Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin secreting cells (HIT T-15 and NMRI beta-cells)

Non insulin-dependent diabetes mellitus is associated with, in addition to impaired insulin release, elevated levels of free fatty acids (FFA) in the blood. Insulin release is stimulated when beta-cells are acutely exposed to FFA whereas chronic exposure may inhibit glucose-induced insulin secretion . In the present study we investigated the direct effects of long chain acy l-CoA (LCCoA), the active intracellular form of FFA, on insulin exocytosis, Palmitoyl-CoA stimulated both insulin release from streptolysin-O-permeabi lized HIT cells and fusion of secretory granules to the plasma membrane of mouse pancreatic beta-cells, as measured by cell capacitance, The LC-CoA ef fect was chain length-dependent, requiring chain lengths of at least 14 car bons. LC-CoA needed to be present to stimulate insulin release, and consequ ently there was no effect following its removal. The stimulatory effect was observed after inhibition of protein kinase activity and in the absence of ATP, even though both kinases and ATP, themselves, modulate exocytosis. Th e effect of LC-CoA was inhibited by cerulenin, which has been shown to bloc k protein acylation. The data suggest that altered LC-CoA levels, resulting from FFA or glucose metabolism, may act directly on the exocytotic machine ry to stimulate insulin release by a mechanism involving LC-CoA protein bin ding.