Under Ca2+-free conditions, activation of the pancreatic beta-cell with forskolin and 12-O-tetradecanoylphorbol 13-acetate (TPA) is permissive for the augmentation of insulin release by glucose and other nutrients. The ability of fatty acids to mimic the effect of glucose and thereby augment insulin secretion in the absence of extracellular Ca2+ is the focus of the present study. In the absence of extracellular Ca2+, glucose, palmitate, and myristate had no effect on insulin release. When, under Ca2+-free conditions, the islets were treated with forskolin to raise cyclic AMP levels and activate protein kinase A and with TPA to activate protein kinase C, glucose, palmitate, and myristate all augmented release to approximately the same extent. No other saturated fatty acid with chain lengths in the C = 6-22 range augmented the release of insulin. This selective augmentation by palmitate or myristate was not seen with forskolin alone, and was seen slightly with TPA and strongly with the combination of forskolin and TPA. The response, which developed slowly and had a time course similar to that of second-phase insulin release, was abolished by the physiological inhibitor norepinephrine. The results suggest that the mechanism underlying the Ca2+-independent augmentation of insulin release by glucose and other nutrients involves the proposed malonyl-CoA/long-chain acyl-CoA pathway with specificity for myristoyl- and palmitoyl-CoA esters and/or their derivatives.

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