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

目的探讨G蛋白偶联受体(GPR) 40激动剂SZZ15-11的抗糖尿病作用及机制。方法采用基于荧光素酶报告基因的转录激活检测方法考察化合物的GPR40激活作用;用小鼠原代胰岛评价化合物的促胰岛素分泌能力;用正常ICR小鼠单次给药,评价其对血糖、血胰岛素和胰高血糖素样肽-1分泌及胃排空的影响,采用自发2型糖尿病KKAy小鼠模型长期给药,评价其对血糖的影响。结果化合物SZZ15-11对GPR40激动的EC_(50)为1. 2μmol·L^(-1),在10μmol·L^(-1)浓度下可使高葡萄糖(16. 8 mmol·L^(-1))条件下原代胰岛的胰岛素分泌增加61. 1%(P <0. 05);单次给予该化合物(50 mg·kg^(-1))可显著降低正常ICR小鼠口服葡萄糖负荷后血糖的水平(P <0. 05),使血糖曲线下面积(AUC)下降13. 1%,使正常小鼠葡萄糖刺激的胰岛素分泌增加46. 6%(P <0. 05);此外还可显著延缓正常小鼠胃排空速率,使小鼠血清对乙酰氨基酚浓度-时间曲线下面积降低(P <0. 05);在50和100 mg·kg^(-1)剂量下,能使正常小鼠葡萄糖负荷后的血GLP-1水平增加(P <0. 05);自发性2型糖尿病KKAy小鼠连续灌胃(50和100 mg·kg^(-1)) 4周,其空腹血糖显著降低(P <0. 05),糖化血红蛋白水平降低(P <0. 01和P <0. 05)。结论新型GPR40激动剂SZZ15-11可葡萄糖依赖性地促进胰岛素和GLP-1分泌,从而改善2型糖尿病模型小鼠的糖代谢,是一个潜在的抗糖尿病候选药物,值得进一步研究。

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 1.2μmol·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 of50 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.