Bile Acid Injection Regulated Blood Glucose in T2DM Rats Via the TGR5/GLP-1 Rather than FXR/FGF15 Pathway.

Background and Aims: Type 2 Diabetes mellitus (T2DM) has reached an epidemic status worldwide. Targeting bile acid signaling has therapeutic potential for treating T2DM. However, the effect of bile acid on T2DM and related mechanisms remains unclear. Here, we explored the role of bile acid in T2DM and elucidated the mechanisms involved. Methods: We established an STZ-induced rat model of T2DM and divided it into an bile acid-treated group and saline control group according to the random number table method. We incubated the bile acid-treated group with human bile acid via middle small intestine intubation and the saline control group was incubated with the same amount of normal saline. We compared the fasting body mass, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h-PG), fasting plasma insulin (FINS), fasting plasma triglyceride (TG), cholesterol, and total bile acid levels between the two groups one week before surgery and one to four weeks after surgery. Mechanically, Western blot, IHC, and ELISA assays were employed to detect the effect of bile acid on the TGR5/GLP-1 and FXR/FGF15 pathways. Results: Bile acid injection could increase the FINS level and decrease the 2h-PBG level of T2DM rats. In addition, bile acid injection did not affect FBG, fasting body mass, TG, CH, and total bile acid. At the same time, bile acid injection could activate the TGR5/GLP-1 pathway but could not influence the FXR/FGF15 pathway. Conclusion: Bile acids treatment promotes glucose homeostasis in the STZ-induced T2MD rat model via the following mechanism by activating the TGR5/GLP-1 signaling pathway rather than FXR/FGF15 pathway to improve glucose tolerance and thus achieve glucose homeostasis. The bile acid/TGR5/GLP-1 signaling pathway may be a crucial mechanism of controlling the blood glucose of T2DM rats, and TGR5/GLP-1 pathway may constitute novel targets for treating T2DM.