Stimulus-Secretion Coupling Mechanisms of Glucose-Induced Insulin Secretion: Biochemical Discrepancies Among the Canonical, ADP-Privation, and GABA-Shunt Models

Analysis of precedent and new data should allow now and then to suggest modifications for a future integral view of the stimulus-secretion coupling of glucose-induced insulin secretion. The main purpose of this review is to supply only biochemical considerations about some of the metabolic pathways implicated in the process of insulin secretion. It is emphasized that glucose β-cells’ threshold to activate secretion (5 mM) might depend on the predominance of anaerobic glycolysis at this basal glucose concentration. This argues against the predominance of phosphoenolpyruvate (PEP) over mitochondrial pyruvate oxidation for the initiation of insulin secretion. Full quantitative and qualitative reproduction, except the threshold effect, of glucose-induced insulin release by a permeable methylated analogue of succinic acid indicates that mitochondrial metabolism is enough for a sustained insulin secretion. Mitochondrial PEP generation is skipped if the GABA shunt pathway is exclusively coupled to the citric acid cycle, as proposed in the “GABA shunt” model of stimulus-secretion coupling. More or less strong, or maintained, depolarization by KCl or sulfonylureas might induce the opening of β-cells Cx36 hemichannels allowing the loss of adenine nucleotides, and other metabolites, mimicking the effect of an excessive mitochondrial ATP demand. A few alterations of the OxPhos regulation in human T2D islets have been described but the responsible mechanism(s) is (are) not yet known. Finally, some experimental data argued as proof of the relative irrelevance of mitochondrial function in the insulin secretion-coupling mechanism for the initiation and/or sustained stimulation of hormone release are discussed.