Hypoglycemic activity of CDCA (chenodeoxycholic acid) and GW4064 in type I and type II diabetic mouse model systems

Abstract

Farnesoid X receptor (FXR) is an orphan nuclear receptor that plays roles in diverse metabolic pathways including blood glucose. Previously we tested a signal transduction pathway of the phosphoinositide 3‐kinase (PI3K) pathway in in vitro model. In HepG2 cells and Caco‐2 cells, FXR in the presence of GW4064 (synthetic FXR agonist) and CDCA (chenodeoxycholic acid, physiological FXR agonist) enhanced activity of PI3K in FXR:PI3K immunocomplex that led to increase in glucose (GLC) uptake and glycogen synthase (GS) activity. However, positive effects on PI3K were reversed in the presence of wortmannin. We also confirmed that in vivo effects of FXR were comparable to those of insulin in mouse models. GW4064 reversed hyperglycemia in Db/Db mice in vivo. In addition, we found the comparable hypoglycemic effects of FXR in the C57BL/6 mice which were treated with streptozotocin that resulted in type I diabetic hyperglycemia. Time course and levels of antihyperglycemic effects of GW4064 were comparable to those of insulin. Accordingly, we report insulin‐mimetic action of FXR both in vitro and in vivomodel systems.