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In the present study, a novel pathway by which palmitate potentiates glucose-induced insulin secretion by pancreatic beta cells was investigated.Groups of freshly isolated islets were incubated in 10 mM glucose with palmitate, LY294002, wortmannin, and fumonisin B1 for measurement of insulin secretion by radioimmunoassay (RIA). Also, phosphorylation and content of AKT and PKC proteins were evaluated by immunoblotting.Glucose plus palmitate and glucose plus LY294002 or wortmannin (PI3K inhibitors) increased glucose-induced insulin secretion by isolated pancreatic islets. Glucose at 10 mM induced AKT and PKCζ/λ phosphorylation. Palmitate (0.1 mM) abolished glucose stimulation of AKT and PKCζ/λ phosphorylation possibly through PI3K inhibition because both LY294002 (50 μM) and wortmannin (100 nM) caused the same effect. The inhibitory effect of palmitate on glucose-induced AKT and PKCζ/λ phosphorylation and the stimulatory effect of palmitate on glucose-induced insulin secretion were not observed in the presence of fumonisin B1, an inhibitor of ceramide synthesis.These findings support the proposition that palmitate increases insulin release in the presence of 10 mM glucose by inhibiting PI3K activity through a mechanism that involves ceramide synthesis.