吡格列酮对胰岛α细胞胰岛素抵抗的影响  

Effect of pioglitazone on islet α cell with respect to insulin resistance

作　　者：杜瑞琴[1] 李宏亮[1] 杨文英[1] 萧建中[1] 王冰[1] 楼大钧[1] 白秀平[1] 潘琳 

机构地区：[1]卫生部中日友好医院内分泌科,北京100029 [2]临床医学研究所细胞生物实验室

出　　处：《中华内分泌代谢杂志》2008年第1期29-33,共5页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金资助项目（30640081）志谢 感谢四川大学华西医院内分泌科李秀钧教授课题组对本研究的大力支持和前期的卓越工作.

摘　　要：目的研究高脂饲养大鼠胰岛α细胞的分泌功能和胰岛素信号转导分子基因的表达变化以及吡格列酮干预的影响。方法雄性SD大鼠分为正常饲养组（NC）、高脂饲养组（HF）、高脂＋吡格列酮组（HP）。喂养20周后检测空腹血胰岛素（FINS）、胰高血糖素、游离脂肪酸（FFA）水平；正常血糖高胰岛素钳夹试验评价外周胰岛素抵抗程度；胰岛表面灌注检测高糖状态胰高血糖素的动态分泌变化；同时各组大鼠随机入组8只给予大剂量链脲佐菌素去β细胞处理，得到去β细胞正常组（NC—B）、高脂组（HF-B），高脂＋吡格列酮干预组（HP-B）。实时定量PCR方法比较3组去β细胞大鼠α细胞胰高血糖素、胰岛素受体底物1（IRS-1）、胰岛素受体底物2（IRS-2）、磷脂酰肌醇3激酶（PI3K）的mRNA表达。结果（1）HF组葡萄糖输注率（GIR）明显低于NC组，血FINS、胰高血糖素、FFA均显著高于NC组（P〈0．05或P〈0．01）；而HP组以上各项指标较HF组均明显改善。（2）胰岛表面灌注HF组基础胰高血糖素的分泌高于NC组（P〈0．01），16．7mmol／L葡萄糖灌注后NC组胰岛胰高血糖素的分泌明显下降，HF组胰岛的胰高血糖素分泌灌注后未受高糖抑制，HP组逆转了这种变化。（3）与NC—B组相比，HF—B组α细胞胰高血糖素mRNA的表达增高34．2％，IRS-2及PI3KmRNA分别降低28．5％、21．3％（均P〈0．01），而IRS-1仅降低7．1％（P〉0．05）。HP-B组较HF-B组胰高血糖素、IRS-2及P13K mRNA分别增加40．6％、57．2％、60．6％。结论 高脂饲料诱导的肥胖大鼠胰岛α细胞胰高血糖素分泌功能亢进并存在胰岛素信号转导分子表达降低，二者均与血FFA水平升高有关，而吡格列酮能逆转这种变化。Objective To study changes of the secretory function and insul!n signal transduction molecules in islet α cells and the effects of pioglitazone intervention in high-fat-chow plus β cell-deleting rat models. Methods Forty-five normal 8-week-old male SD rats were randomly divided into 3 groups, equally： normal chow group （NC）, high-fat-chow group （HF）, and pioglitazone-treated group （HP, pioglitazone 15 mg · kg^-1 d^-1 and high-fat-chow）. At the end of 20-week-experiment, fasting serum insulin （FINS）, glucagon （Glc）, free fatty acids （FFA） were determined. The glucose infusion rate （GIR） was measured by using euglycemic hyperinsulinemia clamp to evaluate the peripheral insulin resistance. The contents of Glc in perfusion medium during islet surface perfusion were measured by RIA. At the same time, the β cell-deleting rat models were established by injecting large dose Streptozocin （100 mg/kg） in the three groups： HF-B group, HP-B group and NC-B group （ n = 8, each group）. Five days later, the rats were sacrificed, and thepancreatic islets were isolated and collected. The expressions of Glc, insulin receptor substrate-1 （IRS-1）, insulin receptor substrate-2 （IRS-2）, phosphatidylinositol-3-kinase （PI3K） genes in islets were detected by RT-PCR. Results （ 1 ） The GIR was significantly decreased in HF group compared with NC group [ （5.25 ± 1.2 vs 13.56± 1.7）mg · min^-1· kg^-1 , P 〈0. 01 ]. The concentrations of serum FINS, Glc, FFA in HF group were higher than those in NC group （P 〈 0. 05 or P 〈 0. 01 ）. Pioglitazone intervention reversed these effects [ GIR （ 12.67±1.5 ） mg · min -1 · kg^-1 （2） The basal Glc secretion of the islet cells of HF group was higher than NC group [ （157±15 vs 51 ±8）ng/L, P 〈 0. 01 ], and 16.7 mmol/L glucose could inhibit Glc secretion from the cells of the NC group rats [ （31 ± 3） ng/L, P 〈0.01 ], but not of the HF group rats. Pioglitazone intervention could reverse these effects. （3）

关 键 词：胰岛Α细胞 胰岛素抵抗 游离脂肪酸 吡格列酮 

分 类 号：R587.1[医药卫生—内分泌] R587.102[医药卫生—内科学]