No-Flow Ischemia Inhibits Insulin Signaling in Heart by Decreasing Intracellular pH (original) (raw)
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Insulin signalling in the heart
Cardiovascular Research, 2008
The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. In addition, insulin participates in the regulation of long-chain fatty acid uptake, protein synthesis and vascular tonicity. Significant advancements have been made over the last 20 years in the understanding of the signal transduction elements involved in these insulin effects. Amongst these molecular mechanisms, the phosphatidylinositol 3kinase/protein kinase B (Akt) pathway is thought to play a crucial role. Under pathological conditions, such as type-2 diabetes, myocardial ischemia and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified. These molecular signalling alterations are often linked to atypical crosstalks with other signal transduction pathways. On the other hand, pharmacological modifications of parallel and interdependent signalling components, such as the AMP-activated protein kinase pathway, is now considered to be a good therapeutic approach to treat insulin signalling defects such as insulin resistance and type-2 diabetes. In this review, we will focus on the description of the molecular signalling elements involved in insulin action in the heart and vasculature under these different physiological, pathological and therapeutical conditions.
Frontiers in Physiology, 2016
Insulin is a peptide hormone produced by the β cells, of the islets of Langerhans. Functionally, is the most potent anabolic hormone, promoting the synthesis and storage of carbohydrates, lipids and proteins, while inhibiting their degradation and release into circulation. This hormone stimulates the uptake of glucose, amino acids, and fatty acids; and increases the expression of enzymes involved in the glycogen, lipid, and protein synthesis. At the same time, it reduces the activity of the enzymes that catalyse degradation of same molecules (Saltiel and Kahn, 2001). Cellular effects of insulin are mediated by the activation of insulin receptors (IRs A/B), and a signaling pathway involved in the regulation of nutrients metabolism, mitochondrial biogenesis, cellular grown, proliferation, differentiation, and migration (Nystrom and Quon, 1999). IRs are glycoproteins consisting of an extracellular α-subunit (135 kDa) and a transmembrane βsubunit (95 kDa). These receptors are allosteric enzymes in which the α-subunit regulates tyrosine kinase activity of the β-subunits. The binding of insulin to the α-subunit results in dimerization, forming the α 2 β 2 complex in the plasma membrane. The complex α 2 β 2 generates the autophosphorylation of β-subunit at tyrosine (Tyr) 1158 (Tyr 1158), Tyr 1162 , and Tyr 1163 , the first step in the activation cascade induced by insulin (Patti and Kahn, 1998). Phosphorylation of IR induces the tyrosine kinase activity toward insulin receptor substrate (IRS) 1 (IRS-1) or 2 (IRS-2), generating binding sites for Src homology 2 (SH2) domain proteins, including phosphatidylinositol 3-kinase (PI3K), RAS guanine nucleotide exchange factor complex known as growth factor receptor-bound protein 2/son of sevenless (GRB2/SOS), and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) and other SH2 proteins (Copps and White, 2012). These proteins provide specific docking sites for the recruitment of downstream signaling proteins, leading to activation of mitogenactivated protein kinase (MAPK), protein kinase B (PKB/Akt) and protein kinase C (PKC) signaling cascades (White, 2003; Schultze et al., 2012).
Regulation of glucose metabolism by insulin in cardiomyocytes
REGULATION
Cardiac function is improved during ischemia by stimulating glucose metabolism and subsequent decreasing of fatty acid (FA) oxidation. The impairment of heart glucose metabolism may contribute to the heart dysfunction and cardiomyopathy.
Insulin improves postischemic recovery of function through PI3K in isolated working rat heart
Molecular and cellular biochemistry, 2003
Insulin improves contractile function after ischemia, but does not increase glucose uptake in the isolated working rat heart. We tested the hypothesis that the positive inotropic effect of insulin is independent of the signaling pathway responsible for insulin-stimulated glucose uptake. We inhibited this pathway at the level of phosphatidyl inositol 3-kinase (PI3K) with wortmannin. Hearts were perfused for 70 min at physiological workload with Krebs-Henseleit buffer containing [2-(3)H] glucose (5 mM, 0.05 microCi/ml) and oleate (0.4 mM, 1% BSA) in the presence (WM, n = 5) or absence (control, n = 7) of wortmannin (WM, 3 micromol/L). After 20 min, hearts were subjected to 15 min of total global ischemia followed by 35 min of reperfusion. Insulin (1 mU/ml) was added at the beginning of reperfusion (WM + insulin n = 8, insulin n = 8). Cardiac power before ischemia was 8.1 +/- 0.7 mW. Recovery of contractile function after ischemia was significantly increased in the presence of insulin ...
Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms
Cardiovascular Research, 1997
Abbreviations: ACC s acetyl-CoA carboxylase; AMP-PK s protein serinerthreonine kinase activated by 5 X -AMP; CPT-I s carnitine palmitoyltransferase-I; CREB protein s cyclic AMP-response element binding protein; ERKs s extracellular signal-regulated kinases: the MAP kinases originally Ž identified are now known to represent a sub-set of a wider family; the original members of the family are now referred to as 'ERKs' extracellular .Ž . signal-regulated kinase ; other sub-types of MAP kinases are JNKs c-Jun, N-terminal kinases and p38rRK; p125-FAK s 125-kDa focal adhesion Ž. protein tyrosine kinase; Grb s growth-factor-receptor bound protein; GSK-3 s glycogen synthase kinase-3; HDL s high-density lipoprotein;
Journal of Biological Chemistry, 1997
Insulin receptor substrate (IRS)-2 is structurally and functionally similar to IRS-1. Indeed, stimulation with insulin or insulin-like growth factor I led to the rapid tyrosine phosphorylation of both IRS-1 and IRS-2, which in turn activated phosphatidylinositol (PI) 3-kinase in L6 cells and rat skeletal muscle. However, IRS-2 was rapidly dephosphorylated (3-10 min after the addition of insulin/insulin-like growth factor I), whereas IRS-1 phosphorylation continued for at least 60 min. The time courses of the PI 3-kinase activity associated with IRS-1 and IRS-2 paralleled the tyrosine phosphorylation of these proteins. Preincubation with sodium orthovanadate, an inhibitor of protein tyrosine phosphatase, blocked the rapid dephosphorylation of IRS-2, suggesting the involvement of tyrosine phosphatase. The activation of PI 3-kinase apparently plays an important role in the rapid dephosphorylation of IRS-2, as IRS-2 dephosphorylation was inhibited markedly by suppressing PI 3-kinase activity with wortmannin or overexpression of the dominant negative p85 subunit of PI 3-kinase, which cannot bind the p110 catalytic subunit. In addition, platelet-derived growth factor stimulation prior to insulin stimulation decreased IRS-associated PI 3-kinase and significantly inhibited the dephosphorylation of IRS-2. Taken together, these observations suggest that IRS-2 plays a unique role in mediating the signals from the insulin receptor to downstream molecules and that this effect is more transient than that of IRS-1. Tyrosine phosphatase and IRS-associated PI 3-kinase activity thus contribute to the rapid dephosphorylation of IRS-2.