Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction.
OBJECTIVE
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 toxicity. Whereas oxidative stress is provoked under diabetic conditions, we examined the possible implication of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1/Sdi1) in beta-cell dysfunction mediated by oxidative stress.


METHODS
Oxidative stress was induced in isolated rat pancreatic islet cells by treatment with H(2)O(2) and mRNA expression of p21 and insulin was examined by northern blot analyses. Also, the expression of p21 and insulin mRNA was examined in Zucker diabetic fatty rat. In islet cells p21 was overexpressed using adenovirus and its effect on insulin gene transcription was examined.


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 expression was induced and the insulin mRNA expression was reduced. As support for the implication of p21 in impairment of beta-cell function, the p21 overexpression in the islet cells suppressed the insulin gene transcription.


CONCLUSIONS
The expression of cyclin-dependent kinase inhibitor p21, which can be induced by oxidative stress, increases in pancreatic islet cells upon development of diabetes. By suppressing cell proliferation and insulin biosynthesis, the p21 induction is likely to be implicated in the beta-cell glucose toxicity.
Kaneto
H
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan.
Kajimoto
Y
Y
Fujitani
Y
Y
Matsuoka
T
T
Sakamoto
K
K
Matsuhisa
M
M
Yamasaki
Y
Y
Hori
M
M
D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D007328:Insulin; D012333:RNA, Messenger; D011994:Recombinant Proteins