Glutamate is not a Major Conveyer of ATP-sensitive K⁺ Channel-Independent Glucose Action in Pancreatic Islet β Cell

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Insulinotropic action of glucose can be categorized as 1) triggering of release, 2) augmentation of exocytosis elicited by Ca²⁺, and 3) time-dependent potentiation (TDP) of the exocytotic machinery. Glucose-induced closure of ATP-sensitive K⁺ (K⁺_ATP) channel is required for the first but not for the latter two. We examined the egitimacy of a novel hypothesis that glutamate is a conveyer of the K⁺_ATP channel-independent glucose action, using intact rat pancreatic islets. To this end, we compared glucose and cell permeable glutamate donors such as dimethylglutamate and glutamine for their potency of augmentation and TDP in the presence of diazoxide (250μmol/l), a K⁺_ATP channel opener. One millimolar leucine was employed as an activator of glutamate dehydrogenase (GDH) as needed. A high concentration (16.7mmol/l) of glucose applied simultaneously with a depolarizing concentration (50mmol/l) of K⁺ augmented (5.80 fold) insulin release elicited by the latter. Pretreatment of the islets with 16.7mmol/l glucose caused TDP so that insulin release subsequently elicited by 50mmol/l K⁺ alone was enhanced (4.70 fold). The augmentation and TDP caused by dimethylglutamate and glutamine (10mmol/l each), respectively, were very weak (12% of the glucose effect utmost), and dramatically enhanced upon activation of GDH by leucine. Insulinotropic effect of the glutamate donors, but not that of 50mmol/l K⁺, was eliminated by 2mmol/l NaN₃, a mitochondrial poison. Glutamate per se serves as a weakly metabolizable mitochondrial fuel, but not a direct conveyer of the K⁺_ATP channel-independent glucose action in the islet β cell.