Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

Abstract

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro‐ and macrovascular complications. Metformin is usually the first‐line glucose‐lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose‐lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon‐like peptide 1 (GLP‐1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP‐1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose‐lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.

The Sensing Liver: Localization and Ligands for Hepatic Murine Olfactory and Taste Receptors

“…Notably, bitter chemicals have been shown to alter food intake via modulation of ghrelin ( Janssen et al, 2011 ), contribute to lipid metabolism ( Cancello et al, 2020 ), and accelerate microorganism clearance in the ciliated airway ( Shah et al, 2009 ). With respect to the liver, bile acids are extremely bitter substances ( Sansome et al, 2020 ), leading to speculation that some of the identified T2Rs respond to these steroid acids that are produced by the liver. Using both RNAscope and hepatic AML12 cell, we localized a total of 3 bitter T2Rs to hepatocytes, the parenchymal cells of the liver (Tas2r108 and via RNAscope and Tas2r135 and Tas2r143 in AML12 cells).…”

Bile Acids in Patients with Uncontrolled Type 2 Diabetes Mellitus – The Effect of Two Days of Oatmeal Treatment

“…Bile acid sequestration by BAS, -glucans or other fibres facilitates the transport of luminal BA to the distal L cell-rich parts of the intestine [34]. Interestingly, it is now recognized that metformin reduces intestinal BA resorption substantially, such that intraluminal BA induced GLP-1 secretion may, at least in part, account for its glucose-lowering effect [35]. However, a recent study showed that only the acute administration of CDCA increases plasma GLP-1 and glucagon concentrations in patients with T2DM and healthy controls while administration of colesevelam, or CDCA together with colesevelam, did not promote GLP-1 secretion or GLP-1-associated effects [36].…”

Statins and glycaemic control in type 2 diabetes: Are bile acids relevant?

“…When infused into various regions of the intestine, bile acids reduce glycaemic excursions following small intestinal glucose infusions and increase plasma levels of glucagon-like peptide-1 (GLP-1), an incretin hormone which potentiates insulin secretion, suppresses glucagon secretion, and slows gastric emptying. 12 The changes in bile acid circulation following bariatric surgery have been linked to improvement in glycaemic control. 12 In this regard, a reduction of luminal bile acids could contribute to impaired glucose tolerance, perhaps particularly after higher potency statins.…”

“…12 The changes in bile acid circulation following bariatric surgery have been linked to improvement in glycaemic control. 12 In this regard, a reduction of luminal bile acids could contribute to impaired glucose tolerance, perhaps particularly after higher potency statins. Notably, individual bile acids may bind preferentially to different receptors, mediating distinct biological functions 12 and that bile acid sequestrants (which increase gastrointestinal exposure to less soluble bile acids) have been shown to improve glucose control in T2D.…”

“…12 In this regard, a reduction of luminal bile acids could contribute to impaired glucose tolerance, perhaps particularly after higher potency statins. Notably, individual bile acids may bind preferentially to different receptors, mediating distinct biological functions 12 and that bile acid sequestrants (which increase gastrointestinal exposure to less soluble bile acids) have been shown to improve glucose control in T2D. 13 These observations have increased the complexity of the role of bile acids in glucose metabolism.…”