Sitagliptin improves glucose and lipids metabolism by regulating hepatic transcription factor phosphorylation-forkhead box O1 in diabetic KKAy mice
10.13699/j.cnki.1001-6821.2015.03.015
- VernacularTitle:磷酸西格列汀改善2型糖尿病 KKAy小鼠糖脂代谢及作用机制探讨
- Author:
Shuai-Nan LIU
1
;
Quan LIU
;
Shao-Cong HOU
;
Yue WANG
;
Zhu-Fang SHEN
Author Information
1. 中国医学科学院、北京协和医学院 药物研究所天然药物活性物质与功能国家重点实验室
- Keywords:
sitagliptin;
diabetic KKAy mice;
forkhead box O1;
gluconeogenesis;
fatty acid synthetase
- From:
The Chinese Journal of Clinical Pharmacology
2015;(3):206-211
- CountryChina
- Language:Chinese
-
Abstract:
Objective To evaluate the effects of the sitagliptin ( Sita) on glucose and lipids metabolism in type 2 diabetic KKAy mice.Methods Female diabetic KKAy mice selected by insulin tolerance test ( ITT) were divided into two groups.Model group ( Mod) was orally administered by gavage with water, Sita group at a dose of 15 mg· kg-1 · d -1 for about 90 days.ITT, glucose tolerance tests ( OGTT ) , intraperitoneal sodium pyruvate tolerance test were determined.Fasting plasma lipids, glucose, insulin levels and hepatic lipids contents were detected at the end of treatment.Pancreas morphology changes andβcell mass were evaluated by hematoxylin-eosin, insulin and glucagon stainning.The changes of protein expression in the liver were also analyzed by Western Bolt.Results Sita significantly improved insulin sensitivity, glucose intolerance and gluconeogenesis in diabetic KKAy mice.Fasting plasma glucose were decreased and insulin levels increased after 90 days Sita treatment (P<0.05, P <0.001).In addition, lipid profiles such as plasma triglyceride (TG, P<0.01), total cholesterol (TC, P<0.01), high density lipoprotein cholesterol ( HDC-C, P<0.01) and low densi-ty lipoprotein cholesterol ( LDL-C, P<0.01 ) levels and TC contents ( P<0.05 ) were also significantly diminished after Sita treatment.It was shown that Sita up-regulated the hepatic protein expression of phosphorylation-forkhead box O1 (phospho-FoxO1, P<0.01).Moreover, the protein expres-sion of gluconeogenesis related glucose-6 -phosphatase ( G6 P ) and phosphoenolpyruvate carboxykinase ( PEPCK ) were decreased in Sita group ( P<0.01, P<0.001) , and fatty acid synthesis related fatty acid synthase ( FAS) were also decreased ( P<0.001).Conclusion These results indicated that chronic administration of Sita improved dyslipi-demia and glucose homeostasis in diabetic KKAy mice, which is related to up-regulation of the hepatic expression of phospho-FoxO1 , which involved in gluconeogenesis and lipid metabolism.
