11β-HSD1抑制剂改善db/db小鼠胰岛素敏感性的实验研究

doi:10.6040/j.issn.1671-7554.0.2016.1379

摘要/Abstract

摘要： 目的探讨11β-HSD1抑制剂H8对db/db小鼠胰岛素敏感性的影响。方法实验动物40只分成5个组,每组8只,分别是db/db对照组(Dia组)、罗格列酮组(Ros组)、姜黄素组(Cur组)、姜黄素类似物H8组(H8组)、db/m对照组(Con组)。H8灌胃给药42 d后尾静脉采血检测葡萄糖耐量(OGTT)、胰岛素耐量(IPITT);在第0、1、3、6周尾静脉采血检测空腹血糖值;眼球取血检测胰岛素抵抗系数(HOMA-IR);酶学检测肝脏、脂肪中11β-HSD1活性;ELISA法检测血清中糖皮质激素水平。结果 OGTT结果显示,与Dia组相比较,Ros组和H8组各时间点血糖值均有所降低;IPITT结果显示,相对于Dia组,Ros组和H8组血糖值均有所下降;空腹血糖在给药后第1~6周,H8组与Dia组比较明显降低;与Dia组比较,Ros组、Cur组和H8组胰岛素抵抗指数(HOMA-RI)明显降低(P<0.001);与Dia组对比,H8组可以明显的抑制肝脏(P<0.01)和脂肪(P<0.01)中11β-HSD1的活性;与Dia组对比,H8组GC水平降低(P<0.001)。结论 11β-HSD1的抑制剂H8可以降低db/db小鼠肝脏GC水平,进而提高胰岛素的敏感性。

关键词: 11β-羟基类固醇脱氢酶1抑制剂, 胰岛素抵抗, db/db小鼠

Abstract: Objective To explore the effects of H8, an inhibitor of 11β-HSD1, on insulin sensitivity in db/db mice. Methods A total of 40 db/db mice were divided into 5 groups: db/db model group(Dia), rosiglitazone treatment group(Ros), curcumin treatment group(Cur), curcumin analogues H8 treatment group(H8), and db/m control group(Con). H8 was intragastriclly administered once per day for 6 weeks, and then oral glucose tolerance test(OGTT)and intraperitoneal insulin tolerance test(IPITT)were performed at the end of the 6th week. Fasting blood glucose levels, collected from the tail vein, were measured in 0th, 1th, 3th, and 6th week. At the end of the experiment, the inner canthus vein blood was collected to examine HOMA-RI index. The activity of 11β-HSD1 in liver and adipocytes and the level of glucocorticoid in serum were detected with enzyme method and ELISA, respectively. Results The results of OGTT showed that the blood glucose level was significantly reduced in the Ros group and H8 group than in the Dia group. The IPITT results revealed that the blood glucose level was significantly reduced in the Ros group and H8 group than in the Dia group. Fasting blood glucose level of H8 group was significantly lower than that of Dia group from the 1th to 6th week after the treatment. The HOMA-IR indicator of the Ros group, Cur group and H8 group was significantly lower compared with that of the Dia group(P<0.001). Compared with Dia group, H8 had 山东大学学报 (医学版)55卷10期 -李洪志,等.11β-HSD1抑制剂改善db/db小鼠胰岛素敏感性的实验研究 \=-significantly inhibited 11β-HSD1 activity in liver(P<0.01)and adipocytes(P<0.01), and reduced level of GC(P<0.001). Conclusion H8, an 11β-HSD1 inhibitor, could reduce the hepatic GC level in db/db mice, thereby increasing the sensitivity of insulin.

Key words: Insulin resistance, db/db mouse, 11β-HSD1 inhibitor

中图分类号:

R965.1

李洪志,申永超,刘洁婷,赵孝金,初彦辉,袁晓环. 11β-HSD1抑制剂改善db/db小鼠胰岛素敏感性的实验研究[J]. 山东大学学报（医学版）, 2017, 55(10): 59-64.

LI Hongzhi, SHEN Yongchao, LIU Jieting, ZHAO Xiaojin, CHU Yanhui, YUAN Xiaohuan. An 11β-HSD1 inhibitor improves insulin sensitivity in db/db mice[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(10): 59-64.

参考文献

[1] Song A, Xu M, Bi Y, et al. Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults[J]. PLoS One, 2011, 6(4): e19228.
[2] 裴蕾蕾, 孙中华, 李哲, 等. 西格列汀联合大剂量胰岛素治疗2型糖尿病的临床观察[J]. 山东大学学报(医学版), 2015, 53(2): 39-42. PEI Leilei, SUN Zhonghua, LI Zhe, et al. Effects of sitagliptin combined with high-dose insulin on type 2 diabetes mellitus[J]. Journal of Shandong University(Health Sciences), 2015, 53(2): 39-42.
[3] 李涛, 傅继华, 王天莹. 糖皮质激素诱导胰岛素抵抗的研究进展[J]. 海峡药学, 2015, 27(5): 1-5. LI Tao, FU Jihua, WANG Tianying. Research progress on glucocorticoid-induced insulin resistance[J]. Strait Pharmaceutical Journal, 2015, 27(5):1-5.
[4] Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes[J]. J Clin Endocrinol Metab, 2003, 88(1): 285-291.
[5] 阮莉莉, 邹朝春. 11β-羟基类固醇脱氢酶与代谢综合征的相关性[J]. 上海交通大学学报(医学版), 2014, 34(6): 924-928. RUAN Lili, ZOU Chaochun. Correlation between 11β-hydroxysteroid dehydrogenase and metabolic syndrome[J]. Journal of Shanghai Jiaotong University Medical Science, 2014, 34(6): 924-928.
[6] 陈玉鹏, 黄芳. 中药活性成分治疗糖尿病胰岛素抵抗的机制研究进展[J]. 药学进展, 2016, 40(3): 197-204. CHEN Yupeng, HUANG fang. Research progress on the mechanisms of active ingredients from traditional chinese medicines in treatment of diabetic insulin resistance[J]. Prog Pharm Sci, 2016, 40(3): 197-204.
[7] Yuan X, Li H, Bai H, et al. Synthesis of novel curcumin analogues for inhibition of 11beta-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties[J]. Eur J Med Chem, 2014, 77: 223-230.
[8] Stulnig TM, Waldhäusl W. 11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes[J]. Diabetologia, 2004, 47(1): 1-11.
[9] da Rocha Junior LF, Rêgo MJ, Cavalcanti MB, et al. Synthesis of a novel thiazolidinedione and evaluation of its modulatory effect on IFN- γ, IL-6, IL-17A, and IL-22 production in PBMCs from rheumatoid arthritis patients[J]. Biomed Res Int, 2013: 926060.
[10] Rahimi-Madiseh M, Heidarian E, Kheiri S, et al. Effect of hydroalcoholic Allium ampeloprasum extract on oxidative stress, diabetes mellitus and dyslipidemia in alloxan-induced diabetic rats[J]. Biomed Pharmacother, 2017, 86: 363-367.
[11] Morgan SA, McCabe EL, Gathercole LL, et al. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess[J]. Proc Natl Acad Sci U S A, 2014, 111(24): E2482-2491.
[12] 刘永贵,解学星,吴疆,等. 治疗2型糖尿病的新靶点药物研究进展[J].现代药物与临床, 2015, 30(2): 222-227. LIU Yongkui, XIE Xuexing, WU Jiang, et al. Research progress on drugs with new targets in treatment of type 2 diabetes[J]. Drugs & Clinic, 2015, 30(2): 222-227.
[13] 崔同军, 叶磊, 辛婧. 11β-羟基类固醇脱氢酶通过改变糖皮质激素活性参与机体多个病理环节[J]. 医学综述, 2013, 19(1): 40-42. CUI Tongjun, YE Lei, XIN jing. 11β-HSD involved in pathological link through the conversion of glucocorticoid[J]. Medical Recapitulate, 2013, 19(1):40-42.
[14] Paterson JM, Morton NM, Fievet C, et al. Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice[J]. Proc Natl Acad Sci U S A, 2004, 101(18): 7088-7093.
[15] Morgan SA, Sherlock M, Gathercole LL, et al. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle[J]. Diabetes, 2009, 58(11): 2506-2515.
[16] Oh H, Jeong KH, Han HY, et al. A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models[J]. Eur J Pharmacol, 2015, 768: 139-148.
[17] Okazaki S, Takahashi T, Iwamura T, et al. HIS-388, a novel orally active and long-acting 11β-hydroxysteroid dehydrogenase type 1 inhibitor, ameliorates insulin sensitivity and glucose intolerance in diet-induced obesity and nongenetic type 2 diabetic murine models[J]. J Pharmacol Exp Ther, 2014, 351(1): 181-189.
[18] Anderson A, Walker BR. 11β-HSD1 inhibitors for the treatment of type 2diabetes and cardiovascular disease[J]. Drugs, 2013, 73(13): 1385-1393.
[19] Byun SY, Shin YJ, Nam KY, et al. A novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, UI-1499[J]. Life Sci, 2015, 120: 1-7.
[20] Bengmark S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases[J]. JPEN J Parenter Enteral Nutr, 2006, 30(1): 45-51.

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