Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion
Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion
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DOI：
10.2337/db14-0432
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发表时间：
2015-03-01
期刊：
影响因子：
7.7
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Hashimoto, Shinji;Kubota, Naoto;Kadowaki, Takashi
内皮细胞被认为是正常胰腺细胞功能所必需的。目前的研究试图证明胰岛素受体底物-2（Irs 2）在内皮细胞胰岛素分泌方面的作用。内皮细胞特异性Irs 2基因敲除（ETIrs 2KO）小鼠表现出葡萄糖诱导的、精氨酸诱导的和胰高血糖素诱导的胰岛素分泌受损，并表现出葡萄糖耐受不良。在使用分离的胰岛的分批孵育和灌流实验中，葡萄糖诱导的胰岛素分泌在对照和ETIrs 2KO小鼠之间没有显著差异。相反，在灌注实验中，葡萄糖诱导的胰岛素分泌在ETIrs 2KO小鼠中显著受损。ETIrs 2KO小鼠的胰岛血流明显受损。用马来酸依那普利治疗这些基因敲除小鼠后，改善了胰岛血流量，葡萄糖刺激的胰岛素分泌几乎完全恢复到与对照小鼠相同的水平。这些数据表明，内皮细胞中Irs 2缺失导致胰岛血流量减少，这可能导致葡萄糖诱导的胰岛素分泌受损。因此，内皮细胞中的Irs 2可作为预防和改善2型糖尿病和代谢综合征的新的治疗靶点。
Endothelial cells are considered to be essential for normal pancreatic -cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell-specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome.