Oxidative stress and pancreatic beta-cell dysfunction.
Oxidative stress is induced under diabetic conditions through various pathways, including the electron transport chain in mitochondria and the nonenzymatic glycosylation reaction, and is likely involved in progression of pancreatic beta-cell dysfunction developing in diabetes. beta-Cells are vulnerable to oxidative stress, possibly due to low levels of antioxidant enzyme expression. When oxidative stress was induced in vitro in beta cells, the insulin gene promoter activity and mRNA levels were suppressed, accompanied by the reduced activity of pancreatic and duodenal homeobox factor-1 (PDX-1) (also known as IDX-1/STF-1/IPF1), an important transcription factor for the insulin gene. The suppression of oxidative stress by a potent antioxidant, N-acetyl-l-cysteine or probucol, led to the recovery of insulin biosynthesis and PDX-1 expression in nuclei and improved glucose tolerance in animal models for type 2 diabetes. As a possible cause of this, we recently found that PDX-1 was translocated from the nucleus to the cytoplasm in response to oxidative stress. Furthermore, the addition of a dominant-negative form of c-Jun N-terminal kinase (JNK) inhibited the oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating the phenomenon. Taken together, the oxidative stress-mediated activation of the JNK pathway leads to nucleocytoplasmic translocation of PDX-1 and thus is likely involved in the progression of beta-cell dysfunction found in 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
Matsuoka
Taka-aki
TA
Kajimoto
Yoshitaka
Y
Yamasaki
Yoshimitsu
Y
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D005947:Glucose / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology
D000975:Antioxidants; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D048670:MAP Kinase Kinase 4; D005947:Glucose