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Departments of 1 Physiological Sciences2 Cell and Molecular Biology, Lund University, Lund, Sweden3 The Oxford Centre for Diabetes, Endocrinology and Metabolism, The Churchill Hospital, Oxford OX3 7LJ, UK
We have investigated the in vitro effects of the saturated free fatty acid palmitate on mouse pancreatic ß-cells by a combination of electrophysiological recordings, intracellular Ca2+ ([Ca2+]i) microfluorimetry and insulin release measurements. Addition of palmitate (1 mM, bound to fatty acid-free albumin) to intact islets exposed to 15 mM glucose increased the [Ca2+]i by 
30% and insulin secretion 2-fold. Palmitate remained capable of increasing [Ca2+]i and insulin release in the presence of tolbutamide and in islets depolarized by high K+ in combination with diazoxide, indicating that the stimulation occurs independently of closure of ATP-regulated K+ channels (KATP channels). Palmitate (0.5 mM) augmented exocytosis (measured as an increase in cell capacitance) in single ß-cells and increased the size of the readily releasable pool (RRP) of granules 2-fold. Whole-cell peak Ca2+ currents rose by 25% following addition of 0.5 mM palmitate, an effect that was abolished in the presence of 10 µM isradipine indicating that the free fatty acid specifically acts on L-type Ca2+ channels. The actions of palmitate on exocytosis and Ca2+ currents were not mimicked by intracellular application of palmitoyl-CoA. We conclude that palmitate increases insulin secretion by a KATP channel-independent mechanism exerted at the level of exocytosis and that involves both augmentation of L-type Ca2+ currents and an increased size of the RRP.
(Received 8 April 2004;
accepted after revision 16 April 2004;
first published online 16 April 2004)
Corresponding author C. S. Olofsson: Department of Physiological Sciences, BMC B11, SEM-221 84 Lund, Sweden. Email: charlotta.olofsson{at}mphy.lu.se
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