title: Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner.
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.
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Tananat
authors.initials: T
authors.lastname: Denkaew
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Sarawuth
authors.initials: S
authors.lastname: Phosri
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Darawan
authors.initials: D
authors.lastname: Pinthong
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Warisara
authors.initials: W
authors.lastname: Parichatikanond
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shimauchi
authors.affiliation: Department of Pharmacology (S.M., T.D., S.P., W.P.) and Center of Excellence for Innovation in Drug Design and Discovery (S.M.), Faculty of Pharmacy, and Department of Pharmacology (D.P.), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Division of Cardiocirculatory Signaling (T.S., M.N.), Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Translational Pharmaceutical Sciences (T.S., M.N.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Precursory Research for Embryonic Science and Technology (M.N.), Japan Science and Technology Agency, Siatama 332-0012, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D051275:Glucose Transporter Type 4; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D017868:Cyclic AMP-Dependent Protein Kinases; D008790:Metoprolol; D007545:Isoproterenol