Pyrrolidine dithiocarbamate protects pancreatic β-cells from oxidative damage through regulation of FoxO1 activity in type 2 diabetes rats

Abstract

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 b-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 b-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 b-cell apoptosis. PDTC treatment significantly reduced the oxidative damage and the b-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 bcells from oxidative damage and improve insulin production through regulation of PDX-1 and FoxO1 in a DM rat model.

An experimental study on effects of pyrrolidine dithiocarbamate on ischemia-reperfusion injury in testis

“…Consequently, PDTC reduces the production of inflammatory cytokines. 13 Protective role of PDTC against I/R injury was the main concern of the current study. Previous reports have documented the beneficial effects of PDTC in testicular injury due to cisplatin, renal damage attributed to extracorporeal shock wave lithotripsy, acute respiratory distress syndrome, and focal cerebral ischemia.…”

Salidroside, A Natural Antioxidant, Improves β-Cell Survival and Function via Activating AMPK Pathway

“…Studies have shown that inactivation of FOXO1 contributes to β-cell protection under oxidative damage ( Ding et al, 2014 ; Shao et al, 2014 ). It is known that in β-cells FOXO1 acts as a negative regulator of PDX1 functions and mediate β-cell dysfunction and apoptosis.…”

“…AMPK/mTOR signaling mediates protecting β-cells against diabetic oxidative stress ( Wang et al, 2016 ). Oxidative stress also induces activation of FOXO1 which suppresses the function of PDX1 to reduce insulin expression consequently ( Ding et al, 2014 ).…”

HDAC4 mutations cause diabetes and induce β‐cell FoxO1 nuclear exclusion

“…Deacetylated FoxO1 protects β‐cell function by limiting mitochondrial lipid utilization through decreasing fatty acid oxidation and enhancing insulin secretion in the context of diabetes (Kim‐Muller et al, ); which is in consist in the findings that the levels of acetylated FoxO1 are markedly increased in pancreatic tissues of diabetic, compared to healthy rats (Ding et al, ). We found elevated levels of acetylated FoxO1 in the pancreatic β‐cells exposed to the HDAC4 mutations compared to the wild type, indicating the failure of FoxO1 deacetylation in the diabetic patients.…”