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.

The effects of metformin on gut microbiota and the immune system as research frontiers

“…There is additional complexity in relation to factors that influence the gut metformin concentration following oral ingestion [27]. It is noteworthy that metformin concentration in the gut lumen can be over 100-fold that present in serum, implying that mechanisms of action requiring high millimolar concentrations that are not achieved systemically [28] may be relevant to effects on the microbiota.…”

“…These may include alterations in bile acid physiology, enteric hormones (reviewed in [27]), and effects on duodenal AMPK signalling that contribute to suppression of hepatic gluconeogenesis [33]. While recent work has provided clear evidence that metformin alters gut microbiota, the classic mechanisms of action such as inhibition of gluconeogenesis also remain relevant to its efficacy in treatment of type 2 diabetes, and further research is needed to estimate the proportion of the benefit of metformin attributable to changes in gut microbiota.…”

60 years of metformin use: a glance at the past and a look to the future

“…That it inhibits hepatic gluconeogenesis is probably beyond doubt, but exactly how it does so is unclear. Whether other actions on the gastrointestinal tract and perhaps even a gut-brain-liver axis are more important is hotly debated [11]. Furthermore, evidence that metformin actually alters the underlying diabetes disease process is lacking.…”

Metformin: clinical use in type 2 diabetes

“…These side effects may relate to drug accumulation in the enterocytes of the small intestine. Slow-release formulations (extended-release metformin [metformin XR]) are associated with fewer GI symptoms [33].…”