Abstract
Since it was reported in 1991 by Schaffer et al. that myocardial contractile responsiveness was altered in NIDDM in the absence of alterations in the β-adrenergic receptor population, researchers have been seeking a post-receptor defect to account for this. The present study addresses this issue by comparing alterations occurring in the myocardial β-receptor signalling pathway in two different models of rat NIDDM, as well as the response of the pathway after stimulation with isoproterenol in the presence or absence of insulin. The characteristics of the β-receptor population, adenylyl cyclase activity and cAMP levels were determined at three different ages. The main results demonstrate that: (i) the two models of NIDDM myocardium differ biochemically; (ii) the β-adrenergic signalling system of the insulin deficient model was altered more than the hyperinsulinemic model and (iii) the observed exaggerated cAMP response of NIDDM hearts after stimulation with a β-adrenergic agonist is in contrast with lower responsivity.
Similar content being viewed by others
References
Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, Haider: Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 60: 885–899, 1977
Zaninetti D, Greco-Perotto R, Assimacopoulos-Jeannet F, Jeanrenaud B: Effects of insulin on glucose transport and transporters in rat heart. Biochem J 250: 277–283, 1988
Gotzsche O: Myocardial cell dysfunction in diabetes mellitus. A review of clinical and experimental studies. Diabetes 35: 1158–1162, 1986
Ganguly PK, Dhalla KS, Innes IR, Beamish RE, Dhalla NS: Altered norepinephrine turnover and metabolism in diabetic cardiomyopathy. Circ Res 59: 684–693, 1986
Atkins FL, Dowell RT, Love S: β-Adrenergic receptors, adenylate cyclase activity and cardiac dysfunction in the diabetic rat. J Cardiovasc Pharmacol 7: 66–70, 1985
Williams RS, Schaible TF, Scheuer J, Kennedy R: Effects of experimental diabetes on adrenergic and cholinergic receptors of rat myocardium. Diabetes 32: 881–886, 1983
Heyliger CE, Pierce GN, Singal PK, Beamish RE, Dhalla NS: Cardiac alpha-and beta-adrenergic receptor alterations in diabetic cardiomyopathy. Basic Res Cardiol 77: 610–618, 1982
Gotzche O: The adrenergic b-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial β-receptor. Diabetes 32: 1110–1116, 1983
Wichelhaus A, Russ M, Petersen S, Eckel J: G protein expression and adenylate cyclase regulation in ventricular cardiomyocytes from STZ-diabetic rats. Am J Physiol 267: H548–H555, 1994
Ingebretsen WR, Peralta C, Monsher M, Wagner LK, Ingebretsen CG: Diabetes alters the myocardial cAMP-protein kinase cascade system. Am J Physiol 240: H375–382, 1981
Miller TB Jr: Phosphorylase activation hypersensitivity in hearts of diabetic rats. Am J Physiol 246: E134–140, 1984
Schaffer SW, Allo S, Punna S, White T: Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart. Am J Physiol 261: E396–376, 1991
Ozuari A, Ozturk Y, Yildizoglu-Ari N, Ozcelkay AT, Altan VM: The effects of glyburide and insulin on the cardiac performance in rats with non-insulin-dependent diabetes mellitus. Gen Pharmacol 24: 165–169, 1993
Banyasz T, Kalapos I, Kelemen SZ, Kovacs T: Changes in cardiac contractility in IDDM and NIDDM diabetic rats. Gen Physiol Biophys 15: 357–369, 1996
Collins S, Daniel KW, Tohlfs EM, Ramkumar V, Taylor IL, Gettys TW: Impaired expression and functional activity of the beta 3-and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol Endocrinol 8: 518–527, 1994
Keely SL, Corbin JD, Park CR: Regulation of adenosine 3':5'-monophosphate-dependent protein kinase: Regulation of the heart enzyme by epinephrine, glucagon, insulin and 1-methyl-3-isobutylxanthine. J Biol Chem 250: 4832–4840, 1975
Narayanan N, Derby JA: Alterations in the properties of beta-adrenergic receptors of myocardial membranes in aging: impairments in agonist-receptor interactions and guanine nucleotide regulation accompany diminished catecholamine-responsiveness of adenylate cyclase. Mech Ageing Dev 19: 127–139, 1982
Scarpace PJ: Decreased beta-adrenergic responsiveness during senescence. Fed Proc 45: 51–54, 1986
Sakai M, Danziger RS, Xiao RP, Sprugeon HA, Lakatta EG: Contractile response of individual cardiac myocytes to norepinephrine declines with senescence. Am J Physiol 262: H184–189, 1992
Zaninetti D, Crettax M, Jeanrenaud B: Dysregulation of glucose transport in hearts of genetically obese (fa/fa) rats. Diabetologia 25: 525–529, 1983
Portha B, Blondel O, Serradas P, Mc Evoy R, Giroix M-H, Kergoat M, Bailbe D: The rat models of non-insulin dependent diabetes induces by neonatal streptozotocin. Diabetes Metab 15: 61–75, 1989
Strasser RH, Braun-Dullaeus R, Walendzik H, Marquetant R: α1-Receptor-independent activation of protein kinase C in acute myocardial ischaemia. Mechanisms for sensitization of the adenylyl cyclase system. Circ Res 70: 1304–1312, 1992
Lowry AO, Rosenbrough NF, Farr AL, Randall RJ: Protein with the folin phenol reagent. J Biol Chem 193: 265–275, 1951
Kaplan RS, Pedersen PL: Determination of microgram quantities of protein in the presence of milligram levels of lipid with Amido Black 10B. Analyt Biochem 150: 97–104, 1985
Strasser RH, Krimmer J, Braun-Dullaeus R, Marquetant R, Kübler W: Dual sensitization of the adrenergic system in early myocardial ischaemia: Independent regulation of the β-adrenergic receptors and the adenylyl cyclase. J Mol Cell Cardiol 22: 1405–1423, 1990
Salomon Y, Londos C, Rodbell MA: A highly sensitive adenylyl cyclase assay. Anal Biochem 58: 541–548, 1974
Jakobs KH, Saur W, Schultz G: Reduction of adenylyl cyclase activity in lysates of human platelets by the α-adrenergic component of epinephrine. J Cyclic Nucl Res 2: 381–392, 1976
Hsu KL, Chiang FT, Lo HM, Tsai CH, Tseng CD, Tweng YZ: Cardiac contractility in noninsulin dependent diabetes mellitus evaluated using the relation between endsystolic wall stress and velocity of circumferential fiber shortening. Jpn Heart J 38: 463–471, 1997
Yu ZW, Jansson PA, Posner BI, Smith U, Eriksson JW: Peroxovanadate and insulin action in adipocytes from NIDDM patients. Evidence against a primary defect in tyrosine phosphorylation. Diabetologia 40: 1197–1203, 1997, 1983
Ingebretsen CG, Haweln-Johnson C, Ingebretsen WR: Alloxaninduced diabetes reduces β-adrenergic receptor number without affecting adenylate cyclase in rat ventricular membranes. J Cardiovasc Pharmacol 5: 454–461, 1983
Ramanadham S, Tenner TE Jr: Alterations in the myocardial betaadrenoceptor system of streptozotocin-diabetic rats. Eur J Pharmacol 136: 377–389, 1987
Nishio Y, Kashiwagi A, Kida Y, Kodama M, Abe N, Saeki Y, Shigeta Y: Deficiency of cardiac beta-adrenergic receptor in streptozotocin-induced diabetic rats. Diabetes 37: 1181–1187, 1988
Kamata K, Satoh T, Tanaka H, Shigenobu K: Changes in electrophysiological and mechanical responses of the rat papillary muscle to alpha-and beta-agonist in streptozotocin-induced diabetes. Can J Physiol Pharmacol 75: 781–788, 1997
Smith CI, Pierce GN, Challa NS: Alterations in adenylate cyclase activity due to streptozotocin-induced diabetic cardiomyopathy. Life Sci 34: 1223–1230, 1984
Michel A, Cros GH, McNeill JH, Serrano JJ: Cardiac adenylate cyclase activity in streptozotocin-treated rats after 4 months of diabetes: Impairment of epinephrine and glucagon stimulation. Life Sci 37: 2067–2075, 1985
Gawler D, Milligan G, Houslay MD: Treatment of streptozotocindiabetic rats with metformin restores the ability of insulin to inhibit adenylate cyclase activity and demonstrates that insulin does not exert this action through the inhibitory guanine nucleotide regulatory protein Gi. Biochem Biophys Res Commun 115: 583–589, 1983
Panagia V, Michiel DF, Dhalla KS, Jijjar MS, Dhalla NS: Role of phosphatidylinositol in basal adenylate cyclase activity of rat heart sarcolemma. Biochim Biophys Acta 676: 395–400, 1981
Kennington AS, Hill CR, Craig J, Bogardus C, Raz I, Ortmeyer HK, Hansen BC, Romero G, Larner J: Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. N Engl J Med 323: 373–378, 1990
Han X, Bonen A: Epinephrine translocates GLUT-4 but inhibits insulin-stimulated glucose transport in rat muscle. Am J Physiol 274: E700–707, 1998
Egan JJ, Greenberg AS, Chang MK, Londos C: Control of endogenous phosphorylation of the major cAMP-dependent protein kinase substrate in adipocytes by insulin and beta-adrenergic stimulation. J Biol Chem 265: 18769–18775, 1990
Muller G, Grey S, Jung C, Bandlow W: Insulin-like signaling in yeast: Modulation of protein phosphatase 2A, protein kinase A, cAMP-specific phosphodiesterase, and glycosyl-phosphatidylinositol-specific phospholipase C activities. Biochemistry 39: 1475–1488, 2000
Okubo M, Bogardus C, Lillioja S, Mott DM: Adenosine 3',5'-monophosphate-dependent protein kinase activity decreases in human muscle after insulin infusion. J Clin Endocrinol Metab 69: 798–803, 1989
Ortmeyer HK: Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant rhesus monkeys. J Basic Clin Physiol Pharmacol 8: 223–235, 1997
Kida Y, Nyomba BL, Bogardus C, Mott DM: Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin-resistant humans. J Clin Invest 87: 673–679, 1991
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huisamen, B., Marais, E., Genade, S. et al. Serial changes in the myocardial β-adrenergic signalling system in two models of non-insulin dependent diabetes mellitus. Mol Cell Biochem 219, 73–82 (2001). https://doi.org/10.1023/A:1011014909231
Issue Date:
DOI: https://doi.org/10.1023/A:1011014909231