VALIDATION OF THE ROLES OF NOVEL DIABETES TARGET GENES

Abstract

Diabetes has become a major public health issue of the 21st century. Despite their capacity to successfully maintain normal whole-body glycemic control, no drug is currently effective in curing diabetes. Emerging data suggest both bile acids and gut microbiome as novel essential endogenous factors regulating host glucose metabolism. This thesis first found that BA-induced alteration of the gut microbiome in the absence of CYP8B1 may contribute to improved insulin sensitivity in mice, providing new information and validating Cyp8b1 inhibition as a potential therapeutic target for diabetes. Moreover, we described for the first time that, although humanizing the BA pool in mice results in increased human-like hydrophobic BAs, and subsequent increase in hepatotoxicity, a benefit in fat absorption, hepatic steatosis, and glucose metabolism is also observed, through a distinct CDCA-mediated signaling pathway. Further studies are needed to elucidate how circulating CDCA enhances the insulin signaling pathway in skeletal myotubes.