Journal
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
Volume 46, Issue 7, Pages 582-589Publisher
OXFORD UNIV PRESS
DOI: 10.1093/abbs/gmu034
Keywords
pyrrolidine dithiocarbamate (PDTC); diabetes; oxidative damage; FoxO1; PDX-1
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Funding
- Natural Science Foundation of Hebei Province in China [C2009001232]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Personnel of China
- Department of Science and Technology of Hebei Province [10276105D-66]
- Health Bureau of Hebei Province [20090168]
- Hebei Education Department in China [2008135]
- NIH, National Institute on Aging
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Pyrrolidine dithiocarbamate (PDTC) can lower the blood glucose level and improve the insulin sensitivity in diabetic rats. However, the mechanisms underlying this effect of PDTC treatment in diabetic rats remained uncertain. In this study, we evaluated the mechanisms by which PDTC conferred protection against oxidative damage to pancreatic islet beta-cells in rats with experimental type 2 diabetes mellitus (DM). DM in the rats was elicited by long-term high-fat diet accompanied with a single intraperitoneal (i.p.) injection of a low dose of streptozotocin. After a 7-day administration of PDTC (50 mg/kg/day i.p.), blood glucose levels were measured and pancreatic tissues were collected for the determination of various biochemical and enzymatic activities using immunohistochemistry, immunofluorescence, and western blot techniques. The percentage of apoptotic pancreatic islet beta-cells was detected by flow cytometry. The results showed that diabetic rats had elevated blood glucose levels and insulin resistance, accompanied with an increase in malondialdehyde content, nitrotyrosine production, and inducible nitric oxide synthase expression. A decrease in superoxide dismutase and glutathione peroxidase activities was also observed in DM rats, culminating with elevated beta-cell apoptosis. PDTC treatment significantly reduced the oxidative damage and the beta-cell apoptosis, and also increased the insulin production through down-regulating FoxO1 acetylation and up-regulating nuclear PDX-1 level. These data suggested that PDTC can protect islet beta-cells from oxidative damage and improve insulin production through regulation of PDX-1 and FoxO1 in a DM rat model.
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