中国临床药理学杂志2019，Vol.35Issue(8)：780-784,5.DOI:10.13699/j.cnki.1001-6821.2019.08.016
新型G蛋白偶联受体40激动剂SZZ15-11的抗糖尿病作用及机制初探
Primary exploration on antidiabetic effect and mechanism of novel GPR40 agonists SZZ15 -11
摘要
Abstract
Objective To evaluate the anti-diabetic effect and mechanism of a novel G protein coupled receptor 40 (GPR40) agonist SZZ15 -11. Methods Transactivation assay based on luciferase reporter gene was performed to explore the agonist activity of the compounds to GPR40. The primary mouse islets were used to evaluate the insulinotropic ability of the compounds. After oral administration of the tested compounds once,the plasma concentrations of glucose,insulin and glucagon like peptide 1 (GLP-1) were determined in normal mice followed oral glucose loading. The effect of the compounds on gastric emptying was also evaluated in normal mice given orally once. In spontaneous type 2 diabetic KKAy mice orally administrated compound for one month,the plasma glucose concentration were measured. Results The compound SZZ15 -11 activated GPR40 with EC50 of 1. 2 μmol·L-1. It significantly promoted glucose-stimulated insulin secretion (GSIS) in mouse primary islets by 61. 1％ (P < 0. 05) under high glucose conditions (16. 8 mmol·L-1). Oral administration of SZZ15-11 (50 mg·kg-1) once decreased the plasma concentrations of glucose in normal ICR mice followed oral glucose loading,reduced the area under the curve (AUC) by 13. 1％ (P < 0. 05) ,and increased insulin secretion after oral glucose load by 46. 6％ (P < 0. 05). SZZ15-11 also obviously delayed the gastric emptying rate in normal mice at a dose of 50 mg·kg-1,which reduced the area of the serum acetaminophen concentration-time curve (P <0. 05). At two doses of 50 and 100 mg·kg-1,plasma GLP -1 levels in normal mice after oral glucose load was increased (P <0. 05). In the type 2 diabetic KKAy mice administrated with SZZ15 -11 at the dose of 50 and 100 mg·kg-1 for 4 weeks,the fasting blood glucose was decreased significantly decreased (P < 0. 01 and P < 0. 05). Conclusion The novel GPR40 agonist SZZ15 -11 promoted glucose-dependent insulin and GLP-1 secretion,thus ameliorated glucose metabolism in type 2 diabetic mice. It will be a potential anti-diabetic compound candidate which is worth of further exploration.关键词
G蛋白偶联受体40/2型糖尿病/胰高血糖素样肽-1/葡萄糖刺激的胰岛素分泌Key words
G protein coupled receptor 40/type 2 diabetes mellitus/glucagon like peptide 1/glucose-stimulated insulin secretion分类
医药卫生引用本文复制引用
周甜,申竹芳,李彩娜,环奕,刘率男,刘泉,孙素娟,李荣翠,潘璇,刘站柱..新型G蛋白偶联受体40激动剂SZZ15-11的抗糖尿病作用及机制初探[J].中国临床药理学杂志,2019,35(8):780-784,5.基金项目
国家"重大新药创制"科技重大专项基金资助项目(2018ZX09711001-003 -005) （2018ZX09711001-003 -005）
中国医学科学院医学与健康创新工程基金资助项目(2017-I2M-1 -010) （2017-I2M-1 -010）
北京协和医学院研究生创新基金资助项目(2017 -1007 -09) （2017 -1007 -09）
