Stimulation of islet protein kinase C translocation by palmitate requires metabolism of the fatty acid.

The secretory, metabolic, and signaling aspects of glucose/palmitate interaction on beta-cell function have been studied on rat islets. Palmitate potentiated the glucose-induced insulin response of perifused islets at suprathreshold (>3 mmol/l) sugar concentrations. This potentiating effect could be suppressed by 8-bromo-cGMP, which also blocks palmitate metabolism. Palmitate did not modify glucose utilization, but it slightly reduced glucose oxidation and concomitantly increased lactate production. The very low rate of palmitate oxidation (80-fold lower than that of 20 mmol/l glucose) might explain its lack of effect on glycolysis and hence that the glucose/fatty acid cycle is inoperative in islet cells. However, glucose determines the metabolic fate of exogenous palmitate, which is mainly diverted toward lipid synthesis at high sugar concentrations and might then generate lipid messengers for cell signaling. Palmitate did not increase glucose-induced production of inositol-1,4,5-trisphosphate, but it stimulated the translocation of protein kinase C activity from a cytosolic to a particulate fraction at 20 but not at 3 mmol/l glucose. This increased translocation was partially or completely blocked by hydroxycitrate or 8-bromo-cGMP, respectively, which are agents interfering with palmitate metabolism (inhibiting lipid synthesis). The metabolic interaction between glucose and palmitate might generate lipid messengers (diacylglycerol, phosphatidylserine) necessary for the activation of islet protein kinase C, which would in turn result in a potentiation of glucose-induced insulin secretion.

The stimulation of insulin secretion by D-glyceraldehyde correlates with its rate of oxidation in islet cells.

D-Glyceraldehyde's capacity to mimic the effect of D-glucose on insulin secretion has not yet been sufficiently substantiated. It has been recently proposed, however, that they might act through different mechanisms in insulin-secreting tumoral cells. Therefore, we have performed a dose-related study of both the secretory and metabolic effects of D-glyceraldehyde on islets, which have been compared with those produced by D-glucose. D-Glyceraldehyde's capacity to stimulate secretion was paralleled in a dose-dependent manner by its rate of oxidation to 14CO2. Partial inhibition of D-glyceraldehyde oxidation by beta-iodoacetamide resulted in a proportional decrease in the secretory response. L-Glyceraldehyde, which was apparently very poorly oxidized by islets, did not stimulate secretion. The ratio of the maximum insulin responses D-glyceraldehyde and D-glucose (57%) correlated with the ratio of their respective maximum rates of oxidation (68%). At sub-maximal concentrations there was a potentiation of the secretagogue effects of the hexose by the triose, which was not apparent at a maximum effective dose of glucose. It is concluded that D-glyceraldehyde mimics the secretory effect of glucose because, similarly to the hexose, it is metabolized through islet aerobic glycolysis. The lower potency of D-glyceraldehyde as an insulin secretagogue than D-glucose is determined by the lower capacity of islets to oxidize the triose compared with the hexose. D-Glyceraldehyde, unlike D-glucose, is metabolized in islets to D-lactate. Alternative routes for the metabolism of D-glyceraldehyde might explain some of the secretagogue differences between the triose and the hexose.