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.