Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner

Overview

Journal Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2015 Dec 15

PMID 26652903

Citations 21

Authors

Supachoke Mangmool

Tananat Denkaew

Sarawuth Phosri

Darawan Pinthong

Warisara Parichatikanond

Tsukasa Shimauchi

Motohiro Nishida

Affiliations

Soon will be listed here.

Abstract

Insulin resistance is a condition in which cells are defective in response to the actions of insulin in tissue glucose uptake. Overstimulation of β-adrenergic receptors (βARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which sustained βAR stimulation affects insulin resistance in the heart are incompletely understood. In this study, we demonstrate that sustained βAR stimulation resulted in the inhibition of insulin-induced glucose uptake, and a reduction of insulin induced glucose transporter (GLUT)4 expression that were mediated by the β2AR subtype in cardiomyocytes and heart tissue. Overstimulation of β2AR inhibited the insulin-induced translocation of GLUT4 to the plasma membrane of cardiomyocytes. Additionally, βAR mediated cardiac insulin resistance by reducing glucose uptake and GLUT4 expression via the cAMP-dependent and protein kinase A-dependent pathways. Treatment with β-blockers, including propranolol and metoprolol antagonized isoproterenol-mediated insulin resistance in the heart. The data in this present study confirm a critical role for protein kinase A in βAR-mediated insulin resistance.

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References

Shah A, Shannon R . Insulin resistance in dilated cardiomyopathy. Rev Cardiovasc Med. 2003; 4 Suppl 6:S50-7. View

Hoffmann C, Leitz M, Oberdorf-Maass S, Lohse M, Klotz K . Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol. 2004; 369(2):151-9. DOI: 10.1007/s00210-003-0860-y. View

Mazumder P, ONeill B, Roberts M, Buchanan J, Yun U, Cooksey R . Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes. 2004; 53(9):2366-74. DOI: 10.2337/diabetes.53.9.2366. View

Chiasson J, Shikama H, Chu D, EXTON J . Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle. J Clin Invest. 1981; 68(3):706-13. PMC: 370852. DOI: 10.1172/jci110306. View

Kashiwagi A, Huecksteadt T, Foley J . The regulation of glucose transport by cAMP stimulators via three different mechanisms in rat and human adipocytes. J Biol Chem. 1983; 258(22):13685-92. View

Kirsch D, Baumgarten M, Deufel T, Rinninger F, Kemmler W, Haring H . Catecholamine-induced insulin resistance of glucose transport in isolated rat adipocytes. Biochem J. 1983; 216(3):737-45. PMC: 1152569. DOI: 10.1042/bj2160737. View

Cohn J, Levine T, Olivari M, Garberg V, Lura D, Francis G . Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984; 311(13):819-23. DOI: 10.1056/NEJM198409273111303. View

van Putten J, Krans H . Long-term regulation of hexose uptake by isoproterenol in cultured 3T3 adipocytes. Am J Physiol. 1985; 248(6 Pt 1):E706-11. DOI: 10.1152/ajpendo.1985.248.6.E706. View

Joost H, Steinfelder H . Forskolin inhibits insulin-stimulated glucose transport in rat adipose cells by a direct interaction with the glucose transporter. Mol Pharmacol. 1987; 31(3):279-83. View

10.

Kaestner K, McLenithan J, Janicot M, Lane M . Transcriptional repression of the mouse insulin-responsive glucose transporter (GLUT4) gene by cAMP. Proc Natl Acad Sci U S A. 1991; 88(5):1933-7. PMC: 51140. DOI: 10.1073/pnas.88.5.1933. View

11.

Thomas R, Holt B, Schwinn D, Liggett S . Long-term agonist exposure induces upregulation of beta 3-adrenergic receptor expression via multiple cAMP response elements. Proc Natl Acad Sci U S A. 1992; 89(10):4490-4. PMC: 49108. DOI: 10.1073/pnas.89.10.4490. View

12.

Swan J, Anker S, Walton C, Godsland I, Clark A, Leyva F . Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol. 1997; 30(2):527-32. DOI: 10.1016/s0735-1097(97)00185-x. View

13.

Doggrell S, Henderson C . The offset of beta-adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline. J Auton Pharmacol. 1998; 18(5):263-9. DOI: 10.1046/j.1365-2680.1998.18592.x. View

14.

Mancia G, Grassi G, Giannattasio C, Seravalle G . Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension. 1999; 34(4 Pt 2):724-8. DOI: 10.1161/01.hyp.34.4.724. View

15.

Morisco C, Condorelli G, Trimarco V, Bellis A, Marrone C, Condorelli G . Akt mediates the cross-talk between beta-adrenergic and insulin receptors in neonatal cardiomyocytes. Circ Res. 2004; 96(2):180-8. DOI: 10.1161/01.RES.0000152968.71868.c3. View

16.

Mulder A, Tack C, Olthaar A, Smits P, Sweep F, Bosch R . Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation. Am J Physiol Endocrinol Metab. 2005; 289(4):E627-33. DOI: 10.1152/ajpendo.00079.2004. View

17.

Murray A, Lygate C, Cole M, Carr C, Radda G, Neubauer S . Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovasc Res. 2006; 71(1):149-57. DOI: 10.1016/j.cardiores.2006.02.031. View

18.

Sucharov C, Mariner P, Nunley K, Long C, Leinwand L, Bristow M . A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction. Am J Physiol Heart Circ Physiol. 2006; 291(3):H1299-308. DOI: 10.1152/ajpheart.00017.2006. View

19.

Mangmool S, Haga T, Kobayashi H, Kim K, Nakata H, Nishida M . Clathrin required for phosphorylation and internalization of beta2-adrenergic receptor by G protein-coupled receptor kinase 2 (GRK2). J Biol Chem. 2006; 281(42):31940-9. DOI: 10.1074/jbc.M602832200. View

20.

Mlinar B, Marc J, Janez A, Pfeifer M . Molecular mechanisms of insulin resistance and associated diseases. Clin Chim Acta. 2006; 375(1-2):20-35. DOI: 10.1016/j.cca.2006.07.005. View