替米沙坦通过抑制胰岛内质网应激减少STZ致长期高脂喂养大鼠糖尿病的发生  

Blockade of renin-angiotensin system decreases the incidence of streptozotocin-induced diabetes in rats with long-term high fat diet via inhibiting endoplasmic reticulum stress

作　　者：李进[1,2] 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,湖北武汉430022 [2]河南省平顶山市第一人民医院内分泌科,河南平顶山467000

出　　处：《中国病理生理杂志》2010年第1期17-22,共6页Chinese Journal of Pathophysiology

基　　金：湖北省自然科学基金资助项目(No.2005ABA158)

摘　　要：目的:研究肾素血管紧张素Ⅱ受体阻断剂替米沙坦对长期高脂喂养大鼠链脲佐菌素(STZ)致糖尿病的发病率和胰岛β细胞功能的影响及其作用机制。方法:以高脂高热量饮食饲养Wistar大鼠,16周后以替米沙坦干预,24周后1次性给予小剂量STZ,注射STZ1周后行静脉胰岛素释放实验检测胰岛β细胞功能;采用反转录-聚合酶链反应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:与高脂+STZ组相比,高脂+替米沙坦+STZ组大鼠糖尿病发病率明显下降,胰岛素最大分泌量增加了56.9%,早期胰岛素分泌指数(EISI)及急性胰岛素分泌反应(AIR)升高了1.98倍和0.88倍,β细胞内胰岛素表达量及胰岛素阳性表达细胞密度明显增加,胰岛β细胞内质网应激凋亡相关分子免疫球蛋白结合蛋白、C/EBP同源蛋白基因表达及Bax蛋白表达均显著下降。结论:肾素血管紧张素系统(RAS)阻断可以增强长期高脂喂养大鼠对STZ性糖尿病的抵抗性,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阻断而改善β细胞功能、减少糖尿病发生的重要机制之一。AIM： To investigate the effects and mechanisms of reninangiotensin system （RAS） blockade on pancreatic islet 15 - cell function in rats with injection of streptozotocin （ STZ ） and long - term high - fat diet. METHODS： Normal male Wistar rats fed with 16 weeks - long high calorie, and high -fat diet were treated with telmisartan （TI, n = 15 ）, and injected with STZ after 24 weeks. One week later, islet function was evaluated by intravenous insulin releasing test （IVIRT）. The immunoglobulin binding protein （BIP）/glucose -regulated protein （GRP78）, C/EBP -homolo- gous protein （CHOP）/growth arrest and DNA -damage -inducible gene 153 （GADD153） 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 immunohistochemistry. RESULTS： The incidence of diabetes was 80% （ 12/15 ）in the high -fat diet ＋ STZ group （HS） and 33% （5/15） in the high - fat diet ＋ STZ ＋ telmisartan group （TS）. Compared to HS group, maximum of insulin secretion in TS group was increased 56. 9%. Early insulin secretion index （EISI） and acute insulin response （AIR） were increased by 1.98 times and 0. 88 times, respectively. The expression of insulin and insulin positive cell density （PCD） were increased obviously in β- cells. The expression levels of BIP, CHOP and Bax in the islets were decreased significantly. CONCLU- SION： Blockade of RAS increases the resistance to streptozotocin - induced diabetes in rats with long - term high - fat diet, and the expression of apoptosis - related molecules is downregulated in endoplasmic reticulum. The mechanism that RAS blockade improves pancreatic islets function and reduces diabetes incidence to some extent may be via attenuating endoplasmic reticulum stress.

关 键 词：肾素-血管紧张素系统 内质网应激 糖尿病 细胞凋亡 

分 类 号：R587.1[医药卫生—内分泌]