Suppressive effects of a selective inducible nitric oxide synthase (iNOS) inhibitor on pancreatic beta-cell dysfunction
Tóm tắt
Type 1 diabetes mellitus is an autoimmune disease characterized by dysfunction and destruction of the pancreatic beta cells. Interleukin-1β (IL-1β) has been reported to cause suppression of insulin secretion from pancreatic islets via induction of inducible nitric oxide synthase (iNOS) followed by nitric oxide (NO) production. In this study, we investigated the effects of inhibition of iNOS on pancreatic beta-cell dysfunction in non-obese diabetic (NOD) mice and IL-1β-treated isolated rat pancreatic islets using a novel specific inhibitor, ONO-1714. Female NOD mice which received subcutaneous infusion of ONO-1714 (4 µg/kg/day or 40 µg/kg/day) from 10 to 14 weeks after birth were compared with untreated NOD mice. In addition, pancreatic islets were isolated from Sprague-Dawley rats and cultured for 24 h with IL-1β (100 U/mL) with or without ONO-1714 or the non-selective NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). We measured insulin secretion and insulin content of the islets by ELISA, iNOS mRNA expression by reverse transcription-polymerase chain reaction, and NO generation by Griess Reagent System. Hyperglycaemia was observed in NOD mice. ONO-1714 treatment blunted this increase and tended to preserve insulin secretion, although body weight increase did not differ between the groups. Insulitis was also attenuated in the ONO-1714-administered group compared to the control group. Furthermore, in isolated rat pancreatic islets ONO-1714 prevented IL-1β-induced inhibition of insulin secretion, this protection being evident in much lower concentrations than with L-NMMA. While ONO-1714 completely inhibited IL-1β-induced NO production, it did not reduce expression of islet iNOS mRNA. These findings indicate that ONO-1714 is promising as a therapeutic agent for autoimmune diabetes.
Tài liệu tham khảo
Castano L, Eisenbarth GS (1990) Type-1 diabetes: a chronic autoimmune disease of human, mouse, and rat. Ann Rev Immunol 8:1053–1058
Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39:1005–1029
Rabinovitch A (1993) Roles of cytokines in IDDM pathogenesis and islet β-cell destruction. Diabetes Rev 1:215–240
Comens PG, Wolf BA, Unanue ER et al. (1987) Interleukin 1 is potent modulator of insulin secretion from isolated rat islets of Langerhans. Diabetes 36:963–970
Mandrup-Poulsen T, Bendtzen K, Nerup J et al. (1986) Mechanisms of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans. Allergy 41:250–259
Palmer J, Helqvist S, Spinas G et al. (1989) Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans. Diabetes 38:1211–1216
Corbett JA, McDaniel ML (1992) Does nitric oxide mediate autoimmune destruction of β-cells? Possible therapeutic interventions in IDDM. Diabetes 41:897–903
Kolb H, Kolb-Bachofen V (1992) Type 1 (insulin-dependent) diabetes mellitus and nitric oxide. Diabetologia 35:796–797
Eizirik DL, Pavlovic D (1997) Is there a role for nitric oxide in β-cell dysfunction and damage in IDDM? Diabetes Metab Rev 13:293–308
Eizirik DL, Flodstrom M, Karlsen AE et al. (1996) The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells. Diabetologia 39:875–890
Delaney CA, Pavlovic D, Hoorens A et al. (1997) Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology 138:2610–2614
Eizirik DL, Cagliero E, Bjorklund A et al. (1992) Interleukin-1β induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which in similar to that observed in activated macrophages. FEBS Lett 308:249–252
Karlsen AE, Anderson HU, Vissing H et al. (1995) Cloning and expression of cytokine-inducible nitric oxide synthase cDNA from rat islets of Langerhans. Diabetes 44:753–758
Corbett JA, Wang JL, Sweetland MA et al. (1992) Interleukin-1beta induces the formation of nitric oxide by beta cells purified from rodent islets of Langerhans. Evidence for the beta-cells as a source and site of action of nitric oxide. J Clin Invest 90:2384–2391
Kroncke KD, Kolb-Bachofen V, Berschick B et al. (1991) Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. Biochem Biophys Res Commun 175:752–758
Welsh N, Eizirik DL, Bendtzen K et al. (1991) Interleukin-1β-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 129:3167–3173
Corbett JA, Lancaster JR, Sweetland MA et al. (1991) Interleukin-1β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. J Biol Chem 266:21351–21354
Southern C, Schulster D, Green IC (1990) Inhibition of insulin secretion by interleukin-1β and tumor necrosis factor-α via an L-arginine-dependent nitric oxide generating mechanism. FEBS 276:42–44
Rabinovitch A, Suarez-Pinzon WL (1998) Cytokines and their roles in pancreatic islet β-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 55:1139–1149
Corbett JA, McDaniel ML (1994) Reversibility of interleukin-1β-induced islet destruction and dysfunction by the inhibition of nitric oxide synthase. Biochem J 299:719–724
Naka M, Nanbu T, Kobayashi K et al. (2000) A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative. Biochem Biophys Res Commun 270:663–667
Wu G (1995) Nitric oxide synthase and the effect of aminoguanidine and NG-monomethyl-L-arginine on the onset of diabetes in the spontaneously diabetic BB-rat. Diabetes 44:360–364
Lindsay RM, Smith W, Rossiter SP (1995) Nω-nitro-L-arginine methyl ester reduces the incidence of IDDM in BB/E rats. Diabetes 44:365–368
Takamura T, Kato I, Kimura I et al. (1998) Transgenic mice overexpressing Type 2 nitric oxide synthase in pancreatic β cells develop insulin-dependent diabetes without insulitis. J Biol Chem 273:2493–2496
Faust A, Kleemann R, Rothe H et al. (1996) Role of macrophases and cytokines in B-cell death. Lessons from animal diabetes VI. Birkhauser, Boston, pp 47–56
Bowman MA, Simell OG, Peck AB et al. (1996) Pharmacokinetics of aminoguanidine administration and effects on the diabetes frequency in non obese diabetic mice. J Pharmacol Exp Ther 279:790–794
Saurez-Pinzon WL, Mabley JG, Strynadka K (2001) An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice. J Autoimmun 16:449–455
Ryndgren T, Sandler S (2002) Efficacy of 1400 W, a novel inhibitor of inducible nitric oxide synthase, in preventing interleukin-1-beta-induced suppression of pancreatic islet function in vitro and multiple low-dose streptozotocin-induced diabetes in vivo. Eur J Endocrinol 147:543–551
Sampio RC, Tanus-Santos JE, Melo SEFC et al. (2002) Hypertension plus diabetes mimics the cardiomyopathy induced by nitric oxide inhibition in rats. Chest 122:1412–1420
Duplain H, Burcelin R, Sartori C et al. (2001) Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 342:342–345