How do reducing equivalents increase insulin secretion?

Glucose stimulation of insulin secretion in pancreatic β cells involves cell depolarization and subsequent opening of voltage-dependent Ca2+ channels to elicit insulin granule exocytosis. This pathway alone does not account for the entire magnitude of the secretory response in β cells. In this issue, Ferdaoussi, Dai, and colleagues reveal that insulin secretion is amplified by cytosolic isocitrate dehydrogenase-dependent transfer of reducing equivalents, which generates NADPH and reduced glutathione, which in turn activates sentrin/SUMO-specific protease-1 (SENP1). β Cell-specific deletion of Senp1 in murine models reduced the amplification of insulin exocytosis, resulting in impaired glucose tolerance. Further, their studies demonstrate that restoring intracellular NADPH or activating SENP1 improves insulin exocytosis in human β cells from donors with type 2 diabetes, suggesting a potential therapeutic target to augment insulin production.