MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

Abstract

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently -despite elusive mechanisms of action -bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

“…emerged as new targets for pharmacological agents (2,3). TGR5 activation has been linked to increased energy expenditure in muscle and brown adipose tissue, immunosuppressive effects in immune cells, and -perhaps most importantly in the present context -secretion of intestinal L cell satiety products such as peptide YY (PYY) and the incretin hormone glucagon-like peptide-1 (GLP-1) (2,4).…”

Importance of the bile acid receptors in different metabolisms

“…Stimulation of Glucagon Like Peptide 1 (GLP 1) released from incretin peptides as a result of TGR5 receptor stimulation in intestinal L-cells may be shown as a concrete example of the relationship between bile acids and diabetes. GLP1 is required to improve blood sugar by stimulating insulin secretion and suppressing the release of glucagon [10]. FXR expression in pancreatic β-cells is important for the effect of bile acids on glucose metabolism [11].…”

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“…Medications used in the treatment of dyslipidemia that sequester bile acids have an important effect on the metabolism and on glycemic control in T2DM patients, and today these drugs are considered a therapeutic option for this disease [140,142]. In addition to the effects on bile acids, these medications change intestinal transit, improve the composition of the gut microbiota and increase the secretion of GLP-1 in L cells which also has an important implication in glycemic control in T2DM patients that use this type of medication [143] . In the clinical practice, questions remain about the beneficial metabolic effects of natural products as well as other possible stimulants of GLP-1.…”