title: Inhibition of nitric oxide generation: normalization of in vitro insulin secretion in mice with multiple low-dose streptozotocin and in mice injected with mononuclear splenocytes from diabetic syngeneic donors.
abstract: We studied the effect on in vitro glucose-induced insulin secretion of in vivo administration of L-Ng-monomethyl-arginine (L-NMMA), a competitive inhibitor of nitric oxide (NO) synthase, to mice injected with multiple low-dose streptozotocin (mld-SZ). In addition, the effect of L-NMMA treatment on the capacity of mononuclear spleen cells (MS) from mld-SZ mice to transfer alterations in insulin secretion from normal syngeneic receptors was also investigated. We also studied the effect of in vivo treatment with L-NMMA on anti-beta-cell cellular immune aggression (CIA) by coculturing MS from mld-SZ mice with rat dispersed islet cells. Our results show that mld-SZ mice treated with 0.25 mg L-NMMA/g body weight had normoglycemia, first and second-phase glucose-stimulated insulin secretion similar to those obtained in nondiabetic mice-effects not observed with a lower dose of L-NMMA (0.17 mg/g body weight)-and a diminished anti-beta-cell CIA. We also demonstrate that mice injected with MS from syngeneic donors treated with mld-SZ plus 0.25 mg L-NMMA/g had normal levels for first-phase glucose-stimulated insulin secretion and an absence of CIA. Taken together, these findings seem to indicate that prevention of in vivo NO production may block the onset of diabetes in mld-SZ mice, and that L-NMMA administration to diabetic donor mice prevents inhibition of first-phase insulin secretion and CIA in the transferred recipient mice. Although a nonimmunological mechanism or mechanisms of diabetes prevention by L-NMMA cannot be excluded, these results suggest that L-NMMA treatment could also be acting on T-cell-dependent immune reactions.
authors.affiliation: Laboratorio de Diabetes Experimental, Centro de Investigaciones Endocrinológicas, Hospital de Ninos Dr. R. Gutierrez, Buenos Aires, Argentina.
authors.forename: L M
authors.initials: LM
authors.lastname: Karabatas
authors.forename: L
authors.initials: L
authors.lastname: Fabiano de Bruno
authors.forename: C F
authors.initials: CF
authors.lastname: Pastorale
authors.forename: C
authors.initials: C
authors.lastname: Cullen
authors.forename: J C
authors.initials: JC
authors.lastname: Basabe
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D017690:Cell Transplantation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007111:Immunity, Cellular; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013154:Spleen / Q000473:pathology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase