Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

1. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 1

   Metabolic flexibility of cardiomyocyte in use of glucose, fatty acids, lactate, amino acids and ketone bodies for the generation of ATP to support cardiac contractile function. Insulin stimulates anabolic metabolism, including glucose uptake, glycolysis, and synthesis of glycogen, ribonucleotide and lipid synthesis, whereas insulin inhibits the β-oxidation of fatty acids. An excess amount of ATP can be stored in creatine phosphate, and activated pentose phosphate pathway promotes synthesis of macromolecules and cardiac hypertrophy. Hexosamine biosynthetic pathway promotes glycosylation of many cellular proteins and bioactivity of target proteins and biological responses, particularly under hyperglycemia or insulin resistance. β-Oxidation, fatty acid beta-oxidation; ACC, acetyl-CoA carboxylase; AR, aldose reductase; ATGL, adipose triglyceride lipase; CK, creatine kinase; creatine-P, creatine phosphate; CTP1, carnitine-palmitoyltransferase-1; DGAT, diacylglycerol O-acyltransferase; F-1,6-BP, fructose-1,6-biphosphate; F-2,6-BP, fructose-2,6-biphosphate; F-6-P, fructose-6-phosphate; Fasn, fatty acid synthase; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; Gck, glucokinase; GFA, glutamine fructose-6-phosphate aminotransferase; Glut, glucose transporter; HBP, hexosamine biosynthetic pathway; MPC, mitochondrial pyruvate carrier; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; Ox phos, oxidative phosphorylation; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase kinase-4; PEP, phosphoenolpyruvate; PFK1, phosphofructokinase-1; PFK2, phosphofructokinase-2; PPP, pentose phosphate pathway; TAG, triglycerides; TCA, tricarboxylic acid.
2. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 2

   Insulin/IGF-1 signaling via IRS1,2-coupled PI-3K→AKT→Foxo1 and mTOR activation in control of energy metabolism, protein synthesis, mitochondrial function, autophagy, apoptosis and gene expression of angiotensinogen and β-myosin heavy chain in cardiomyocytes. Insulin or IGF-1 binding to the insulin receptor or IGF-1 receptor stimulates the receptor tyrosine kinases, recruiting IRS-1,-2 and activating PI-3K to generate second messenger PIP3, which then activates PDK1 and mTORC2 for the activation of downstream effectors, including Akt that promotes mTORC1 activity and protein synthesis and inactivation of AMPK and autophagy. In addition to promoting glut-1,-4 gene expression and their cellular membrane association, PI-3K and Akt also suppress transcription factor Foxo1, which promotes apoptosis and autophagy, gene expression of angiotensinogen and β-myosin heavy chain, heme oxygenase-1, whereas suppresses glucokinase gene expression for glucose oxidation and unitization. Hyperinsulinemia or other metabolic and mechanic stress activates intracellular protein kinases, such as p38α, promotes serine and threonine phosphorylation of IRS, inhibits tyrosine phosphorylation of IRS and promotes IRS ubiquitination or degradation and desensitizes insulin/IGF-1 signaling propagation for Akt activation. Foxo1, forkhead/winged helix transcription factor O-class member 1; Hmoxo-1, heme oxygenase-1; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex-1; mTORC2, mammalian target of rapamycin complex-2; PDK1, phosphoinositide-dependent protein kinase-1; PI-3K, phosphatidylinositol (PI)-3-kinase; pS/T, phosphorylated serine or threonine; pY, phosphorylated tyrosine.
3. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 3

   Crosstalk between insulin/IGF-1 signaling and β-adrenergic receptor signaling in control of cardiac catabolism and anabolism via the GRK2. Binding of catecholamine agonists to the G-protein-coupled receptor (GCPR) that has seven transmembrane domains produces a conformational change in the GPCR, which promotes the binding of G-protein to the intracellular-binding site on the receptor. The G-protein is heterotrimeric and activated Gα and Gβγ subunits are responsible for the activation of specific effectors, which produce different second messengers that generate a wide range of cellular responses, particularly for Ca²⁺ handling, cardiac contractility, catabolism and apoptosis. The desensitization of GPCR is triggered by interaction with GRK-2 that phosphorylates the β-AR and enhances its interaction with β-arrestin. GRK-2 also activates PDE-4D gene expression by activating MAPK, thus suppressing cAMP production and PKA activity. An increase in receptor affinity toward β-arrestin for Gα protein uncoupling to Gβγ subunit arrests the signal propagation. It is expected that GRK-2 may interact and phosphorylate IRS-1 and IRS-2, desensitizing insulin/IGF-1 signaling in the activation of PI-3K and Akt for control of anabolism and survival. β, G-protein β subunit; β-AR, beta-adrenergic receptors; γ, G-protein γ subunit; AC, adenylate cyclase; cAMP, cyclic 3′,5′-adenosine monophosphate; Gα, G-protein α subunit; GRK-2, G-protein coupled receptor kinase-2; PDE-4D, phosphodiesterase 4D.
4. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 4

   A proposed model for the dynamic changes of cardiac IRS-1 and IRS-2 synthesis in control of metabolic adaptation, cardiac insulin resistance, remodeling and heart failure. The cardiac IRS-1 and IRS-2 protein levels are tightly correlated to the severity of heart failure and associated with myocardial intracellular protein kinases and Foxo1 activation. Under feeding conditions, IRS proteins slightly decreased to less than 25% and ATP homeostasis is maintained by glucose and free fatty acid (FFA) oxidation. Under insulin-resistant state, further downregulation of IRS protein by less than 50% desensitizes glucose uptake and utilization with enhanced FFA oxidation; thus, ATP homeostasis can be well maintained even when obesity occurs. However, downregulation of IRS proteins by more than 50% will result in cardiac dysfunction and 100% loss of IRS proteins will cause severe heart failure and death, in which a number of factors including activation of p38α, GRK-2, AMPK and Foxo1, as well as inactivation of Akt are shown.

• © 2017 Society for Endocrinology