Metformin but not glyburide prevents high glucose-induced abnormalities in relaxation and intracellular Ca2+ transients in adult rat ventricular myocytes.

Abstract

We have recently demonstrated that adult rat ventricular myocytes maintained in a high glucose (HG) culture medium exhibit abnormalities in excitation-contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowers blood pressure in hyperinsulinemic animals, but its direct impact on cardiac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricular myocytes were cultured for 1 day in a serum-free insulin-containing medium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) in the presence or absence of metformin or the sulfonylurea glyburide. Mechanical properties were evaluated using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2-loaded myocytes. As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient decay. Culturing cells with metformin (50 micromol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes. Incubation of the cells with metformin also prevented slower intracellular Ca2+ clearing induced by HG. However, the HG-induced relaxation defects were not improved by glyburide (50-300 micromol/l). Interestingly, metformin also improved HG-induced relaxation abnormalities in the absence of insulin, whereas it failed to protect against HG in the presence of the tyrosine kinase inhibitor genistein (50 micromol/l). These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action.