Insulin Signaling and Heart Failure

Abstract

Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed.

Keywords: diabetes mellitus; heart failure; insulin receptor; insulin resistance; myocardium.

Figure 1. Schematic of insulin signaling pathway

Simplified summary of key elements involved in insulin signal transduction that ultimately regulate multiple cellular processes. Upon binding to its ligand, insulin and IGF-1 receptors undergo autophosphorylation, which increases their tyrosine kinase activities. Tyrosine phosphorylation and activation of the docking proteins insulin receptor substrates 1 and 2 (IRS1/2), engages regulatory subunits of the phosphatidylinositol-3-kinase (PI3K) that generates phosphatidylinositol 3,4,5 tris phosphate (PIP3) from phosphatidylinositol 3,4, bis phosphate (PIP2). The serine threonine kinases phosphoinositide dependent protein kinase 1 (PDPK1) and Akt1 or Akt2 bind to PIP3 by their PH domains. PDPK1 phosphorylates Akt on Thr 308 and mTORC2 phosphorylates Akt1/2 on Ser 473. Once activated, Akt in turn phosphorylates multiple targets of which a subset is shown. Phosphorylation of these targets induces pleiotropic cellular responses: Bcl2 phosphorylation inhibits apoptosis, FOXO protein phosphorylation promotes nuclear exclusion, thereby repressing the expression of FOXO-regulated transcripts that mediate autophagy and apoptosis. TSC1/2 phosphorylation promotes mTOR activation, which increases mRNA translation, promotes protein synthesis, cell growth, mitochondrial fusion and also inhibits autophagy. Phosphorylation of glycogen synthase kinase (GSK) removes the repression of glycogen synthase, which in concert with increased availability of glucose promotes glycogen synthesis. Phosphorylation of endothelial nitric oxide synthase (NOSIII) or eNOS by Akt increases the generation of nitric oxide (NO) to promote vasodilation. Akt phosphorylation mediates the translocation of vesicles containing the GLUT4 glucose transporter in part by phosphorylating downstream targets such as AS160 (not shown), leading to increased glucose transport following insertion into the plasma membrane. Akt also mediates in part, translocation of the fatty acid translocase CD36. Insulin signaling also promotes activation of the mitogen activated protein kinases (ERK1/2) to increase the expression of various genes.

Figure 2. Summary of mechanisms that lead to insulin resistance in heart failure or in the metabolic syndrome

Signaling events in skeletal muscle, liver, adipose tissue and brain (not shown) impair insulin signaling in each respective organ leading to metabolic perturbations as illustrated, which alter the systemic milieu in ways that may adversely impact cardiac structure and function.

Figure 3. Molecular mechanisms linking increased or decreased insulin signaling with adverse left ventricular (LV) remodeling and heart failure progression

In early stages of heart failure mediated by pressure overload, or in the early stages of the metabolic syndrome, hyperinsulinemia leads to activation of insulin receptor substrate 1(IRS1) and Akt1 to promote pathological hypertrophy, mitochondrial dysfunction and decreased autophagy, which contribute to accelerated LV remodeling. As heart failure progresses, despite systemic hyperinsulinemia insulin signaling pathways may become desensitized leading to loss of cytoprotective consequences of Akt signaling and persistent nuclear localization of forkhead (FOXO) proteins that will accelerate heart failure by various mechanisms such as increased apoptosis and exacerbation of lipotoxicity.