Insulin Signaling in Cardiac Health and Disease

Insulin is an evolutionarily conserved hormone which integrates metabolic signals to growth through the regulation of a plethora of biochemical pathways. In the present chapter, we describe fundamental mechanism(s) of insulin signaling mediating the vast majority of biological effects in cardiac development, energy maintenance, and function. We detail these processes at the molecular level, including evidence on the contribution of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) as primary effectors of insulin signal transduction in the myocardium. In addition, the mitogenic effects of insulin on the myocardium with specific focus on intramyocellular pathways regulating protein synthesis are covered, including transcriptional effectors of these processes such as the forkhead transcription factors (FOXO) and nuclear factor of activated T-cells. Lastly, we discuss how aberrant insulin signaling affects these normal physiological processes to cause serious detrimental effects on cardiac health. Specifically, we present mechanisms of cardiovascular disease pathology secondary to disrupted cardiac insulin signaling in chronic diseases such as obesity, type 2 diabetes, hypertrophy, ischemic injury, and contractile failure. Insulin-dependent metabolic alterations and how they mechanistically influence gene and protein expression in controlling loading, sensing and clearance of cytosolic calcium are also presented to summarize our current understanding of the metabolic and mitogenic role of insulin signaling in healthy and diseased hearts.