Activation of G12-type G proteins in pancreatic β cells protects against impaired glucose homeostasis

Impaired insulin secretion represents a key feature of type 2 diabetes (T2D), a major global health burden. Insulin release from pancreatic β cells is regulated by G protein-coupled receptors linked to different functional classes of G proteins. The potential metabolic role of β cell G12/13 (G12 hereafter) signaling remains unexplored. Thus, we studied the potential metabolic outcomes of β cell G12 activation by using a combination of mouse gene knockout technology and β cell-specific chemogenetic approaches. We found that selective activation of β cell G12 signaling strongly promoted insulin secretion, thus protecting mice against obesity-associated metabolic deficits and improving glycemic control in a mouse model of T2D. Mechanistic studies with perifused pancreatic mouse islets identified ROCK as a key downstream effector of G12 signaling and potent trigger of insulin secretion. Collectively, these findings suggest that G protein-coupled receptors linked to G12 in β cells represent potential targets for antidiabetic drugs.