How do reducing equivalents increase insulin secretion?

Abstract

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.

Figure 1. Triggering and amplification of glucose-stimulated insulin secretion.

In β cells, glucose uptake and metabolism result in depolarization and subsequent opening of voltage-gated Ca²⁺ channels, which in turn triggers insulin granule secretion. Amplification of insulin secretion requires pyruvate metabolism in the mitochondria, which in β cells is driven by high rates of pyruvate carboxylation and generation of oxaloacetate (inset). Several metabolites downstream of oxaloacetate have been evaluated for their ability to amplify GSIS, including citrate, malate, aspartate, and PEP. Of these, generation of PEP in the mitochondria is critical for GSIS. In this issue, Ferdaoussi, Dai, and colleagues demonstrate that the transfer of reducing equivalents mediated by the conversion of isocitrate to α-ketoglutarate by ICDc in the cytosol generates NADPH and maintains glutathione in its reduced form, GSH. GSH then activates SENP1, which deSUMOylates a target protein (not yet identified), thus promoting (or derepressing) insulin release. Glutamate metabolism is also involved in insulin secretion, and mutations in the inhibitory GTP-binding site of GDH, which converts glutamate to α-ketoglutarate in the mitochondria, increase insulin secretion. Reductive carboxylation of α-ketoglutarate in the mitochondria generates isocitrate and is thus a potential pathway through which glutamate metabolism may feed into the ICDc/SENP1-mediated amplification pathway.