Insulin Attenuates Cardiac Myocyte Contractility via NADPH Oxidase: Implications for Diabetic Cardiomyopathy

Abstract

Insulin is known to modulate metabolic responses in cardiac myocytes (CM), yet the role of insulin in regulation of CM contractility is less well understood. Type 2 diabetes mellitus (T2D) leads to diabetic cardiomyopathy, yet little is known about the role of insulin in CM function. Here we explore the role of insulin on CM contractility in adult mouse CM. Insulin had no effect on basal CM contractility, but inhibited the increase in contractility seen after stimulation of ß‐adrenergic receptors (ß‐AR) by isoproterenol (ISO; 40+/‐5% inhibition, p<0.01, n=115‐124 cells). The attenuation of ISO‐stimulated contractility by insulin was blocked by the NADPH oxidase inhibitor apocynin, implicating reactive oxygen species (ROS) in cardiac insulin responses. We found that insulin inhibited ß‐AR stimulation of CM Ca2+ transients (35+/‐4% inhibition, p<0.01, n=39‐41 cells); again, insulin inhibition of this ß‐AR response was blocked by apocynin. We analyzed CM contractile responses in CM isolated from mice fed a high‐fat diet, a model of T2D. We found that the insulin‐promoted decrease in contractility was blocked in CM isolated from diabetic mice. The phosphorylation of insulin‐dependent signaling proteins (insulin receptor, IRS‐1, Akt) was effectively abrogated in diabetic mice, consistent with myocyte insulin resistance. These data establish a central role for NADPH oxidase in insulin‐dependent physiological responses in CM, and show that these responses are deranged in mice with T2D. These observations suggest that alterations in ROS‐ and insulin‐dependent pathways play a role in the pathophysiology of diabetic cardiomyopathy. Research support: NIH and AHA.