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P2Y Purinergic Potentiation of Glucose-Induced Insulin Secretion and Pancreatic Beta-Cell Metabolism

¹ Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France
² Innodia, Montpellier, France

Purine nucleotides and their analogs increase insulin secretion through activation of pancreatic ß-cell P2Y receptors. The present study aimed at determining the role of glucose metabolism in the response to P2Y agonists and whether ATP-activated K⁺ channels (K_ATP channels) are involved in this response. The experiments were performed in the rat isolated pancreas, perfused with a Krebs-bicarbonate buffer supplemented with 2 g/l bovine serum albumin under dynamic glucose conditions from 5 mmol/l baseline to 11 mmol/l. ADPßS (0.5 µmol/l) was selected as a stable and selective P2Y agonist. This compound, ineffective on the 5 mmol/l glucose background, induced a significant threefold increase in insulin release triggered by the glucose challenge. The effect of ADPßS was markedly reduced (P < 0.001) in the presence of an inhibitor of glucose metabolism. In addition to glucose, the ADP analog also amplified the ß-cell insulin response to 15 mmol/l methyl pyruvate (P < 0.05), but it was ineffective on the insulin response to 2.5 mmol/l methyl succinate. A nonmetabolic stimulus was applied using tolbutamide (185 µmol/l). Insulin secretion induced by the K_ATP channel blocker was strongly reinforced by ADPßS (P < 0.001), which prompted us to check a possible interplay of K_ATP channels in the effect of ADPßS. In the presence of diazoxide 250 µmol/l and 21 mmol/l KCl, ADPßS still amplified the second phase of glucose-induced insulin secretion (P < 0.001). We conclude that P2Y receptor activation is able to promote insulin secretion through a mechanism, involving ß-cell metabolism and a rise in intracellular calcium; this effect does not result from a direct inhibitory effect on K_ATP channels.

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