Page 151 - Human Bile Acid Metabolism: a Postprandial Perspective

surgery.53 Patti and colleagues54 showed that fasting bile acid plasma concentrations were negatively correlated to postprandial glucose and positively correlated to postprandial GLP-1 plasma concentrations in patients who had undergone RYGB surgery. The surgery might increase luminal bile acid delivery to the distal bowel and thereby enhance TGR5-mediated GLP-1 secretion with beneficial effects on glucose and insulin concentrations. Alternatively, the increased plasma bile acid concentrations could increase systemic TGR5 activation, leading to increased energy expenditure as described later in this Review. By contrast, Jørgensen and colleagues55 showed that although diabetes resolution occurs very rapidly (<1 week), postprandial bile acid concentrations only increase slowly in the months following the surgery, questioning an acute effect.
Generally, bile acids might contribute to GLP-1 and insulin secretion via TGR5, but there is no robust evidence that TGR5 activation contributes directly to increased insulin sensitivity in human beings (figure 3). Additionally, possible confounding factors related to food intake exist when comparing rodent biology to human biology, such as day versus night feeding cycles, feeding behaviour (meals vs grazing), and exposure to stress. As such, bile acid-based therapies for patients with type 2 diabetes to increase GLP-1 secretion seem promising, but require further study.
TGR5 and bile acid sequestrants 8
Preclinical data
Bile acid sequestrants are non-absorbable resins that bind negatively charged bile salts, and other negatively charged molecules, in the intestinal lumen. These complexes are then excreted in the faeces, diverting bile acids from the enterohepatic circulation. The reduced bile acid concentration in the enterohepatic circulation increases bile acid synthesis, which uses cholesterol as its substrate, ultimately lowering plasma cholesterol. In addition to combating dyslipidaemia, bile acid sequestrant therapy lowers HbA1c in patients with type 2 diabetes.56 In Tgr5–/– enteroendocrine cells from tissue explants and in Tgr5–/– mice, these metabolic improvements (ie, amelioration of dyslipidaemia and lower HbA1c) after bile acid sequestrant treatment have been shown to be dependent on TGR5-mediated GLP- 1 release.35,41 Bile acids bound to the sequestrant colesevelam are still able to activate
Review: clinical relevance of TGR5
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