Palmitate increases L‐type Ca 2+ currents and the size of the readily releasable granule pool in mouse pancreatic β‐cells

We have investigated the in vitro effects of the saturated free fatty acid palmitate on mouse pancreatic β‐cells by a combination of electrophysiological recordings, intracellular Ca 2+ ([Ca 2+ ] i ) microfluorimetry and insulin release measurements. Addition of palmitate (1 m m , bound to fatty acid‐free albumin) to intact islets exposed to 15 m m glucose increased the [Ca 2+ ] i by ∼30% and insulin secretion 2‐fold. Palmitate remained capable of increasing [Ca 2+ ] 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 (K ATP channels). Palmitate (0.5 m m ) augmented exocytosis (measured as an increase in cell capacitance) in single β‐cells and increased the size of the readily releasable pool (RRP) of granules 2‐fold. Whole‐cell peak Ca 2+ currents rose by ∼25% following addition of 0.5 m m palmitate, an effect that was abolished in the presence of 10 μ m isradipine indicating that the free fatty acid specifically acts on L‐type Ca 2+ channels. The actions of palmitate on exocytosis and Ca 2+ currents were not mimicked by intracellular application of palmitoyl‐CoA. We conclude that palmitate increases insulin secretion by a K ATP channel‐independent mechanism exerted at the level of exocytosis and that involves both augmentation of L‐type Ca 2+ currents and an increased size of the RRP.