Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization

• Intestinal BA sequestration lowers plasma glucose in type 2 diabetes.
• Interfering with entero-hepatic BA modulates the membrane TGR5 and nuclear FXR receptors.
• BA sequestration increases splanchnic glucose utilization via entero-hepatic FXR signaling.

Intestinal bile acid (BA) sequestration efficiently lowers plasma glucose concentrations in type 2 diabetes (T2D) patients. Because BAs act as signaling molecules via receptors, including the G protein-coupled receptor TGR5 and the nuclear receptor FXR (farnesoid X receptor), to regulate glucose homeostasis, BA sequestration, which interrupts the entero-hepatic circulation of BAs, constitutes a plausible action mechanism of BA sequestrants. An increase of intestinal L-cell glucagon-like peptide-1 (GLP-1) secretion upon TGR5 activation is the most commonly proposed mechanism, but recent studies also argue for a direct entero-hepatic action to enhance glucose utilization. We discuss here recent findings on the mechanisms of sequestrant–mediated glucose lowering via an increase of splanchnic glucose utilization through entero-hepatic FXR signaling.