Primary exploration on antidiabetic effect and mechanism of novel GPR40 agonists SZZ15 -11
10.13699/j.cnki.1001-6821.2019.08.016
- VernacularTitle: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
- Author:
Tian ZHOU
1
;
Cai-Na LI
;
Yi HUAN
;
Shuai-Nan LIU
;
Quan LIU
;
Su-Juan SUN
;
Rong-Cui LI
;
Xuan PAN
;
Zhan-Zhu LIU
;
Zhu-Fang SHEN
Author Information
1. 中国医学科学院&北京协和医学院药物研究所
- Keywords:
G protein coupled receptor 40;
type 2 diabetes mellitus;
glucagon like peptide 1;
glucose-stimulated insulin secretion
- From:
The Chinese Journal of Clinical Pharmacology
2019;35(8):780-784
- CountryChina
- Language:Chinese
-
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.
