Pyrrolidine dithiocarbamate protects pancreatic β-cells from oxidative damage through regulation of FoxO1 activity in type 2 diabetes rats.
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 β-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 β-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 β-cell apoptosis. PDTC treatment significantly reduced the oxidative damage and the β-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 β-cells from oxidative damage and improve insulin production through regulation of PDX-1 and FoxO1 in a DM rat model.
Department of Endocrinology, Fourth Hospital, Hebei Medical University, Shijiazhuang 050011, China.
Haiyan
H
Ding
Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China tienian_zhu@hotmail.com 6810c@163.com.
Tienian
T
Zhu
Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China.
Xiaomei
X
Yin
Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China.
Jiankun
J
Liu
Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China.
Lizhong
L
Zhang
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Michel
M
Bernier
Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China tienian_zhu@hotmail.com 6810c@163.com.
Ruijing
R
Zhao
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1
D000975:Antioxidants; D051858:Forkhead Transcription Factors; D005979:Glutathione Peroxidase; D007328:Insulin; D008315:Malondialdehyde; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines; D013482:Superoxide Dismutase; D013859:Thiocarbamates; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C020972:pyrrolidine dithiocarbamic acid
FoxO1; PDX-1; diabetes; oxidative damage; pyrrolidine dithiocarbamate (PDTC)