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60 years of Metformin - what have we learnt?

Dr Chee L Khoo

Metformin belongs to the biguanide class of drugs which originates from Galega officinalis. Galega officinalis has been used in folk medicine for centuries and contain compounds related to guanidine, a substance shown to decrease blood glucose. However, the compounds were too toxic for human use. Guanidine was evaluated in unsuccessful clinical trials in the 1920-30s. Less toxic derivatives were investigated around that time including the biguanides. This led to the discovery of metformin. Cell

Metformin was first described in the scientific literature in 1922 by Emil Werner and James Bell. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. This result was completely forgotten and was soon overshadowed by insulin. French physician, Jean Sterne reawakened interest in metformin in 1957. He had noted the fact that flumamine (metformin hydrochloride) lowered blood glucose in influenza patients (in whom this drug was being used as an anti-influenza agent).

Metformin and the Liver

Metformin’s effects on the liver are widely known, reducing hepatic gluconeogenesis and improving insulin sensitivity.  The molecular mechanism of the effects on the liver is still unclear. Metformin accumulates within mitochondria to concentrations up to 1000-fold higher than in the extracellular medium. It is thought that metformin inhibit mitochondrial Respiratory Chain Complex 1 which increases ADP:ATP and AMP:ATP ratios. Changes in the ratios in turn switches off gluconeogenesis (GN) via the following mechanisms:

  • Acutely via Fructose 1,6-bisphosphate (FBP)
  • Via activated AMP Protein Kinase (AMPK)
  • Via reduction in cAMP which inhibit glucagon related GN

Activated AMPK also inhibit fat synthesis and increase fat oxidation by direct phosphorylation of the two isoforms of acetyl-CoA carboxylase (ACC1/ACC2). Reduction of fat in the liver increases insulin sensitivity.


We know that metformin reduces gut uptake of glucose and hence, reduce hyperglycaemia. From human genetic studies, T2D patients who has a genetic impairment in hepatic uptake of metformin, metformin’s efficacy in reducing HbA1c is not affected. Further, a delayed-release metformin that is largely retained in the gut, with minimal systemic absorption, is as effective at lowering blood glucose as the standard immediate-release formulation in individuals with type 2 diabetes.

Metformin’s action on the gut is believed to include:

  • Increase colonic uptake and metabolism of glucose (i.e. without absorbing glucose into plasma)
  • Increase GLP1-RA – immediate release and delayed release which reduce glucose by increasing insulin secretion as well increase signalling to the brain (see below)
  • Activated AMPK which increase brain neurotransmitter signalling which affect hepatic glucose metabolism via efferent vagal nerve (gut-brain-liver axis)
  • Favourable change in intestinal microbiome

Metformin’s function may be partly explained by its effect on the human microbiota (e.g. decreased Intestinibacter levels, increased Caenorhabditis elegans lifespan) and gut metabolome (e.g. increased butyrate synthesis), although the precise mechanisms for these changes are yet to be determined.

Metformin and inflammation and ageing

Metformin can reduce diabetes risk in those aged 60 years or over, and also that ageing outcomes, such as frailty and impaired physical and cognitive function, are improved with its use. Metformin is thought to reduce DNA damage by reducing inflammation and reactive oxygen species. It also reduce ceramides, which contribute to reduced myoblast numbers in the elderly, may also help to improve tissue health and function.

Metformin and Cancer

Data from epidemiological studies suggest that metformin may reduce cancer incidence and mortality. Two main routes are proposed to contribute to metformin’s anti-neoplastic activity: (1) an indirect route via a reduction in insulin, which may slow tumour proliferation in individuals with hyper-insulinaemia; and (2) reduction of energy consumption in pre-neoplastic and neoplastic cells via direct action on respiratory Complex I of the electron transport chain.

Side effects of Metformin

We all know about the GI side effects of metformin. The side effects may simply relate to the high concentration of metformin in intestinal enterocytes, potentially explaining why slow-release formulations of metformin, which disperse slowly and reduce local luminal metformin concentrations, reduce GI intolerance. Other alternative mechanisms cited include stimulation of serotonin release from enterochromaffin cells or reduction of serotonin transport via the serotonin transported, SERT. A third mechanism of of intolerance may be due to changes in the intestinal microbiome.

By understanding the mechanisms by which metformin work, we might be able to harness the full potential of the drug. It might also increase our understanding on how to reduce the GI side effects of metformin.


  • Graham Rena1 & D. Grahame Hardie2 & Ewan R. Pearson. The mechanisms of action of metformin. Diabetologia (2017) 60:15771585
  • Marshall, S.M. Diabetologia (2017) 60: 1561.
  • Bailey, C.J. Diabetologia (2017) 60: 1566.

The views expressed are views of the authors and do not necessarily represent the views of the board of SSW GP Link

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