COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease believe d to be caused by an inflammatory process in the pancreas leading to select ive destruction of the beta cells. Inducible cyclooxygenase (COX-2) is expr essed under inflammatory conditions and its product prostaglandin E-2 (PGE( 2)) is an important inflammation mediator. We report here that administrati on of the selective COX-2 inhibitor NS-398 prevents the onset of diabetes i n mice brought on by multiple low-doses of streptozotocin (STZ). Histologic al observations indicated that STZ-mediated destruction of beta cells was p revented by NS-398 treatment. Delayed (day 3) administration of NS-398 was also protective in this model. No protective effect was observed when NS-39 8 was administered prior to a high, toxic dose of STZ. These results demons trate the critical importance of COX-2 activity in autoimmune destruction o f beta cells, and point to the fact that COX-2 inhibition can potentially d evelop into a preventive therapy against IDDM. (C) 2000 Academic Press.