibitor might be a useful strategy for preventing diabetes-associated ventricular remodeling and diabetic cardiac complication. Disclosure H. Lee: None. S. Choi: None. Y. Kang: None. T. Kim: None. N. Lee: None. H. Moon: None. S. Han: None. D. Kim: None. K. Lee: None.