Augmentation of Ca2+-stimulated insulin release by glucose and long-chain fatty acids in rat pancreatic islets - Free fatty acids mimic ATP-sensitiveK+ channel-independent insulinotropic action of glucose

Glucose augments Ca2+-stimulated insulin release from the pancreatic beta-c ell in an ATP-sensitive KC channel (K-ATP channel)-independent manner. In s tudying the mechanisms underlying this action, we used rat pancreatic islet s and examined the effects of exogenous free fatty acids (FFAs), which are precursors of long-chain acyl-CoA (LC-CoA), on KCl-induced Ca2+-stimulated insulin release. Myristate, palmitate, and stearate augmented insulin relea se induced by 50 mmol/l KCl in the presence of 2.8 mmol/l glucose. Added ac utely, their potency was weak compared with that of glucose-induced augment ation. The FFA-induced augmentation became much greater, however, when isle ts were preincubated with FFAs under stringent Ca2+-free conditions (with 1 mmol/l EGTA) before the KCl stimulation. Under these conditions, 16.7 mmol /l glucose augmented 13-fold insulin release induced by 50 mmol/l KCl, wher eas palmitate or myristate (both at a free concentration of 10 mu mol/l) pr oduced 5.8- and 5.2-fold augmentations. Effects of FFAs and glucose were co ncentration-dependent. The temporal profiles of augmentation induced by 11. 1 mmol/l glucose and 10 mu mol/l palmitate were similar. Glucose and palmit ate caused almost identical augmentation patterns for the initial 10 min of stimulation; subsequently, glucose augmentation was better sustained than palmitate augmentation. This suggests the existence of a longer-term glucos e-specific signaling moiety that cannot be mimicked by FFAs. Our results pr ovide direct evidence that FFAs can mimic the K-ATP, channel-independent ac tion of glucose. Taking these results together with previous results, we co nclude that glucose augments Ca2+-stimulated insulin release, at least in p art, by increasing malonyl-CoA and cytosolic LC-CoA. However, one or more o ther glucose-specific signaling molecules are required for the full express ion of augmentation.