The mechanisms of action of metformin

Abstract

Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4342-z) contains a slideset of the figures for download, which is available to authorised users.

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

“…Reduction in hepatic glucose output is the principal action of metformin although its mechanism(s) have not been clearly identified. The previously held view that metformin reduces glucose synthesis via activation of AMPK has been challenged; recent data indicate that lowered hepatic glucose output with metformin may result from inhibition of electron transport in mitochondrial respiratory Complex I [29] (this is described in more detail in the commentary by Rena et al in this issue of Diabetologia [30]), as well as antagonism of glucagon action in the liver [31].…”

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

“…Metformin and AICAR both activate AMPK. Previous work, including experiments in which AMPK activity was genetically ablated, indicate that AMPK is not essential for regulation of HGP, although both drugs activate AMPK 13, 14, 15, 17, 18. In the current study, we used AMPK activation purely as a marker of drug entry into the cell.…”

“…Studies using cAMP analogues have shown previously that the T2D drug metformin and 5‐Aminoimidazole‐4‐carboxamide ribonucleoside (AICAR) repress cAMP‐stimulated hepatocyte glucose production (HGP) 13, 14, 15. Inside cells, AICAR is phosphorylated by adenosine kinase to form ZMP, which then mimics AMP to activate AMPK 16.…”

“…Inside cells, AICAR is phosphorylated by adenosine kinase to form ZMP, which then mimics AMP to activate AMPK 16. Metformin and AICAR are both activators of AMPK; however, earlier studies, including some carried out in mice where the catalytic subunits of AMPK are genetically ablated, demonstrated that suppression of HGP occurs independently of AMPK activation 13, 14, 15, 17, 18. Metformin is transported across hepatocyte cell membranes, at least in part, by an organic cation transporter (OCT) family of transporters 18, 19, 20.…”

Metformin: clinical use in type 2 diabetes

“…incorporation into the diabetes pharmacopeia. Interestingly, and despite this popularity, there still remains controversy about the drug's precise mechanism of action, although most data point to a reduction in hepatic glucose production being predominately involved (described further by Rena et al in this issue of Diabetologia) [4]; although, recent data suggests that some of the drug's effect may involve the stimulation of intestinal release of incretin hormones. Herein, we will review the most salient aspects of the clinical use of metformin in individuals with type 2 diabetes mellitus.…”