Page 152 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
TGR5,41 thus bile acid sequestrants increase the postprandial GLP-1 response by promoting the delivery of bile acids to the distal intestine where L-cell density is higher. Similarly, 2-week oral administration of an inhibitor of the ileal sodium/ bile acid cotransporter in diabetic rats decreased intestinal bile acid reabsorption and increased faecal excretion of bile acids.57 Glucose concentrations during an oral glucose tolerance test were dose-dependently lowered, accompanied by greater GLP-1 and insulin secretion.57
Clinical data
In human beings, bile acid sequestering agents have been reported to lower plasma glucose concentrations, although the causal mechanisms probably involve more than TGR5 activation alone.28,56,58 Two clinical studies in patients with type 2 diabetes given bile acid sequestrant therapy used plasma GLP-1 concentration as an endpoint and both reported an increase in GLP-1 secretion.59 However, Brufau and colleagues28 found no correlation between the effects of 6 weeks of sequestrant therapy on glucose metabolism and various parameters of bile acid metabolism in patients with type 2 diabetes, or in healthy controls. Inhibition of the ileal sodium/bile acid cotransporter in human beings actually increases peak GLP-1 concentrations, in accordance with higher luminal bile acid concentrations that activate TGR5.60
In conclusion, although rodent studies suggest that bile acid-mediated TGR5 signalling strongly increases GLP-1 secretion and insulin release, corresponding evidence for these mechanisms in human beings does not exist. The distal intestinal L cells, where Tgr5 is expressed abundantly, are the most potent sites of bile acid-induced GLP-1 secretion. However, orally administered bile acids induce minimal GLP-1 secretion, with almost no effect on glucose and insulin concentrations.36,61 Here, the postprandial mechanisms in humans (interplay of nutrients, bile acids, incretins, and gastrointestinal transit time) are complex and variable. Rates of gastric emptying differ between species and could play a role in the differential effects seen with bile acid sequesterant-based treatments. Other species differences may also contribute to the different effects seen with such treatments between species.
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