Arsenite reduces insulin secretion in rat pancreatic β-cells by decreasing the calcium-dependent calpain-10 proteolysis of SNAP-25
Arsenite reduces insulin secretion in rat pancreatic β-cells by decreasing the calcium-dependent calpain-10 proteolysis of SNAP-25
复制标题
DOI：
10.1016/j.taap.2008.05.018
复制
发表时间：
2008-09-15
影响因子：
3.8
通讯作者：
Ostrosky-Wegman, Patricia
中科院分区：
文献类型：
--
作者：
Diaz-Villasenor, Andrea;Burns, Anna L.;Ostrosky-Wegman, Patricia
在高砷暴露地区的居民中，2 型糖尿病的患病率一直在增加。我们之前已经证明，在大鼠胰腺β细胞中，低剂量的亚砷酸盐会损害胰岛素的分泌，但不会改变其合成。为了进一步研究亚砷酸盐减少胰岛素分泌的机制，我们评估了亚砷酸盐对触发 RINm5F 细胞中胰岛素胞吐作用的钙-钙蛋白酶途径的影响。还进行了细胞周期和增殖分析以补充表征。在亚慢性低亚砷酸盐剂量（0.5-2μM）的存在下，葡萄糖刺激的胰岛素分泌所需的游离[Ca2+]i振荡被减弱。钙蛋白酶的整体活性随着 2 μM 亚砷酸盐的增加而增加。然而，在用葡萄糖 (15.6 mM) 刺激的胰岛素分泌过程中，1 mu M 亚砷酸盐降低了 calpain-10 的活性，通过 SNAP-25 蛋白水解来测量。这两种蛋白质都需要将胰岛素颗粒与膜融合以产生胰岛素胞吐作用。亚砷酸盐还以剂量依赖性方式诱导 β 细胞系增殖减慢，反映为分裂细胞的减少及其在 G2/M 期的停滞。获得的数据表明，亚砷酸盐损害胰岛素分泌的机制之一是减少游离 [Ca2+]i 的振荡，从而减少 SNAP-25 的钙依赖性钙蛋白酶 10 部分蛋白水解。接触亚砷酸盐对细胞分裂和增殖的影响可能是胰岛素分泌减少的间接结果。 (C) 2008 Elsevier Inc. 保留所有权利。
An increase in the prevalence of type 2 diabetes has been consistently observed among residents of high arsenic exposure areas. We have previously shown that in rat pancreatic beta-cells, low arsenite doses impair the secretion of insulin without altering its synthesis. To further study the mechanism by which arsenite reduces insulin secretion, we evaluated the effects of arsenite on the calcium-calpain pathway that triggers insulin exocytosis in RINm5F cells. Cell cycle and proliferation analysis were also performed to complement the characterization. Free [Ca2+]i oscillations needed for glucose-stimulated insulin secretion were abated in the presence of subchronic low arsenite doses (0.5-2 mu M). The global activity of calpains increased with 2 mu M arsenite. However, during the secretion of insulin stimulated with glucose (15.6 mM), 1 mu M arsenite decreased the activity of calpain-10, measured as SNAP-25 proteolysis. Both proteins are needed to fuse insulin granules with the membrane to produce insulin exocytosis. Arsenite also induced a slowdown in the beta cell line proliferation in a dose-dependent manner, reflected by a reduction of dividing cells and in their arrest in G2/M.Data obtained showed that one of the mechanisms by which arsenite impairs insulin secretion is by decreasing the oscillations of free [Ca2+]i, thus reducing calcium-dependent calpain-10 partial proteolysis of SNAP-25. The effects in cell division and proliferation observed with arsenite exposure can be an indirect consequence of the decrease in insulin secretion. (C) 2008 Elsevier Inc. All rights reserved.