The Pancreatic β-Cell: The Perfect Redox System

Pancreatic beta-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K+ channel (K-ATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block K-ATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed K-ATP ensemble is insufficient to reach the -50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl- channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca2+-influx (fortified by endoplasmic reticulum Ca2+). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA beta-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin redox kiss to target proteins.

Automated summary

Pancreatic beta-cell insulin secretion is regulated by NADPH oxidase 4-mediated H2O2 production, requiring both ATP and H2O2 elevation to close the K-ATP channel. Additionally, simultaneous activation of other channels is necessary for the pulsatile exocytosis of insulin granule vesicles.