Inhibiting Insulin-Mediated β ₂ -Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction

Abstract

Background Type-2 diabetes and obesity independently increases the risk of heart failure via incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in hearts of subjects with type-2 diabetes and obesity. Methods High fat diet feeding was used to induce obesity and diabetes 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 β-blocker carvedilol or G-protein receptor kinase 2 (GRK2) inhibitor. We examined the 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 PKA phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with diabetes. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and (GRK2) and β-arrestin2-dependent transactivation of a β2AR-ERK signaling cascade. Thus pharmacological inhibition of β2AR or GRK2, or genetic deletion of β2AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of ERK and PDE4D induction, to prevent diabetes-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 diabetes.

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

“…In contrast, long-term treatment with βAR agonist induced down-regulation of PDE3B and up-regulation of PDE4D [120]. In line with the observation in adipocytes, our recent study shows that in rodent hearts, hyperinsulinemia induces upregulation of PDE4D protein expression and activity, which correlates with cardiac dysfunction [121] (Figure 2). …”

Impact of paroxetine on proximal β-adrenergic receptor signaling

“…However, the Food and Drug Administration-approved SSRI paroxetine was identified using a high throughput aptamer displacement assay to bind directly to GRK2 to inhibit its ability to phosphorylate rhodopsin, tubulin and thyrotropin-releasing hormone receptor, while increasing βAR-stimulated cardiomyocyte (in vitro) and cardiac (in vivo) contractility 7 . Subsequently, paroxetine has been shown to reverse cardiac dysfunction induced by either ischemia 8 or high fat diet 18 , inhibit T cell activation 19 and decrease fibroblast cytokine production 20 . Despite the increasing use of paroxetine in studies in which its effects are attributed to inhibition of receptor desensitization processes classically engaged by GRK2, such as βarr recruitment and GPCR internalization, no studies have confirmed whether it actually attenuates these responses.…”

Of mice and men: models and mechanisms of diabetic cardiomyopathy

“…Recent studies revealed a critical crosstalk between insulin and β-adrenergic signalling, which impairs cardiac contractility in T2D [78, 209]. βAR signalling is increased in heart failure.…”