Hyperglycemia and hyperinsulinemia have additive effects on activation and proliferation of pancreatic stellate cells: Possible explanation of islet-specific fibrosis in type 2 diabetes mellitus
Hyperglycemia and hyperinsulinemia have additive effects on activation and proliferation of pancreatic stellate cells: Possible explanation of islet-specific fibrosis in type 2 diabetes mellitus
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DOI：
10.1002/jcb.21222
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发表时间：
2007-06-01
影响因子：
4
通讯作者：
Yoon, Kun-Ho
中科院分区：
文献类型：
--
作者：
Hong, Oak-Kee;Lee, Seung-Hwan;Yoon, Kun-Ho
在2型糖尿病中观察到的胰岛纤维化是导致进行性β细胞损失和功能障碍的主要因素之一。尽管其重要性，但与胰腺星状细胞（PSC）激活和增殖相关的胰岛限制性纤维化的机制仍有待确定。因此，我们研究了以高血糖和高胰岛素血症为代表的胰岛特异性环境是否对培养的大鼠PSC的活化和增殖具有累加效应。单独或同时用葡萄糖和胰岛素刺激细胞活化和增殖。这两种刺激促进PSC增殖和细胞外信号调节激酶（ERK）1/2磷酸化独立，但也证明了累加效应。丝裂原活化蛋白激酶激酶（MEK）抑制剂U 0126阻断ERK信号传导，抑制葡萄糖和胰岛素诱导的ERK 112磷酸化和PSC增殖。葡萄糖和胰岛素诱导的ERK 1/2磷酸化也刺激结缔组织生长因子基因表达。因此，高血糖症和高胰岛素血症是激活和增殖PSC的两个关键的促有丝分裂因子，并且这两种状态的存在将放大这种反应。
Pancreatic islet fibrosis observed in Type 2 diabetes is one of the major factors leading to progressive beta-cell loss and dysfunction. Despite its importance, the mechanism of islet-restricted fibrogenesis associated with pancreatic stellate cell (PSC) activation and proliferation remains to be defined. Therefore, we studied whether the islet-specific environment represented by hyperglycemia and hyperinsulinemia had additive effects on the activation and proliferation of cultured rat PSCs. Cells were stimulated to activate and proliferate with glucose and insulin, either individually or concomitantly. Both stimuli promoted PSC proliferation and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation independently, but an additive effect was also demonstrated. Blockade of ERK signaling by the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, suppressed both glucose- and insulin-induced ERK 112 phosphorylation and PSC proliferation. Glucose and insulin-induced ERK 1/2 phosphorylation also stimulated connective tissue growth factor gene expression. Thus, hyperglycemia and hyperinsulinemia are two crucial mitogenic factors that activate and proliferate PSCs, and the presence of both states will amplify this response.