Abstract

We have investigated the short-term effects of the saturated free fatty acid (FFA) palmitate on pancreatic α-cells. Palmitate (0.5 or 1 mmol/l bound to fatty acid–free albumin) stimulated glucagon secretion from intact mouse islets 1.5- to 2-fold when added in the presence of 1–15 mmol/l glucose. Palmitate remained stimulatory in islets depolarized with 30 mmol/l extracellular K⁺ or exposed to forskolin, but it did not remain stimulatory after treatment with isradipine or triacsin C. The stimulatory action of palmitate on secretion correlated with a 3.5-fold elevation of intracellular free Ca²⁺ when applied in the presence of 15 mmol/l glucose, a 40% stimulation of exocytosis (measured as increases in cell capacitance), and a 25% increase in whole-cell Ca²⁺ current. The latter effect was abolished by isradipine, suggesting that palmitate selectively modulates l-type Ca²⁺ channels. The effect of palmitate on exocytosis was not mediated by palmitoyl-CoA, and intracellular application of this FFA metabolite decreased rather than enhanced Ca²⁺-induced exocytosis. The stimulatory effects of palmitate on glucagon secretion were paralleled by a ∼50% inhibition of somatostatin release. We conclude that palmitate increases α-cell exocytosis principally by enhanced Ca²⁺ entry via l-type Ca²⁺ channels and, possibly, relief from paracrine inhibition by somatostatin released by neighboring δ-cells.