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Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane

¹Department of Clinical Sciences, Clinical Research Centre, Lund University, SE20502 Malmö, Sweden
²The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LJ, England
³Oxford Centre for Gene Function, University of Oxford, Parks Rd, Oxford OX1 3PT, England
⁴Department of Experimental Medical Research, BMC C11, SE22184 Lund, Sweden

Correspondence: patrik.rorsman{at}drl.ox.ac.uk

Mouse ß-cells cultured at 15mM glucose for 72h had reduced K_ATP-channel activity (-30%), increased voltage-gated Ca²⁺-currents, higher [Ca²⁺]_i (+160%), more exocytosis (monitored by capacitance measurements; +100%), and greater insulin content (+230%) than those cultured at 4.5 mM glucose. However, they released 20% less insulin when challenged with 20mM glucose. Glucose-induced (20mM) insulin secretion was reduced by 60-90% in islets co-cultured at 4.5 or 15mM glucose and either oleate or palmitate (0.5mM). 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 2-fold but reduced K⁺-induced secretion by up to 60%. Basal (1mM glucose) K_ATP-channel activity was 40% lower in islets cultured at 4.5mM glucose plus palmitate and 60% lower in islets cultured at 15mM glucose plus either FFA. Insulin content decreased 75% in islets exposed to the FFAs in the presence of a high (15mM), but not low (4.5mM), glucose concentrations but the number of secretory granules was unchanged. FFA-induced inhibition of insulin secreted was not associated with increased transcript levels of apoptosis markers Bax 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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