Page 147 - Human Bile Acid Metabolism: a Postprandial Perspective

prove superior in controlling type 2 diabetes and obesity compared with other incretin-based treatment strategies. This new treatment concept has gained support from preclinical and clinical studies.2,34−36
Preclinical data
The bile acid–TGR5–GLP-1 pathway was first explored by Thomas and colleagues,2 who showed that glucose tolerance was improved in transgenic mice overexpressing Tgr5, and this improvement was accompanied by increased GLP-1 and insulin secretion. Adding a selective TGR5 agonist to a high-fat diet improved glucose tolerance, insulin and GLP-1 secretion, and insulin sensitivity in both liver and muscle of Tgr5-Tg mice, but not in Tgr5 knockout (Tgr5–/–) mice.2 The insulin-sensitising effect might be explained by the difference in bodyweight, because GLP-1 is not known to directly affect insulin sensitivity.
Enteral administration of several specific TGR5 agonists increases GLP-1
secretion and glucose tolerance.3,37−40 Stimulation of TGR5 on the basolateral side
of the L cell has been suggested as an important mediator of bile acid-induced
GLP-1 secretion.11,37 Rectal administration of taurocholic acid increased Glp-
1 concentrations in the portal vein of wild-type mice but not in Tgr5–/– mice,
showing that luminal bile acid administration can induce TGR5-mediated GLP-1
secretion.41 However, studies now show that TGR5 activation occurs basolaterally
after transport across the enterocyte. Ullmer and colleagues37 used a potent non-
absorbable TGR5 agonist in monkeys and rodents to show that incretin release only 8 occurred after intravenous administration and not after enteral administration.
Another TGR5-dependent pathway that might explain increased insulin secretion and improved glucose tolerance in mice after oral administration of bile acids is the direct effects on pancreatic β cells, independent of Glp-1. Tgr5 is expressed in mouse and human β cells, and activation by lithocholic acid increased insulin secretion to a similar extent under both basal and glucose-stimulated conditions, suggesting that the effect is not glucose dependent.12 The data from these preclinical trials show that bile acids increase both GLP-1 and insulin secretion, which might have a valuable effect in patients with type 2 diabetes.
Review: clinical relevance of TGR5
145