Differential insulin secretory responses to cationic and branched-chain amino acids

The long-term effects on the dynamics of glucose-stimulated insulin release by the cationic amino acids arginine and lysine and the branched-chain amino acid leucine were examined. The rat pancreas perfusion model was utilized and particular emphasis was placed on modulation of the glucose-stimulated synthesis-secretion coupling second phase. In the presence of 16.7 mM glucose, 20 mM arginine, lysine, and leucine each potentiated first-phase insulin release by approximately 50%, compared to glucose-only controls. Conversely, in the presence of 16.7 mM glucose, 20 mM arginine resulted in a 50% inhibition of second-phase (min 30-120) insulin release compared to glucose-only controls. Similarly, 20 mM lysine in the presence of 16.7 mM glucose also caused a comparable inhibition of second-phase insulin release. Paradoxically, 20 mM leucine in the presence of glucose had no significant inhibitory effect on second-phase glucose-stimulated insulin release. The data suggest that these amino acids mediate their effects on first- and second-phase insulin release via different mechanisms of action, which may reflect differences and similarities in charge and/or metabolic fates within the beta cell. The data do not support the hypothesis that cationic charge is solely involved in the stimulus-secretion component, since all three amino acids caused comparable potentiation of first-phase insulin release. Conversely, the inhibitory component of the second secretory phase may be mediated via a common charge-related metabolic pathway in the synthesis-secretion coupling mechanism, since only the cationic amino acids inhibit this component, whereas leucine has no such effect.