Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
Address for correspondence: Hideaki Kaneto, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Voice: 81-6-6879-3633; fax: 81-6-6879-3639. kaneto{at}medone.med.osaka-u.ac.jp
Ann. N.Y. Acad. Sci. 1011: 168-176 (2004).
Oxidative stress is produced under diabetic conditions and is
likely involved in progression of pancreatic ß-cell
dysfunction found in diabetes. Possibly caused by low levels
of antioxidant enzyme expressions, pancreatic ß-cells
are vulnerable to oxidative stress. When ß-cell-derived
HIT-T15 cells or isolated rat islets were exposed to oxidative
stress, insulin gene expression was markedly decreased. To investigate
the significance of oxidative stress in the progression of pancreatic
ß-cell dysfunction in type 2 diabetes, we evaluated
the effects of antioxidants in diabetic C57BL/KsJ-db/db mice.
According to an intraperitoneal glucose tolerance test, the
treatment with antioxidants retained glucose-stimulated insulin
secretion and moderately decreased blood glucose levels. Histological
analyses of the pancreata revealed that the ß-cell
mass was significantly larger in the mice treated with the antioxidants,
and the antioxidant treatment suppressed apoptosis in ß-cells
without changing the rate of ß-cell proliferation.
The antioxidant treatment also preserved the amounts of insulin
content and insulin mRNA, making the extent of insulin degranulation
less evident. As possible mechanism underlying the phenomena,
expression of pancreatic and duodenal homeobox factor-1 (also
known as IDX-1/STF-1/IPF1), an important transcription factor
for the insulin gene, was more clearly visible in the nuclei
of islet cells after the antioxidant treatment. Under diabetic
conditions, JNK is activated by oxidative stress and involved
in the suppression of insulin gene expression. This JNK effect
appears to be mediated in part by nucleocytoplasmic translocation
of PDX-1, which is also downstream of JNK activation. Taken
together, oxidative stress and consequent activation of the
JNK pathway are involved in progression of ß-cell
dysfunction found in diabetes. Antioxidants may serve as a novel
mechanism-based therapy for type 2 diabetes.
