Tsubouchi Hirotaka, Inoguchi Toyoshi, Inuo Mieko, Kakimoto Maiko, Sonta Toshiyo, Sonoda Noriyuki, Sasaki Shuji, Kobayashi Kunihisa, Sumimoto Hideki, Nawata Hajime
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Biochem Biophys Res Commun. 2005 Jan 7;326(1):60-5. doi: 10.1016/j.bbrc.2004.10.201.
Increased oxidative stress may play a key role in the progressive deterioration of pancreatic beta-cells and the development of diabetes. However, the underlying mechanism is not well understood. Exposure of pancreatic beta-cell line, MIN6 cells, to elevated glucose level for 2h induced an increase in reactive oxygen species (ROS) production, as evaluated by the staining of 2',7'-dichlorofluorescein diacetate. This effect was completely blocked by NAD(P)H oxidase inhibitor (diphenylene iodonium) and protein kinase C (PKC) inhibitor (calphostin C), but not affected by other flavoprotein inhibitors (rotenone, oxypurinol, or l-N-monomethyl arginine). Glibenclamide also stimulated ROS production in a dose-dependent manner. This effect was again blocked by diphenylene iodonium and calphostin C. In conclusion, insulin secretagogues, both glibenclamide and elevated glucose level, stimulated ROS production in beta-cells through a PKC-dependent activation of NAD(P)H oxidase. This mechanism may be a novel therapeutic target for preventing the progression of beta-cell deterioration.
氧化应激增加可能在胰腺β细胞的渐进性恶化和糖尿病的发展中起关键作用。然而，其潜在机制尚未完全明确。将胰腺β细胞系MIN6细胞暴露于高糖水平2小时，可诱导活性氧（ROS）生成增加，这通过二氯荧光素二乙酸酯染色来评估。NAD(P)H氧化酶抑制剂（二亚苯基碘鎓）和蛋白激酶C（PKC）抑制剂（钙泊三醇）可完全阻断此效应，但不受其他黄素蛋白抑制剂（鱼藤酮、氧嘌呤醇或L-N-单甲基精氨酸）影响。格列本脲也以剂量依赖方式刺激ROS生成。此效应同样被二亚苯基碘鎓和钙泊三醇阻断。总之，胰岛素促分泌剂，即格列本脲和高糖水平，通过PKC依赖的NAD(P)H氧化酶激活刺激β细胞中的ROS生成。该机制可能是预防β细胞恶化进展的新治疗靶点。
