GPCR and Insulin Signaling: Friends or Foes in Insulin Resistance?

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors that transmit signals from external molecules, such as hormones and neurotransmitters, to the interior of cells and are the most widely distributed membrane receptors in living beings. Their actions are not limited to mediating rapid effects in the cell but also regulate cell proliferation, differentiation, and gene expression. GPCRs have also been recognized for their important role in regulating metabolic actions and their association with diseases and metabolic disorders, such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and insulin resistance. A significant number of reports have demonstrated the strong relationship between insulin actions and GPCRs, such as those for adrenaline/noradrenaline, angiotensin, vasopressin, and corticotropin-releasing factor, ranging from sensitization (positive actions) to negative regulation of insulin actions. This raises the question: Are GPCRs and insulin signaling friends or foes in the development and progression of insulin resistance? This review aims to explore the complex interplay between GPCRs and insulin signaling and how their interactions contribute to the development of insulin resistance.