Wang Q, Liu Y, Fu Q, Xu B, Zhang Y, Kim S, Tan R, Barbagallo F, West T, Anderson E, Wei W, Abel ED, Xiang YK. Inhibiting Insulin-Mediated beta2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction. Circulation 2017; 135(1): 73-88

Abstract

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 beta2-adrenergic receptor (beta2AR) or beta-arrestin2. Wild-type mice fed with high-fat diet were treated with a beta-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 beta-arrestin2-dependent transactivation of a beta2AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of beta2AR or GRK2, or genetic deletion of beta2AR or  beta-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 beta2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.