Glucose-transporter–mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients

Abstract

Insulin causes inotropic effects via Ca 2+-dependent and Ca 2+-independent pathways. The latter one is potentially glucose dependent. We examined inotropic responses and signal transduction of insulin in human atrial myocardium of diabetic and nondiabetic patients to test for the role of glucose transporters. Experiments were performed in isolated atrial myocardium of 88 patients undergoing cardiac surgery and 28 ventricular muscle samples of explanted hearts. Influence of insulin (0.02 μmol/L) on isometric twitch force was examined with and without blocking glucose transporter (GLUT) 4 translocation (latrunculin), sodium-coupled glucose transporter (SGLT) 1 (phlorizin, T-1095A), or PI3-kinase (wortmannin). Experiments were performed in Tyrode solution containing glucose or pyruvate as energetic substrate. Messenger RNA expression of glucose transporters (GLUT1, GLUT4, SGLT1, SGLT2) was analyzed in atrial and ventricular myocardium of both diabetic and nondiabetic patients. Developed force increases after insulin (to 117.8% ± 2.4% and 115.8% ± 1.9%) in trabeculae from patients with and without diabetes. Inotropic effect was reduced after displacing glucose with pyruvate as well as after PI3-kinase inhibition (to 103% ± 2%) or inhibition of glucose transporters GLUT4 (to 105% ± 2%) and SGLT1 (phlorizin to 106% ± 2%, T-1095A to 105% ± 2%), without differences between the 2 groups. In glucose-free pyruvate-containing solution, only inhibition of PI3-kinase but not blocking glucose transporters resulted in further inhibitory effects. Messenger RNA expression did not show significant differences between patients with or without diabetes. Insulin exerts positive inotropic effects in human atrial myocardium. These effects are mediated via a PI3-kinase–sensitive and a glucose-transport–sensitive pathway. Differences in functional effects or messenger RNA expression of glucose transporters were not detectable between patients with and without diabetes.