Overexpression of catalase provides partial protection to transgenic mousebeta cells

Pancreatic beta cells are sensitive to reactive oxygen species and this may play an important role in type 1 diabetes and during transplantation. Beta cells contain low levels of enzyme systems that protect against reactive o xygen species. The weakest link in their protection system is a deficiency in the ability to detoxify hydrogen peroxide by the enzymes glutathione per oxidase and catalase. We hypothesize that the deficit in the ability to dis pose of reactive oxygen species is responsible for the unusual sensitivity of beta cells and that increasing protection will result in more resistant beta cells. To test these hypotheses we have produced transgenic mice with increased beta cell levels of catalase. Seven lines of catalase transgenic mice were produced using the insulin promoter to direct pancreatic beta cel l specific expression. Catalase activity in islets from these mice was incr eased by as much as 50-fold. Northern blot analysis of several tissues indi cated that overexpression was specific to the pancreatic islet. Catalase ov erexpression had no detrimental effects on islet function. To test whether increased catalase activity could protect the transgenic islets we exposed them to hydrogen peroxide, streptozocin, and interleukin-lp. Fifty-fold ove rexpression of catalase produced marked protection of islet insulin secreti on against hydrogen peroxide and significantly reduced the diabetogenic eff ect of streptozocin in vivo. However, catalase overexpression did not provi de protection against interleukin-1 beta toxicity and did not alter the eff ects of syngeneic and allogenic transplantation on islet insulin content. O ur results indicate that in the pancreatic beta cell overexpression of cata lase is protective against some beta cell toxins and is compatible with nor mal function. (C) 1999 Elsevier Science Inc.