TRANSGENIC MICE OVEREXPRESSING TYPE-2 NITRIC-OXIDE SYNTHASE IN PANCREATIC BETA-CELLS DEVELOP INSULIN-DEPENDENT DIABETES WITHOUT INSULITIS

We generated transgenic mice carrying the mouse type 2 nitric oxide sy nthase (NOS2) cDNA under the control of the insulin promoter. Western and immunohistochemical analyses revealed that NOS2 was expressed abun dantly in transgenic islets but not in control islets. When islets wer e isolated and cultured, high levels of nitrite were released from the transgenic islets, In transgenic mice, the beta cell mass was markedl y reduced without the infiltration of macrophages or lymphocytes, and extensive DNA strand breaks were detected in the islets by in situ nic k translation, All the transgenic mice developed hypoinsulinemic diabe tes by 4 weeks of age, and treatment with an inhibitor of NOS2, aminog uanidine (200 mg/kg body weight every 12 h), prevented or delayed the development of diabetes. The present study shows that the production o f nitric oxide by beta cell NOS2 plays an essential role in the beta c ell degeneration.