Insulin Causes [Ca ]i-Dependent and [Ca ]i-Independent Positive Inotropic Effects in Failing Human Myocardium

Background—Insulin has been shown to exert positive inotropic effects in several in vitro and in vivo models, but signal transduction and substrate dependency remain unclear. We examined inotropic responses and signal transduction mechanisms of insulin in human myocardium. Methods and Results—Experiments were performed in isolated trabeculae from end-stage failing hearts of 58 nondiabetic and 3 diabetic patients undergoing heart transplantation. The effect of insulin (0.3 and 3 IU/L) on isometric twitch force (37°C, 1 Hz) was tested in the presence of glucose or pyruvate as energetic substrate. Furthermore, intracellular Ca transients (aequorin method), sarcoplasmic reticulum (SR) Ca content (rapid cooling contractures), and myofilament Ca sensitivity (semiskinned fibers) were assessed. In addition, potential signaling pathways were tested by blocking glycolysis, PI-3-kinase, protein kinase C, diacylglycerol kinase, insulin-like growth factor-1 receptors, or transsarcolemmal Ca entry via the Na /Ca exchanger. Insulin exerted concentration-dependent and partially substrate-dependent positive inotropic effects. The phosphatidylinositol-3-kinase inhibitor wortmannin and the Na /Ca exchanger reverse-mode inhibitor KB-R7943 completely or partially prevented the functional effects of insulin. In contrast, insulin-like growth factor-1 receptor blockade, protein kinase C inhibition, and diacylglycerol kinase blockade were without effect. The inotropic response was associated with increases in intracellular Ca transients, SR Ca content, and increased myofilament Ca sensitivity. Conclusions—Insulin exerts Ca -dependent and -independent positive inotropic effects through a phosphatidylinositol-3-kinase– dependent pathway in failing human myocardium. The increased [Ca ]i originates at least in part from enhanced reverse-mode Na /Ca exchange and consequently increased SR-Ca load. These nongenomic functional effects of insulin may be of clinical relevance, eg, during insulin-glucose-potassium infusions. (Circulation. 2005;111:2588-2595.)