Gαo represses insulin secretion by reducing vesicular docking in pancreatic β cells

OBJECTIVE Pertussis toxin uncoupling–based studies have shown that Gαi and Gαo can inhibit insulin secretion in pancreatic β-cells. Yet it is unclear whether Gαi and Gαo operate through identical mechanisms and how these G-protein–mediated signals inhibit insulin secretion in vivo. Our objective is to examine whether/how Gαo regulates islet development and insulin secretion in β-cells. RESEARCH DESIGN AND METHODS Immunoassays were used to analyze the G α o expression in mouse pancreatic cells. G α o was specifically inactivated in pancreatic progenitor cells by pancreatic cell–specific gene deletion. Hormone expression and insulin secretion in response to different stimuli were assayed in vivo and in vitro. Electron microscope and total internal reflection fluorescence–based assays were used to evaluate how Gαo regulates insulin vesicle docking and secretion in response to glucose stimulation. RESULTS Islet cells differentiate properly in G α o −/− mutant mice. G α o inactivation significantly enhances insulin secretion both in vivo and in isolation. G α o nullizygous β-cells contain an increased number of insulin granules docked on the cell plasma membrane, although the total number of vesicles per β-cell remains unchanged. CONCLUSIONS Gαo is not required for endocrine islet cell differentiation, but it regulates the number of insulin vesicles docked on the β-cell membrane.