Abstract Body: Cardiovascular diseases are a major comorbidity factor in Type 2 diabetes patients and a leading cause of death among them. Yet, mechanistically, how impairment in pancreatic islets alters cardiac function under different metabolic states remains largely unknown. Here, we investigate the role of the G-protein coupled receptor kinase 2 (GRK2) in regulating islet adaptations to an obesogenic diet and its impact on myocardial function. Using a novel inducible β-cell specific GRK2 knockout mouse model (βGRK2KO), we establish that loss of adult β-cell GRK2 delays metabolic islet maladaptation, protecting the heart against obesity induced cardiac dysfunction. Using in vitro islet assays, tolerance tests, and hyperglycemic clamps, βGRK2KO have a delayed metabolic adaptation to dietary challenges. Using hyperinsulinemic-euglycemic clamps βGRK2KO mice are more insulin-sensitive than control mice and have improved cardiac function and myocardial morphology. Thus, genetic ablation of GRK2 in adult β-cells during an obesogenic diet presents advantageous outcome to the heart. Using sequencing analysis, we are investigating mechanistically pathways altered by β-cell GRK2. This study prompts a novel therapeutic window for GRK2 intervention strategies for diabetic patients prone to cardiac dysfunction.