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
2O
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
2O
2 are elevated. Otherwise ATP would block K
ATP, while H
2O
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
2O
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
2O
2 diffusion or hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins.
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