Differential regulation of [Ca2+]i oscillations in mouse pancreatic islets by glucose, α-ketoisocaproic acid, glyceraldehyde and glycolytic intermediates

Glucose induces slow oscillations of the cytoplasmic Ca2+ concentration in pancreatic beta-cells. In order to elucidate the mechanisms responsible for the slow [Ca2+](i) oscillations the effects of various nutrient insulin secretagogues on glucose-induced [Ca2+](i) oscillations in intact mouse pancreatic islets and single beta-cells were studied. These were the glycolytic intermediates, gryceraldehyde and pyruvate, and the mitochondrial substrate, alpha-ketoisocaproic acid (KIC). Glucose, at a 10 or 15 mM concentration, induced the typical slow oscillations of [Ca2+](i) (0.4 min(-1)). At higher glucose concentrations the frequency of these oscillations decreased further (0.2 min(-1)). Glyceraldehyde, an insulin secretagogue like glucose, did not cause slow oscillations of [Ca2+](i) in the absence of glucose. However, it exhibited a synergistic action with glucose. Glyceraldehyde, at 3 or 10 mM concentration, induced slow [Ca2+](i) oscillations at a substimulatory concentration of 5 mM glucose (0.3-0.4 min(-1)) and reduced the frequency of the glucose-induced [Ca2+](i) oscillations at stimulatory concentrations of 10 or 15 mM glucose (0.2 min(-1)). KIC (5 or 10 mM) as well as pyruvate (10 mM), the end product of glycolysis, and its ester methyl pyruvate (10 mM), did not cause slow oscillations of [Ca2+](i) in the absence of glucose. In contrast to glyceraldehyde, however, all three compounds were capable of preventing the slow [Ca2+](i) oscillations induced by glucose. Mannoheptulose (2 mM), an inhibitor of glucokinase and glucose-induced insulin secretion, reversibly blocked any kind of [Ca2+]i oscillation and returned the [Ca2+]i to a basal level through its ability to inhibit glycolytic flux. It can be concluded therefore that only substrates which generate a glucokinase-mediated metabolic flux through glycolysis and produce glycolytic ATP can induce slow [Ca2+](i) oscillations in pancreatic beta-cells. (C) 2000 Elsevier Science B.V. All rights reserved.