Fuel and signal function of 2-keto acids in insulin secretion

The stimulation of insulin release from pancreatic islet tissue by 2-ketoisocaproate was accompanied by a characteristic electrophysiological response and by increases in islet net uptake of 45Ca and respiratory activity. These parameters were closely correlated to changes in islet keto acid content, islet NADPH/NADP+ ratio and to the rates of 2-ketoisocaproate catabolism and amination. The production of 14CO2 from [U-14C]2-ketoisocaproate was reduced by the addition of valine, isovalerate, glutamine or pyruvate to the incubation media. Such an effect, however, did not correspond to the response of insulin secretion of 45Ca uptake observed in the presence of these substrates. These findings suggest that the metabolic sequence between the initial conversion of 2-ketoisocaproate to isovaleryl CoA and its subsequent transformation to acetoacetate and acetyl CoA was not the site of generation of a signal which initiated insulin release. The total rate of oxidation deduced from the sum of the rates of 14CO2 production from [U-14C]2-ketoisocaproate and the [U-14C]-labelled second substrate, however, did follow the secretory response of the tissue. It is proposed that reactions associated with the tricarboxylic acid cycle are important to the stimulus-secretion coupling mechanism of 2-ketoisocaproate-induced insulin release. The question of whether such reactions participate in the generation of a signal which initiates insulin secretion or merely reflect the energetic demands of the secretory process is discussed.