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Inhibition of Purinoceptors Amplifies Glucose-Stimulated Insulin Release With Removal of its Pulsatility

¹ Institute of Physiological Sciences, University of Lund, Lund, Sweden
² Department of Surgery, University of Lund, Lund, Sweden
³ Department of Medical Cell Biology, University of Uppsala, Uppsala, Sweden

External ATP has been proposed to be an autocrine regulator of glucose-stimulated insulin secretion and responsible for the synchronization of the Ca²⁺ rhythmicity in the ß-cells required for a pulsatile release of insulin from the pancreas. The importance of external ATP for glucose-stimulated insulin release was evaluated in rats with the aid of 2-deoxy-N-methyladenosine-3,5-bisphosphate (MRS 2179), an inhibitor of the purinoceptors known to affect the Ca²⁺ signaling in ß-cells. The concentration of cytoplasmic Ca²⁺ was measured in single ß-cells and small aggregates with ratiometric fura-2 technique and the release of insulin recorded from isolated islets and the perfused pancreas. Addition of 1 µmol/l ATP induced premature cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) oscillations similar to those found in ß-cells exposed to 20 mmol/l glucose. In most experiments, the presence of 10 µmol/l MRS 2179 did not remove the glucose-induced [Ca²⁺]_i rhythmicity in single ß-cells or the synchronization seen in coupled cells. Nevertheless, the same concentration of MRS 2179 promptly interrupted the pulsatility (frequency 0.22 ± 0.01/min) of insulin secretion, raising the total amounts released from the pancreas. Prolonged exposure of islets to 1 and 10 µmol/l MRS 2179 enhanced insulin secretion at 20 mmol/l glucose 33% (P < 0.05) and 63% (P < 0.01), respectively, without affecting the release at 3 mmol/l glucose. The results support the idea that neural ATP signals entrain the islets into a common rhythm resulting in pulsatile release of insulin and that glucose stimulation of the secretory activity is counteracted by accumulation of inhibitory ATP around the ß-cells.

Abbreviations: [Ca²⁺]_i, cytoplasmic Ca²⁺ concentration; MRS 2179, 2-deoxy-N-methyladenosine-3,5-bisphosphate; PLA_2, phospholipase A₂

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