Tamarit-Rodriguez, J. Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes. Metabolites2023, 13, 697.
Tamarit-Rodriguez, J. Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes. Metabolites 2023, 13, 697.
Tamarit-Rodriguez, J. Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes. Metabolites2023, 13, 697.
Tamarit-Rodriguez, J. Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes. Metabolites 2023, 13, 697.
Abstract
The stimulus-secretion coupling of glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K+-channel at the plasma membrane by the interaction of ATP with the regulatory Kir6.2 channel subunit The resultant depolarization of the β-cells opens voltage-dependent Ca2+-channels at the plasma membrane that allow an increase of the cytosolic cation concentration that triggers the exocytosis of insulin secretory granules. The resultant secretory response evolves in time as a biphasic secretion with a first and transient peak of approximately 10 minutes duration followed by a sustained phase of secretion lasting as long as the stimulus. Whereas the first transient peak can be reproduced by a simple depolarization of β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide, the sustained phase is agreed to depend on the participation of some metabolic signal that remains to be determined Our group has been investigating for several years the participation of β-cell GABA metabolism, together with that of glucose (the β-cell “specific” nutrient secretagogue) and some other “metabolic” secretagogues (branched-chain alpha-ketoacids and a mixture of L-Leucine + L-glutamine, at supraphysiological concentrations) in their mechanism of stimulation of insulin secretion. All three types of stimuli promote the flux in the GABA shunt of rat islets by different metabolic pathways that end in the production of α-ketoglutarate. This citric acid cycle intermediary is preferentially derived to the GABA shunt instead of its continuous oxidation in the citric acid cycle. Islet content of GABA is significantly suppressed by all the stimuli and blocking the GABA shunt with gabaculine, or ϒ-vinyl-GABA (GABAT inhibitors), diminish the insulin secretory responses as well as total ATP and the ATP/ADP ratio. It is concluded that GABA metabolism is increased in parallel to glucose metabolism and is significantly contributing to the magnitude of the insulin secretory response. Its possible implication in β-cells degradation in type-2 (perhaps also in type 1) diabetes is suggested.
Keywords
Functional role of GABA in insulin secretion stimulation; GABA metabolism in pancreatic islets; GABA and insulin secretion; interaction of glucose and GABA metabolism in pancreatic islets; GABA shunt
Subject
Biology and Life Sciences, Endocrinology and Metabolism
Copyright:
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