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Diabetes is a major risk factor for the development of heart failure. One of the hallmarks of diabetes is insulin resistance associated with hyperinsulinemia. The literature shows that insulin and adrenergic signaling is intimately linked to each other; however, whether and how insulin may modulate cardiac adrenergic signaling and cardiac function remains unknown. Notably, recent studies have revealed that insulin receptor and β2 adrenergic receptor (β2AR) forms a membrane complex in animal hearts, bringing together the direct contact between 2 receptor signaling systems, and forming an integrated and dynamic network. Moreover, insulin can drive cardiac adrenergic desensitization via protein kinase A and G protein-receptor kinases phosphorylation of the β2AR, which compromises adrenergic regulation of cardiac contractile function. In this review, we will explore the current state of knowledge linking insulin and G protein–coupled receptor signaling, especially β-adrenergic receptor signaling in the heart, with emphasis on molecular insights regarding its role in diabetic cardiomyopathy.