The Stimulus-secretion Coupling of Amino Acid-induced Insulin Release: Metabolism and Cationic Effects of Leucine

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH₄ production is close to the summed rates of L-[1-¹⁴ C] leucine decarboxylation and α-ketoisocaproate production, whereas the rates of acetoacetate production and L-[U-¹⁴ C]-leucine oxidation are compatible with the conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO₂. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD⁺ ratio (but not the NADPH/NADP⁺ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on ⁸⁶Rb⁺ and ⁴⁵Ca²⁺ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.