Induction of Glyoxalase 1 to prevent Methylglyoxal-Induced Insulin Resistance in Cardiomyocytes

Abstract

Background: Type 2 Diabetes mellitus is characterized by hyperglycemia and insulin resistance. Methylglyoxal (MG) a highly reactive dicarbonyl compound is also increased in diabetes. MG is detoxified by glyoxalase 1 (Glo-1) enzyme using reduced glutathione (GSH) as a co-factor. MG has been shown to have deleterious effects on cardiovascular cells and impairs insulin signaling. Insulin resistance is associated with diabetic cardiomyopathy. Trans-resveratrol (tRES) and Hesperetin (HES) combination has been shown to increase Glo-1 and improve insulin signaling in obese patients. Aim(s): The aim of this study is to investigate whether tRES-HES combination prevents MG-induced cardiac insulin resistance and the underlying mechanisms in cardiomyocytes in culture. Methodology: (H9C2) rat cardiomyocytes were treated with MG (100 µM) for 24 hours in the presence or absence of tRES-HES (10 µM). Glo-1 activity was determined by the formation of S-D lactoylglutathione; protein expression of P-Akt and P-GSK3b was determined using Western blot. In some experiments, cells were stimulated with insulin (100 nM) for 10 minutes to test insulin sensitivity. Results: MG reduced Glo-1 activity by ~25%, blunted insulin-induced phosphorylation of Akt and Gsk3b and increased the expression of beta-myosin heavy chain by ~50% (a marker of cardiac dysfunction) significantly (P˂0.05) compared to untreated control group of cells. Co-administration of tRES-HES combination restored Glo1 activity, maintained insulin-induced phosphorylation of Akt and GSK3b and prevented the increase in beta myosin heavy chain significantly (P<0.05). Conclusion: Induction of Glo1 prevents MG-induced cardiac insulin resistance and the increase in marker of cardiac dysfunction. This strategy could be helpful in preventing cardiovascular complications associated with diabetes.