Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression

Abstract

To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20-30% due to reduced cardiomyocyte size and had persistent expression of the fetal beta-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial beta-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

“…The IRS1-induced and PI3K-mediated Akt activity promotes GLUT4 translocation in cardiac and skeletal muscle cells, therefore increasing glucose uptake and oxidation. The insulin-induced Akt activity promotes cardiac hypertrophy [30, 31]. Ligand binding to βARs, which are prototypical members of the GPCR superfamily, induces cAMP-dependent PKA activation and phosphorylation of various substrates such as phospholamban (PLB) leading to increased activities of SERCA2 and RyR2 [32–34].…”

“…The cardiac performance in cardiomyocyte-selective InsR knockout (CIRKO) is mildly impaired, but absence of InsR signaling in the cardiomyocytes leads to worsening catecholamine-mediated myocardial injury [30, 141]. On the other side, despite the resistance in insulin-induced Akt activity, the excessive basal cardiac insulin signaling is detrimental, and can exacerbate systolic dysfunction induced by pressure overload in mice [142].…”

Impact of estradiol on insulin signaling in the rat heart

“…11 Insulin signaling influences many functions in the heart, for example metabolic substrate preference, cell size, and the heart's response to ischemia and hypertrophy. 12 Insulin plays a major role in regulating the balance of metabolic fuels received by the myocardium 13 and has direct effects on cardiac glucose transport, glycolysis, glucose oxidation, and glycogen synthesis, altering translocation of glucose transporters (GLUT) GLUT-1 and GLUT-4, changing the activity of cardiac enzymes of carbohydrate metabolism, 14 and suppressing fatty acid utilization by the heart. 15 Insulin's antilipolytic effect reduces the delivery of free fatty acid (FFA) to the heart and reduces fatty acid oxidation rates.…”

“…14,17 Not only that cardiovascular disease is the primary cause of death in individuals with diabetes, but also impaired insulin signaling is a characteristic of the heart in insulin resistant state and it may contribute to altered myocardial substrate utilization, energetics and cardiac electrophysiology. 17 New findings on gene modulation by estrogen receptor (ER) of insulinsensitive tissues indicate that estradiol (E2) participates in glucose homeostasis by modulating the expression of genes that are involved in insulin sensitivity and glucose uptake.…”

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

“…Over the past a few years, creation of insulin receptor substrates (IRS) in genetically engineered mouse models has provided major breakthroughs in our understanding of insulin-dependent control in cardiac energy metabolism and homeostasis, particularly for the role of protein kinase Akt (Guo 2014). Through previous experimentations and evidence, mice lacking the insulin receptor in the heart were born with reduced heart size and mitochondrial dysfunction, reflecting the key role of insulin receptor signaling in the regulation of postnatal cardiac size and substrate utilization (Belke et al 2002). To investigate the role of cardiac insulin signaling, we generated H-DKO mice with heart-specific deletion of both IRS-1 and IRS-2 genes using the Cre/loxP genetic approach.…”