Liver-Specific Overexpression of Gamma-Glutamyltransferase Ameliorates Insulin Sensitivity of Male C57BL/6 Mice.

Yang Long,Yumei Yang,Tao Chen,Haoming Tian,Dan Jia,Libin Wei

doi:10.1155/2017/2654520

Abstract

In the current study, we developed a liver-specific GGT-overexpressing mice model by rapid injection pLIVE-GGT vector through tail vein and investigated the effects of GGT elevation on glucose metabolism and insulin sensitivity. The serum GGT activity was significantly increased after 7 days of pLIVE-GGT1 vector delivery and lasted for about 3 weeks. GGT overexpression reduced the levels of GSSG and GSH in the liver and serum and had no effects on total antioxidative capacity in the liver, kidney, and skeletal muscle except for the pancreas. Increased GGT activity had no effect on the glucose tolerance but could facilitate blood glucose lowering after intraperitoneal insulin administration. The results of Western blotting showed that increased GGT activity enhanced insulin-induced AKT phosphorylation at Ser473. Furthermore, GGT inhibitor could attenuate the changes of insulin-induced blood glucose uptake and AKT phosphorylation in the liver. In summary, the present study developed a liver-specific GGT-overexpressing mice model and found that GGT elevation in short term had no effects on glucose metabolism but could increase insulin sensitivity through enhancing the activity of insulin signaling pathway.

Highlights

The prevalence of type 2 diabetes (T2D) is increasing worldwide, while the underlining mechanism is not fully elucidated
The GGT activities were significantly increased in the culture mediums and the cell lysates from COS7 cells which were transiently transfected with pcDNA3.1-ggt1KOZa but not with pcDNA3.1-ggt1-KOZg. These data indicated that the Kozak sequence ACCATGA, which was added in the recombinant vector pcDNA3.1-ggt1-KOZa, promoted more effective translation than the consensus GCCATGA in the vector pcDNA3.1-ggt1-KOZg
GGT transgenic mice models had been used to study osteoporosis and tumor metastasis [14, 15], but regrettably, no study focused on glucose metabolism

Summary

Introduction

The prevalence of type 2 diabetes (T2D) is increasing worldwide, while the underlining mechanism is not fully elucidated. Several prospective studies and meta-analyses suggested that gamma-glutamyltransferase (GGT), a previously recognized marker of alcoholic drinking and fatty liver, could predict the risk of T2D [1,2,3]. Such an association existed even when GGT was at physiologic level [4], in nonalcoholic drinkers and subjects without nonalcoholic fatty liver disease (NAFLD) [5, 6]. Increased GGT activity would result in altered levels of GSSG/GSH and overproduction of ROS, changing the oxidative status. Other studies showed that elevated serum GGT concentration could be associated with islet beta-cell function and/or insulin resistance [10, 11]

Methods

Results

Conclusion