2092-LB: Receptor-Mediated G12 Signaling Strongly Promotes Insulin Secretion from Pancreatic Beta Cells

Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. The inability of pancreatic β-cells to release enough insulin is key pathological sign. Glucose-induced insulin secretion is regulated by G protein-coupled receptors (GPCRs) located on the cell surface of pancreatic β-cells. Because of the lack of GPCRs that can selectively interact with G proteins of the G12 family (G12/G13), it remains unknown whether G12 signaling has a positive impact on β-cell function. To address this question, we generated a new mouse line that expressed a CNO (clozapine-N-oxide)-sensitive, G12-coupled designer GPCR (G12 DREADD; DREADD = designer receptor exclusively activated by a designer drug) selectively in β-cells (beta-G12D mice). CNO is a small synthetic molecule that can selectively activate the G12 DREADD but is otherwise pharmacologically inert. In addition, we generated a mouse model lacking the α-subunits of G12 and G13 selectively in β-cells (beta-G12/13 KO mice). We then subjected these mutant mice, together with their control littermates, to a series of metabolic tests. We found that selective activation of β-cell G12 signaling strongly enhanced glucose-stimulated insulin secretion, leading to improved glucose tolerance in both lean and obese mice. In obese mice, activation of β-cell G12 signaling counteracted the deficits in glucose homeostasis caused by increased adiposity. The G12D-mediated simulation of insulin release was virtually abolished in beta-G12/13 KO mice. Mechanistic studies with perifused pancreatic islets demonstrated that the increase in insulin release triggered by stimulation of β-cell G12 signaling required the activation of ROCK1, leading to structural changes in the actin cytoskeleton that promoted insulin secretion. Our data strongly suggest that strategies aimed at stimulating β-cell G12 signaling could become clinically useful for the treatment of T2D and related metabolic disorders.