Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920-952.

• Keywords
• ATP-sensitive K+ channel, GLP-1, TRPM channels, branched-chain ketoacid oxidation, fatty acid-stimulated insulin secretion, insulin secretion, mitochondrial Ca2+ transport, pancreatic β-cell metabolism, redox signaling,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Insulin-Secreting Cells * metabolism   MeSH
• Glucose metabolism   MeSH
• Insulin metabolism   MeSH
• Islets of Langerhans * metabolism   MeSH
• Mitochondria metabolism   MeSH
• NAD metabolism   MeSH
• NADP metabolism   MeSH
• Insulin Secretion MeSH
• Secretagogues metabolism   MeSH
• Calcium metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Glucose MeSH
• Insulin MeSH
• NAD MeSH
• NADP MeSH
• Secretagogues MeSH
• Calcium MeSH

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.

• Keywords
• ATP-sensitive K+ channel, GLP-1, GPR40, NADPH oxidase 4, TRPM channels, branched-chain ketoacid oxidation, fatty-acid-stimulated insulin secretion, insulin secretion, pancreatic β-cells, redox signaling,
• Publication type
• Journal Article MeSH
• Review MeSH

Transcript levels for selected ATP synthase membrane FO-subunits-including DAPIT-in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F1α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency.

• Keywords
• ATP synthase oligomers mitochondrial cristae morphology, USMG5/DAPIT, glucose-induced expression, glucose-stimulated insulin secretion, membrane subunits of ATP synthase, mitochondria,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Insulin-Secreting Cells cytology   drug effects   metabolism   MeSH
• Cell Culture Techniques MeSH
• Cell Line MeSH
• Glucose administration & dosage   pharmacology   MeSH
• Protein Conformation MeSH
• Rats MeSH
• Hyaluronic Acid chemistry   MeSH
• Membrane Proteins chemistry   genetics   metabolism   MeSH
• DNA, Mitochondrial drug effects   genetics   MeSH
• Mitochondria drug effects   genetics   metabolism   MeSH
• Models, Molecular MeSH
• Mice MeSH
• Up-Regulation * MeSH
• DNA Copy Number Variations drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Atp5md protein, rat MeSH Browser
• Glucose MeSH
• Hyaluronic Acid MeSH
• Membrane Proteins MeSH
• DNA, Mitochondrial MeSH