Abstract 252: Dysregulation of β-Adrenergic Signaling in Hearts with Hyperinsulinemia

Abstract

Introduction: Epidemiological studies have demonstrated an increased risk of heart failure in diabetics, but the mechanisms linking diabetes mellitus (DM) to heart failure remain unclear. A uniform metabolic disturbance that characterizes type 2 diabetes is hyperinsulinemia, which accelerates adverse left ventricular (LV) remodeling in pressure overload hypertrophy. Hypothesis: We hypothesize that hyperinsulinemia might affect LV contractility by directly impairing β-adrenergic receptor (βAR) signaling. Methods and Results: Insulin receptor and β 2 AR form a cell surface complex, which dissociates upon insulin stimulation in the heart and cardiomyocytes. Insulin dose-dependent significantly inhibits PKA activities induced by a βAR agonist isoproterenol, and subsequently impairs isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Mechanistically, insulin action is mediated via IR and β 2 AR dependent manner. Insulin induces both PKA and GRK2-mediated phosphorylation of the β 2 AR, leading to enhanced β 2 AR/Gi coupling that inhibits adenylyl cyclase-mediated cAMP production. Pretreatment with Gi inhibitor pertussis toxin abolishes the insulin-mediated impairment of β-adrenergic stimulation of cAMP signaling. Further studies reveal that chronic insulin stimulation increases phosphodiesterase 4D protein levels in cardiac myocytes, and that the expression of phosphodiesterase 4D is also increased in animal models with high fat feeding or after 2-weeks of transaortic constriction. This leads further attenuation of βAR-induced cAMP activity for contraction response. Inhibition of phosphodiesterase 4 with rolipram rescues cAMP signaling induced by isoproterenol after insulin treatment. Last, PDE4D protein levels are significantly induced in the myocardium in diabetic patients with heart disease compared to those non-diabetic patients with heart disease. Conclusions: This is the first evidence showing that hyperinsulinemia might adversely impact cardiac contractility by inhibiting βAR signaling, which is due to IR-induced β 2 AR/Gi coupling and phosphodiesterase 4 expression in the βAR signaling cascades.