Arginine-induced insulin release is decreased and glucagon increased in parallel with islet NO production.

Nitric oxide (NO) produced by islet constitutive NO synthase (cNOS) is a putative modulator of islet hormone secretion. We show here for the first time that the release of insulin induced byl-arginine orl-homoarginine is inhibited and that of glucagon stimulated in parallel with the rate of islet NO production. It was found thatl-homoarginine was ≈25-30% less potent thanl-arginine as an insulin secretagogue but equally potent as a glucagon secretagogue. Biochemical determination of islet cNOS activity revealed that the NO production with l-homoarginine as substrate was only ≈40% of that ofl-arginine. Selective inhibition of islet cNOS potentiated insulin release during amino acid stimulation. Moreover, inhibition of cNOS suppressed glucagon release, more so with l-arginine than with l-homoarginine as secretagogue, reflecting the relative rates of their NO production. In K+-depolarized islets, inhibition of cNOS enhanced the insulin response tol-arginine by 50% and that tol-homoarginine by 23%, largely corresponding to their relative NO production. The intracellular NO donor hydroxylamine dose dependently inhibited insulin but increased glucagon secretion in K+-depolarized and amino acid-stimulated islets. We conclude that both amino acids have a dual action on insulin release, since their stimulatory effects are reduced in parallel with the rates of their NO production. Furthermore, the greater NO production induced byl-arginine relative tol-homoarginine corresponds to NO-mediated increases in glucagon release. These NO effects are mainly exerted independently of membrane depolarization events.