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Long-Term Exposure to Glucose and Lipids Inhibits Glucose-Induced Insulin Secretion Downstream of Granule Fusion With Plasma Membrane

¹ Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, Sweden
² Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, England
³ Oxford Centre for Gene Function, University of Oxford, Parks Rd, Oxford, England
⁴ Department of Experimental Medical Research, Lund, Sweden

Address correspondence and reprint requests to Patrik Rorsman, OCDEM, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, U.K. E-mail: patrik.rorsman{at}drl.ox.ac.uk

Abbreviations: [Ca²⁺]_i, intracellular free Ca²⁺ concentration; Cpt, carnitin palmitoyl transferase; FFA, free fatty acid; K_ATP channel, ATP-sensitive K⁺ channel; UCP, uncoupling protein

Mouse ß-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K⁺ (K_ATP) channel activity (–30%), increased voltage-gated Ca²⁺ currents, higher intracellular free Ca²⁺ concentration ([Ca²⁺]_i; +160%), more exocytosis (monitored by capacitance measurements, +100%), and greater insulin content (+230%) than those cultured at 4.5 mmol/l glucose. However, they released 20% less insulin when challenged with 20 mmol/l glucose. Glucose-induced (20 mmol/l) insulin secretion was reduced by 60–90% in islets cocultured at 4.5 or 15 mmol/l glucose and either oleate or palmitate (0.5 mmol/l). Free fatty acid (FFA)-induced inhibition of secretion was not associated with any major changes in [Ca²⁺]_i or islet ATP content. Palmitate stimulated exocytosis by twofold or more but reduced K⁺-induced secretion by up to 60%. Basal (1 mmol/l glucose) K_ATP channel activity was 40% lower in islets cultured at 4.5 mmol/l glucose plus palmitate and 60% lower in islets cultured at 15 mmol/l glucose plus either of the FFAs. Insulin content decreased by 75% in islets exposed to FFAs in the presence of high (15 mmol/l), but not low (4.5 mmol/l), glucose concentrations, but the number of secretory granules was unchanged. FFA-induced inhibition of insulin secretion was not associated with increased transcript levels of the apoptosis markers Bax (BclII-associated X protein) and caspase-3. We conclude that glucose and FFAs reduce insulin secretion by interference with the exit of insulin via the fusion pore.

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