The stimulus--secretion coupling 4-methyl-2-oxopentanoate-induced insulin release.

1. Pancreatic islet insulin secretion and 45Ca uptake showed similar responses to variation in the extracellular concentration of 4-methyl-2-oxopentanoate with a threshold at 4 mM and a maximal response at a 25 mM concentration. 2. Islet respiration, acetoacetate production and rates of substrate utilization, oxidation and amination all changed as a simple hyperbolic function of 4-methyl-2-oxopentanoate concentration and exhibited a maximal response at 25 mM. 3. The responses of ATP content, [ATP]/[ADP] ratio, adenylate energy charge and [NADH]/[NAD+] ratio were also hyperbolic in nature but were maximally elevated at lower concentrations of the secretagogue. The islet [NADPH]/[NADP+] ratio, however, was tightly correlated with parameters of metabolic flux, 45Ca uptake and insulin release. 4. NH4+ and menadione, agents that promote a more oxidized state in islet NADP, did not affect islet ATP content or the rates of [U-14C]4-methyl-2-oxopentanoate oxidation or amination, but markedly inhibited islet 45Ca uptake and insulin release. 5. It is proposed that changes in the redox state of NADP and Ca transport may serve as mediators in the stimulus-secretion coupling mechanism of insulin release induced by 4-methyl-2-oxopentanoate.