RAS阻断通过减弱内质网应激保护长期高脂喂养大鼠胰岛功能  

Blockade of renin-angiotensin system improves pancreatic islet function via attenuating endoplasmic reticulum stress in rats fed with long-term high-fat diet

作　　者：李进[1] 袁莉[1] 李新[1] 李海玲[1] 程梭梭[1] 

机构地区：[1]华中科技大学同济医学院附属协和医院内分泌科 ,武汉430022

出　　处：《中华内分泌代谢杂志》2009年第4期429-433,共5页Chinese Journal of Endocrinology and Metabolism

基　　金：湖北省自然科学基金（2005ABA158）

摘　　要：目的研究阻断肾素血管紧张素系统（RAS）对长期高脂喂养诱导的胰岛素抵抗大鼠胰岛β细胞功能和内质网凋亡相关信号分子的影响。方法以高脂高热量饮食的方法建立胰岛素抵抗大鼠模型，16周后分别以培哚普利和替米沙坦干预。24周后采用高胰岛素正葡萄糖钳夹技术检测胰岛素敏感性；行静脉胰岛素释放试验（IVIRT）检测胰岛β细胞功能；采用RT—PCR及免疫组化法检测胰岛内质网应激因子及胰岛素的表达。结果与正常对照组相比，高脂组葡萄糖输注率（GIR）显著降低（P〈0．01），胰岛素分泌高峰明显延迟，急性胰岛素分泌反应（AIR）明显下降，胰岛内质网应激凋亡相关分子免疫球蛋白结合蛋白（BIP）、C／EBP同源蛋白（CHOP）基因表达及Bax蛋白表达均显著升高，而胰岛素表达量下降（均P〈0．01）。培哚普利或替米沙坦干预后，GIR较高脂组显著升高，胰岛素分泌达峰时间前移，AIR较高脂组明显增加，β细胞内胰岛素表达量增加，胰岛BIP、CHOP基因表达及Bax蛋白表达水平均有不同程度下降（P〈0．05或P〈0．01）。结论RAS阻断可以明显改善长期高脂喂养诱导的胰岛素抵抗大鼠胰岛功能，减少β细胞内质网应激介导的凋亡因子的表达；减弱胰岛内质网应激可能是RAS阻断发挥抗β细胞凋亡、改善β细胞功能的重要机制。Objective To investigate the effect of renin-angiotensin system（RAS） blockade on pancreatic islet β-cell function and endoplasmic retieulum mediated apoptosis in insulin-resistant rats fed with long-term high-fat diet. Methods Insulin-resistant rat model was established by feeding high calorie and highfat diet for 16 weeks and then was treated with perindopril （n=15） or telmisartan （n=15） at the dosage of 2 mg · kg^-1 · d^-1 or 10 mg · kg ^-1 · d^-1 respectively. Insulin sensitivity was assessed by euglycemie-hyperinsulinemic clamp technique after 24 weeks. Islet function was evaluated by intravenous insulin releasing test （IVIRT）. The BIP （immunoglobulin binding protein ）/GRP78 （glucose-regulated protein）, CHOP （ C/EBP- homologous protein ）/GADD153 （growth arrest and DNA-damage-indueible gene 153） mRNA expression levels in the islets were detected by RT-PCR. The expression levels of insulin and Bax protein in the islets were examined by immunohistoehemistry. Results Compared with normal control group （n= 15）, glucose infusion rate （GIR） in high-fat diet control group （n= 15） was reduced significantly [ （5.32±0.90 vs 7.80±0.51） mg· kg^-1 · min^-1, P〈0. 01 1, and acute insulin response （AIR） was decreased significantly with the appearance of insulin secretion peak delayed to 10 min. The expression of insulin was decreased significantly in β-cells, the mRNA expressions of BIP,CHOP and the protein expression of Bax were increased to 2.3 times, 1.8 times and 1.9 times, respectively （all P〈0. 01）. Compared with high-fat diet control group insulin sensitivity of perindopril and telmisartan group was increased significantly with the curve of insulin secretion improved, AIR was increased significantly, the expression of insulin was increased in β-cells, the expression levels of BIP, CHOP and Bax in the islets were decreased to certain levels （P〈0. 05 or P〈0. 01）. Conclusion Blockade of RAS improves pancreatic islet function significantly in ra

关 键 词：肾素血管紧张素系统 胰岛功能 胰岛素抵抗 内质网应激 细胞凋亡 

分 类 号：R686[医药卫生—骨科学]