Page 146 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
Here, we review physiological and pharmacological studies of TGR5 in relation to metabolism, and differences in animal and human bile acid physiology (panel 2). We focus on the translation of preclinical animal studies and in-vitro research to clinically significant improvements in the treatment of disorders such as obesity and type 2 diabetes.
TGR5 in GLP-1 secretion and glucose homoeostasis
Background
The association between human bile acid and glucose metabolism originated from the observation that patients with type 2 diabetes have increased bile acid pools.27 In a study of bile acid kinetics from 2010,28 patients with type 2 diabetes were shown to have increased concentrations of deoxycholic acid in the bile acid pool, at the expense of chenodeoxycholic acid. Additionally, cholic acid synthesis was upregulated, whereas the total pool size remained the same, suggesting increased conversion of cholic acid by the gut microbiota. Other studies showed similar increases in deoxycholic acid pool size in patients with type 2 diabetes.29
One of the links between bile acids and glucose homoeostasis is TGR5-mediated GLP-1 secretion (figure 1).2 Subcutaneously injected GLP-1 receptor agonists have been part of the antidiabetic repertoire for the past 10 years. GLP-1 is a peptide hormone secreted by specialised enteroendocrine cells (L cells) in response to meal ingestion.30 GLP-1 amplifies glucose-dependent insulin secretion, inhibits glucagon secretion, and reduces gastric emptying and appetite.31 However, clinical application of GLP-1 has not delivered the impact on diabetes care that was predicted on the basis of its effect in animal studies.32 One theory is that by subcutaneously delivering exogenous GLP-1 receptor agonists, local effects of GLP-1 near its site of secretion in the liver—such as stimulation of local afferent nerve terminals that project to the hypothalamus from the lamina propria, the portal vein, and the liver—are not achieved.33 Because GLP-1 function is thought to be at least partially dependent on this local neural activation, an attempt to increase endogenous GLP-1 secretion is an attractive strategy for the treatment of type 2 diabetes. One approach is to potentiate stimulation of GLP-1 release with agents that are neither deposited (ie, bile acids or synthetic TGR5 receptor analogues) nor absorbed (ie, bile acid binding sequestrants); this approach might
144