Studies of the mechanisms of cadmium-induced pancreatic β-cell dysfunction and death

• Main Authors: Ching-Cheng Hsu, 許景程
• Other Authors: Chen Ya-Wen
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/76620855067910110956

碩士 === 中國醫藥大學 === 基礎醫學研究所 === 98 === Cadmium is a toxic heavy metal and has been widely used in industry. It has been demonstrated that cadmium was easily accumulated by food-chain in many organs of mammal, and caused severe cytotoxicity. Especially, some studies have been found that cadmium levels of urinary in industrial workers are dose-dependently associated with both impaired pancreatic islet beta-cell function and induced diabetic-related syndromes. However, the precise action mechanisms of cadmium-induced pancreatic beta-cells damage remain unclear. The aims of this study were attempted to elucidate whether cadmium induced dysfunction and apoptosis, and to investigate the precise mechanisms by which cadmium caused cytotoxicity in pancreatic?n beta-cell. The number of viable cells was reduced after CdCl2 treatment with pancreatic beta-cell line: RIN-m5F cells for 24h in a dose-dependent manner with a range from 1~10 μM. Lipid peroxidation production and 2`,7`-chlorofluorescein fluorescence intensity, as an indicator of reactive oxygen species formation after exposure of RIN-m5F cells to CdCl2 were significantly increased. Cadmium-induced apoptosis involved a mitochondria-mediated mechanism and caspase-dependent pathway, in that the critical apoptotic events induced by cadmium including: activation of JNK, ERK, and p38 phosphorylation, apoptotic-related mRNA expression, the abilities in disruption of mitochondrial membrane potential and release of cytochrome c from the mitochondria to the cytosol, and activation of PARP cleavage and caspase cascades. In contrast, blockage of JNK, not ERK and p38, by pharmacological inhibitor (SP600125) could be reversed the cadmium-induced apoptosis. Moreover, it was significant decrease the plasma insulin levels of ICR mice after oral administration with 10 mg/kg/day CdCl2 for consecutive weeks and cause dysfunction of glucose regulation(glucose intolence). Taken together, these results indicated that CdCl2 is capable of inducing cellular responses to cause pancreastic beta-cell dysfunctional apoptosis through ROS-mediated JNK-mitochondria-dependant apoptosis pathway. Cadmium may be an important environmental risk factor for diabetes progressing.