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Two Signaling Pathways, from the Upper Glycolytic Flux and from the Mitochondria, Converge to Potentiate Insulin Release¹

Department of Geriatrics, Endocrinology and Metabolism (N.A., T.A., Y.S., K.H.), Shinshu University School of Medicine, Matsumoto, Nagano-ken, Japan, and Department of Pharmacology (T.S., M.K., G.W.G.S.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401

Address all correspondence and requests for reprints to: Toru Aizawa, M.D., Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, 3–1-1 Asahi, Matsumoto, Nagano-ken, Japan 390.

In the rat pancreatic ß cell, low concentrations of glucose potentiate D-glyceraldehyde (GA)-induced insulin release without any potentiation of the triose-induced elevation of cytosolic free Ca²⁺ concentration. Namely, 2–3 mM glucose strongly potentiates 5 mM GA-induced insulin release, and the combination of stimulatory concentration of glucose (10 mM) and 5 mM GA elicits far more than additive insulin release: this glucose action is independent of ATP-sensitive K⁺ channel closure because it can be seen in the presence of diazoxide, an opener of the K⁺ channel. The triose-induced elevation of cytosolic free Ca²⁺ concentration was not potentiated by the presence of 3 mM glucose, and oxidation of labeled GA by the islet cells was not enhanced by the presence of glucose. The glucose action can be mimicked by mannose, but not by galactose, and was suppressed by inhibition of glucose phosphorylation with mannoheptulose or 2-deoxyglucose. Glucose also potentiates 2-ketoisocaproate-induced insulin release. In contrast, a combination of GA and 2-ketoisocaproate elicits only additive insulin release. Strikingly, 3 mM glucose does not potentiate insulin release in response to a depolarizing concentration of K⁺. Therefore, at least two signal pathways, one from upper glycolytic flux and one from mitochondrial metabolism, must converge to provide the potentiation of insulin release. We conclude that the upper glycolytic flux, acting at a site unrelated to the elevation of cytosolic free Ca²⁺, potentiates insulin release triggered by triose and mitochondrial fuels.

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