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

Charlotta S. Olofsson, Stephan Collins, Martin Bengtsson, Lena Eliasson, Albert Salehi, Kenju Shimomura, Andrei Tarasov, Cecilia Holm, Frances Ashcroft, Patrik Rorsman

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Abstract

Mouse β-cells cultured at 15 mmol/l glucose for 72 h had reduced ATP-sensitive K+ (KATP) channel activity (-30%), increased voltage-gated Ca2+ currents, higher intracellular free Ca 2+ 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.

Original languageEnglish
Pages (from-to)1888-1897
Number of pages10
JournalDiabetes
Volume56
Issue number7
DOIs
Publication statusPublished - 1 Jul 2007

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    Olofsson, C. S., Collins, S., Bengtsson, M., Eliasson, L., Salehi, A., Shimomura, K., Tarasov, A., Holm, C., Ashcroft, F., & Rorsman, P. (2007). Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. Diabetes, 56(7), 1888-1897. https://doi.org/10.2337/db06-1150