Bile acid signalling in type 2 diabetes and its co-morbidities

Bile acids (BAs) regulate several aspects of metabolism (lipid, glucose, and energy metabolism) by interacting with nuclear (such as FXR/NR1H4) and membrane-bound (such as TGR5/GPBAR1) receptors. BA signalling pathways are increasingly viewed as potential therapeutic targets for a wide range of (metabolic syndrome-related) diseases, including type 2 diabetes (T2D). This dissertation explores the molecular mechanisms by which BAs are associated with T2D, insulin resistance (IR), and their co-morbidities and how they may affect metabolic parameters that are frequently dysregulated in these (pathological) conditions. A mouse model with a BA composition similar to that of a human has been created and characterised. Cyp2c70-/- mice exhibit a sex-dependent cholangiopathy (particularly females). UDCA treatment completely restores this liver phenotype and BA sequestration with colesevelam ameliorates liver pathology in Cyp2c70-/- mice without affecting insulin sensitivity, accompanied by a decrease in the hydrophobicity of biliary BAs. Surprisingly, Cyp2c70-/- mice were protected from high-fat diet induced fatty liver disease. In a human study, no associations between BA composition and weight-loss-induced improvements in insulin sensitivity were detected. In conclusion, the results presented and discussed in this PhD dissertation indicate that BA composition and, consequently, BA hydrophobicity are important and must be considered when interpreting the effects of BAs on glucose metabolism and insulin sensitivity