Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1
Kaur, Achint × Patankar, Jay V de Haan, Willeke Ruddle, Piers Wijesekara, Nadeeja Groen, Albert K Verchere, C Bruce Singaraja, Roshni R Hayden, Michael R #
American Diabetes Association
Diabetes vol:64 issue:4 pages:1168-79
Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of sterol 12α- hydroxylase gene (Cyp8b1) results in complete absence of cholic acid (CA) and its derivatives. Here we investigate the impact of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, insulin sensitivity and β-cell function, mediated by absence of CA in Cyp8b1(-/-) mice. In addition, we show that reduced intestinal fat absorption in the absence of biliary CA leads to increased free fatty acids reaching the ileal L-cells. This correlates with increased secretion of the incretin hormone glucagon like peptide-1 (GLP-1). GLP-1 in turn increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1(-/-) mice. Thus, our data elucidate the importance of Cyp8b1 inhibition on regulation of glucose metabolism.