Palmitate and myristate selectively mimic the effect of glucose in augmenting insulin release in the absence of extracellular Ca2+.

Abstract

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.

Cerulenin, an inhibitor of protein acylation, selectively attenuates nutrient stimulation of insulin release: a study in rat pancreatic islets.

“…The same final concentrations of DMSO were present in paired control tubes. At the end of test incubations, the medium was aspirated and kept at -20°C until radioimmunoassayed for insulin, where rat insulin was used as the standard (3,5,15,16). Glucose oxidation.…”

“…Recent direct supportive evidence includes the effect of fatty acids to augment insulin secretion (13,14). Furthermore, it has been suggested that malonylCoA and LC-CoA could be responsible for the K ATP channel-independent pathways of glucose signaling (15,16). Following up on this hypothesis, we examined the effects of cerulenin, a fungal antibiotic that inhibits protein acylation H. YAJIMA AND ASSOCIATES (17,18), on insulin release.…”

Effect of protein kinase C and insulin on Na+/H+ exchange in red blood cells of essential hypertensives

“…In fact, phorbol ester dependent PKC stimulation inhibits intracellular insulin signalling in vitro 29 and in pancreatic islet cell PMA stimulates insulin release and hyperinsulinaemia. 30 In summary, the present study shows that part of the abnormal kinetics of H ϩ i activation of RBC NHE in hypertensives are secondary to altered PKC regulation. In normotensives, the sigmoidal activation of Na ϩ influx through the NHE indicates that the transporter can be rapidly activated by changes of cell pH: on one hand, a fall of cell pH briskly stimulates Na ϩ influx and H ϩ efflux through the transporter; on the other hand an increase of cell pH inhibits the transporter and prevents further alkalinization.…”

Enhancement of the incretin pathway in response to bariatric surgery is important for restoration of beta cell function

“…This is an ATPsensitive K + channel-independent insulinotropic action [8]. Interestingly, NEFA also augments GSIS via a mechanism that does not involve this channel [5].…”

“…This study is of great interest to us because we consider the malonyl-CoA pathway and the resultant NEFA augmentation of insulin exocytosis to be vital for glucose-stimulated insulin secretion (GSIS), especially for the replenishment of the readily releasable pool of insulin granules during secondphase secretion [2,3]. Prior to the visual demonstration and molecular elucidation of intracellular granule trafficking, this process was known conceptually as 'potentiation' [4], 'augmentation' [5] or 'amplification' [6].…”