Role of bile acid sequestrants in the treatment of type 2 diabetes

Figure 1 Possible mechanisms of the effects of bile acids and bile acid sequestrants on glucose and lipid metabolism. Bile acids activate farnesoid X receptor (FXR) activity in liver, which leads to increased small heterodimer partner (SHP) production that inhibits phosphoenolpyruvate carboxykinase (PEPCK) and therefore inhibits gluconeogenesis in liver. Bile acids also promote energy metabolism in brown adipose tissue and skeletal muscle via the G protein-coupled receptor 5 (TGR5) activation, and increase glucagon-like peptide-1 (GLP-1) secretion via TGR5 activation in L cells in the intestine. On the other hand, bile acid sequestrants (BASs) may decrease FXR activity in liver, and the resulting decrease in SHP production may cause activation of liver X receptor (LXR) activity. LXR activation inhibits PEPCK and therefore inhibits gluconeogenesis. BASs can also increase circulating GLP-1 levels. These mechanisms may explain the glucose-lowering effects of bile acids and BASs. Because bile acids decrease sterol regulatory element-binding protein 1c (SREBP1c) production due to increased SHP, bile acids decrease triglyceride (TG) levels. In contrast, indirect LXR activation by BASs can increase SREBP1c production and circulating TG levels. In the figure, solid and dotted lines respectively show promoting and inhibitory effects. CA: cholic acid; CDCA: chenodeoxycholic acid.