The Pancreatic β-Cell: The Perfect Redox System

Pancreatic β-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 H(2)O(2) 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 H(2)O(2) are elevated. Otherwise ATP would block K(ATP), while H(2)O(2) 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 Ca(2+) channels. Open synergic NSCCs or Cl(−) channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca(2+)-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 Ca(2+)-influx (fortified by endoplasmic reticulum Ca(2+)). ATP plus H(2)O(2) are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H(2)O(2) diffusion or hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins.