Oxidative stress and the JNK pathway as a potential therapeutic target for diabetes.
Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Possibly due to low levels of antioxidant enzyme expressions, beta-cells are vulnerable to oxidative stress. When beta-cell-derived cell lines or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. Furthermore, when diabetic C57BL/ KsJ-db/db mice were treated with antioxidants, glucose tolerance was ameliorated. Histological analyses of the pancreata revealed that the beta-cell mass is significantly larger in the mice treated with the antioxidants. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA. As a possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Furthermore, oxidative stress induces nucleocytoplasmic translocation of PDX-1 through activation of the c-Jun N-terminal kinase (JNK) pathway, which leads to suppression of insulin gene expression. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of beta-cell dysfunction found in diabetes, and thus are a therapeutic target for diabetes.
Kaneto
Hideaki
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan. kaneto@medone.med.osaka-u.ac.jp.
Kawamori
Dan
D
Nakatani
Yoshihisa
Y
Gorogawa
Shin-ichi
S
Matsuoka
Taka-aki
TA
D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D018384:Oxidative Stress; D021381:Protein Transport; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000032:analysis
D000975:Antioxidants; D018398:Homeodomain Proteins; D007328:Insulin; D017382:Reactive Oxygen Species; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D048031:JNK Mitogen-Activated Protein Kinases