Page 150 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
showed that ursodeoxycholic acid (a bile acid found predominantly in bear bile, a synthetic version of which is used to treat gallstones and liver diseases such as primary biliary cirrhosis) mixed with a meal increased postprandial plasma GLP- 1 and decreased plasma glucose concentrations. Insulin concentrations remained unchanged, indicating a higher ratio of insulin to glucose, and thus increased insulin secretion. In another study,36 an intragastric infusion of 1·25 g unconjugated chenodeoxycholic acid slightly increased plasma GLP-1 concentrations without effects on glucose and insulin concentrations. Bile acids are ligands for multiple receptors, so whether these effects are purely TGR5-mediated is unclear.
Only one human trial involving a specific TGR5 agonist has been published to date. The GlaxoSmithKline (Brentford, London) compound SB-756050 is a specific TGR5 agonist.46 Four overlapping cohorts received either placebo, SB- 756050 15 mg, 50 mg, or 100 mg once a day, or 200 mg twice a day for 6 days. However, short-term daily use did not dose-dependently affect plasma glucose, GLP-1, or other endpoints in a consistent fashion. Low, but not higher doses of the compound caused an unexpected increase in glucose excursions in patients with type 2 diabetes after an oral glucose challenge.46 At intermediate doses the concentration of incretin hormones increased, but no effect on glucose was shown. This phenomenon was not seen at lower and higher doses. The authors attribute the variability to differential activation of proximal and more distant TGR5 targets in the gut. The other known specific agonists include the cholic acid derivative 6α-ethyl-23(S)-methylcholic acid (INT777, a compound discovered in 2009 that has been used in all landmark animal studies2) and two groups of non-bile acid-related compounds known as 3-aryl-4-isoxazolecarboxamides47 and 2-aryl-3-aminomethylquinolines.39 None of these compounds have yet been tested in clinical trials.
The notion of bile acid-induced GLP-1 secretion via TGR5 has also gained support from studies in patients with obesity and type 2 diabetes undergoing RYGB surgery, in which the stomach is restricted to a small pouch and is diverted to empty more distally on the mid-jejunum, bypassing the duodenum and much of the jejunum. Type 2 diabetes is resolved in 78% of these patients postoperatively, alongside substantial increases in postprandial GLP-1, PYY, and early-phase insulin secretion.48−51 Postprandial bile acid concentrations, which are lower in patients with obesity than in those who are not obese,52 are restored after RYGB
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