Inhibiting Insulin-Mediated β2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.
BACKGROUND
Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity.


METHODS
High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β2-adrenergic receptor (β2AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function.


RESULTS
High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β2AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β2AR or GRK2, or genetic deletion of β2AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction.


CONCLUSIONS
These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.
Department of Pharmacology, University of California at Davis, CA 95616, USA.|Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
Qingtong
Q
Wang
Department of Pharmacology, University of California at Davis, CA 95616, USA.|Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200000, China.
Yongming
Y
Liu
Department of Pharmacology, University of California at Davis, CA 95616, USA.|Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Qin
Q
Fu
Department of Pharmacology, University of California at Davis, CA 95616, USA.
Bing
B
Xu
Department of Medicine, Division of Endocrinology and Metabolism and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA.
Yuan
Y
Zhang
Department of Pharmacology, University of California at Davis, CA 95616, USA.
Sungjin
S
Kim
Department of Pharmacology, University of California at Davis, CA 95616, USA.
Ruensern
R
Tan
Department of Pharmacology, University of California at Davis, CA 95616, USA.
Federica
F
Barbagallo
Department of Pharmacology, University of California at Davis, CA 95616, USA.
Toni
T
West
Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27834, USA.
Ethan
E
Anderson
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
Wei
W
Wei
Department of Medicine, Division of Endocrinology and Metabolism and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA.
E Dale
ED
Abel
Department of Pharmacology, University of California at Davis, CA 95616, USA.|VA Northern California Health Care System, Mather, CA 95655, USA.
Yang K
YK
Xiang
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D059305:Diet, High-Fat; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000494:pharmacology; D000071560:beta-Arrestin 2 / Q000172:deficiency / Q000235:genetics
D002227:Carbazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D014665:Vasodilator Agents; D000071560:beta-Arrestin 2; D000077261:Carvedilol; D054769:G-Protein-Coupled Receptor Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
diabetic cardiomyopathy; heart failure; insulin; phosphodiesterase; β-adrenergic receptors