Metformin and the gastrointestinal tract

Abstract

Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.

Keywords: Bile acids; DPP-4; GLP-1; Gut/intestine; Lactate; Metformin; Microbiome; OCT1; Review; Serotonin; Uptake.

Fig. 1

Some of the actions of metformin within the GI tract. The upward arrows indicate increases. DPP4, dipeptidyl peptidase-4; FXR, farnesoid X receptor; FDG, fluorodeoxyglucose; GLP-1, glucagon-like peptide-1; OCT, organic cation transporter; PMAT, plasma membrane monoamine transporter; SERT, serotonin transporter

Fig. 2

Species abundance in the microbiome of women with type 2 diabetes (T2D) who are treated with metformin (x-axis) or who are not metformin treated (y-axis). Grey spots represent species that do not differ by metformin exposure. Coloured dots represent species differing by metformin exposure, with the colour representing the bacterial species shown in the key. Figure from Karlsson et al, Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103. Reproduced with permission from Nature Publishing Group