New insights into the anti-diabetic actions of metformin: from the liver to the gut

ABSTRACT

Introduction: Metformin is established as the first-line therapy for type 2 diabetes (T2DM), but its mode of action remains elusive. Elucidation of the mechanisms underlying the anti-diabetic action of metformin may have the potential to optimise its glucose-lowering efficacy and lead to the development of agents acting on novel targets for the management of type 2 diabetes.

Areas covered: This review highlights key pharmacokinetic features of metformin, summarises recent insights into its hepatic and gastrointestinal actions relevant to blood glucose homeostasis, and discusses the common gastrointestinal side effects of metformin. Literature concerning these areas was reviewed on PubMed.

Expert commentary: The mechanisms by which metformin improves glycaemic control in type 2 diabetes are complex. Although novel hepatic pathways continue to be reported in preclinical studies, there is a lack of human evidence for most of these. Considering the fundamental role of the gastrointestinal tract in the regulation of blood glucose homeostasis and pleiotropic actions of metformin on several gastrointestinal targets relevant to glycaemic control, the gut is likely to represent at least as important a site of metformin action as the liver in the management of type 2 diabetes.

KEYWORDS:

• Metformin
• hepatic glucose production
• glucose absorption
• incretin hormones
• bile salt
• gut microbiota

Declaration of interest

M. Horowitz has participated in the advisory boards and/or symposia for Novo Nordisk, Sanofi, Novartis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, and AstraZeneca and has received honoraria for this activity. C. K. Rayner has received research funding from Merck, Sharp & Dohme, AstraZeneca, Novartis, and Sanofi. T. Wu is supported by a Royal Adelaide Hospital Research Committee Early Career Fellowship. The authors’ work in this area has been supported by the National Health and Medical Research Council (NHMRC) of Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.