PHARMACOKINETICS OF AMINOGUANIDINE ADMINISTRATION AND EFFECTS ON THE DIABETES FREQUENCY IN NONOBESE DIABETIC MICE

In vitro studies suggest that intra-islet nitric oxide production may contribute to the pathogenesis of autoimmune insulin-dependent diabete s mellitus. We tested whether aminoguanidine (AG), a competitive inhib itor of inducible nitric oxide synthase, might black beta cell destruc tion and prevent insulin-dependent, diabetes mellitus in vivo. A total of 50 female nonobese diabetic mice, from the time of weaning until 3 2 wk of age, received injections (i.p.) twice daily with 50 mg AG/kg b ody weight and received AG in drinking water (350 mg/liter). A total o f 50 littermates treated with vehicle alone served as controls. A 24-h r pharmacokinetic analysis showed that AG was readily absorbed after i .p. administration, peaked in plasma (9.0 mu g/ml) at 0.5 hr and had a half-life of 1.88 hr. Steady-state values for the area under the curv e for the therapeutic regimen were 20.51 and 16.35 (mu g)(hr)/ml for t he 0000 to 1600 and 1600 to 2400 hr, respectively. In terms of therapy , life-table analysis indicated the frequency of insulin-dependent dia betes mellitus (6/30 AG-treated vs. 11/31 vehicle-treated, P = .25) an d insulitis scores (2.0 +/- 1.1 vs. 2.4 +/- 1.2 in nondiabetic AG- and vehicle-treated mice at 32 wk, respectively, P = .20) were similar in both groups. Flow cytometric analysis revealed no quantitative differ ences in islet infiltrating macrophages, CD4(+) or CD8(+) T lymphocyte s between groups of animals randomly killed at 8, 16 and 32 wk. Althou gh not eliminating a role for nitric oxide in the pathogenesis of insu lin-dependent diabetes mellitus, prophylactic treatment with AG did no t significantly impact the onset of insulitis or diabetes in nanobese diabetic mice.