Inverse agonist of nuclear receptor ERRgamma mediates antidiabetic effect through inhibition of hepatic gluconeogenesis

Cited 47 time in scopus
Metadata Downloads
Title
Inverse agonist of nuclear receptor ERRgamma mediates antidiabetic effect through inhibition of hepatic gluconeogenesis
Author(s)
D K Kim; Gil Tae Gang; D Ryu; M Koh; Y N Kim; S S Kim; J Park; Yong Hoon Kim; T Sim; I K Lee; C S Choi; S B Park; Chul Ho Lee; S H Koo; H S Choi
Bibliographic Citation
Diabetes, vol. 62, no. 9, pp. 3093-3102
Publication Year
2013
Abstract
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder with diverse pathological manifestations and is often associated with abnormal regulation of hepatic glucose production. Many nuclear receptors known to control the hepatic gluconeogenic program are potential targets for the treatment of T2DM and its complications. Nevertheless, the therapeutic potential of the estrogen-related receptor γ (ERRγ) in T2DM remains unknown. In this study, we show that the nuclear receptor ERRγ is a major contributor to hyperglycemia under diabetic conditions by controlling hepatic glucose production. Hepatic ERRg expression induced by fasting and diabetic conditions resulted in elevated levels of gluconeogenic gene expression and blood glucose in wild-type mice. Conversely, ablation of hepatic ERRγ gene expression reduced the expression of gluconeogenic genes and normalized blood glucose levels in mouse models of T2DM: db/db and diet-induced obesity (DIO) mice. In addition, a hyperinsulinemic-euglycemic clamp study and longterm studies of the antidiabetic effects of GSK5182, the ERRgspecific inverse agonist, in db/db and DIO mice demonstrated that GSK5182 normalizes hyperglycemia mainly through inhibition of hepatic glucose production. Our findings suggest that the ability of GSK5182 to control hepatic glucose production can be used as a novel therapeutic approach for the treatment of T2DM.
ISSN
0012-1797
Publisher
Amer Diabetes Assoc
DOI
http://dx.doi.org/10.2337/db12-0946
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.