Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction

Aims/hypothesis. Prolonged poor glycaemic control in patients with Type II (non-insulin-dependent) diabetes mellitus often causes pancreatic beta-cell dysfunction accompanied by decreases in insulin biosynthesis and beta-cell proliferation. This is well known as a clinical concept called glucose tox icity. Whereas oxidative stress is provoked under diabetic conditions, we e xamined the possible implication of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/ CIP1/wSdi1) in beta-cell dysfunction mediated by oxidative stre ss. Methods. Oxidative stress was induced in isolated rat pancreatic islet cell s by treatment with H2O2 and mRNA expression of p21 and insulin was examine d by northern blot analyses. Also, the expression of p21 and insulin mRNA w as examined in Zucker diabetic fatty rat. In islet cells p21 was overexpres sed using adenovirus and its effect on insulin gene transcription was exami ned. Results. When oxidative stress was charged on isolated rat pancreatic islet cells, p21 mRNA expression was induced whereas insulin mRNA was decreased. Also, when diabetes developed in Zucker diabetic fatty rats, p21 expressio n was induced and the insulin mRNA expression was reduced. As support for t he implication of p21 in impairment of beta-cell function, the p21 overexpr ession in the islet cells suppressed the insulin gene transcription. Conclusions/interpretation. The expression of cyclin-dependent kinase inhib itor p21, which can be induced by oxidative stress, increases in pancreatic islet cells upon development of diabetes. By suppressing cell proliferatio n and insulin biosynthesis, the p21 induction is likely to be implicated in the beta-cell glucose toxicity.