The Pancreatic β-Cell: The Perfect Redox System

Abstract

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 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 (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP 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 β-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins.

Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid–Conducting SLC25 Gene Family Transporters

“…Several additional thiol-redox modifications such as S-nitrosylation are possible [ 88 , 89 , 90 , 91 ]. The direct redox activation may also be propagated by proteins capable of SH relay, such as peroxiredoxins, directly affecting cysteine residues of the enzyme [ 6 , 7 , 92 ].…”

“…Since, in numerous types of eukaryotic cells and/or mammalian tissues, mitochondria are dominant sources of reactive oxygen species (ROS) and in certain tissues occupy a rather substantial cell volume, nature has developed mechanisms that prevent excessive ROS production. Therefore, multiple antioxidant systems were evolved within mitochondria to interact with (react to) internally produced ROS [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ].…”

CD36 Signal Transduction in Metabolic Diseases: Novel Insights and Therapeutic Targeting

“…On the other hand, β-cells have a lower abundance of antioxidant defense enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) [ 124 , 125 , 126 ]. As such, the administration of antioxidant supplements can increase the defense capacity of islet cells to cope with oxidative stress [ 127 ].…”

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

“…Since it has been recognized that the second GSIS phase exists in PIs, but not in the b-cells isolated from islets, this cell cooperation was considered to substantiate the second phase. But, the delayed kinetics of the insulin granules (104) (252,253), thus creating silent interburst phases (210) [see the lag between burst [Ca 2+ ] c phases in Fig. 4-part of the records published in Plecita-Hlavata et al (194)].…”