Investigation of the target of metformin

Lead Research Organisation: University of Dundee
Department Name: Cardiovascular and Diabetes Medicine

Abstract

Metformin, which is known chemically as a biguanide, took more than five decades to become one of humanity's most widely used medicines. It is the medicine of choice for type 2 diabetes and is under investigation for use in a much wider variety of diseases associated with age-related metabolic problems. Many of the beneficial clinical effects of metformin within the body are known but unfortunately it is still unclear how metformin triggers these effects and why it doesn't always work. This is the missing piece of the jigsaw that we are providing here. The approach in the work leading up to this proposal has been to modify the chemical structure of metformin, in order to work out which bits of metformin are required for its actions on the cells in our body. Our new finding is that metformin's effects are lost when we interfere with the drug's copper-binding properties. Metformin itself has been known to bind copper for over a century but our latest data suggests that metformin actually targets copper as a key part of its therapeutic effects, something we now wish to understand in more detail. An unusual and striking aspect of this interaction is that metformin forms unusual 'pseudoaromatic' structures with copper that actually change the shape of the metal. In simple terms, the key distinction between other known metal-binding drugs and metformin can be understood most easily by analogy with The Sun and The Wind in Aesop's fable for children, whose lesson is 'Persuasion is better than force'. Other drugs (The Wind) attempt to force metals out of protein binding sites simply because they bind the metal more strongly, while instead guileful metformin (The Sun) acts first by inducing the protein to loosen its grip on the metal by altering the metal coordination environment. Our research will determine whether this trick is important for effects of metformin on muscle and liver cells. By developing a better understanding of one of the agents currently available, this proposal will pave the way to the development of better agents against age-related metabolic disease in future.

Technical Summary

The biguanide metformin is the drug of choice for treatment of type 2 diabetes (T2D) and is under investigation for use in a variety of other age-related disease states. Used in T2D, metformin is associated with reduced risk of cardiovascular and other mortality when compared with other treatment regimes. Around one third of individuals prescribed metformin discontinue use shortly after starting the drug due to gastrointestinal side effects and therefore it would be highly desirable to develop metformin-like compounds with similar properties. Unfortunately however, the mechanism of action of metformin remains incompletely understood and the identity of its proximal target, which would greatly aid development of such drugs, is unknown. In the current work we wish to follow up new evidence that we have obtained that an important direct target of metformin is copper. Previously, we investigated how metal ions can modify the activity of drugs and in our preliminary studies we have gathered strong evidence that copper, whose interaction with metformin has been known for over a century, is required for specific cellular actions of metformin that are linked to its beneficial therapeutic effects. In the current study we aim to elucidate the precise role of copper in metformin action using unique chemical tools and a variety of techniques including western blotting, gene expression analysis and microscopy. This research will establish which effects of metformin are copper-dependent, and of these which depend on metformin's unusual 'pseudoaromatic' metal-binding mode. Research to identify the target of metformin will ultimately facilitate development of new drugs for the treatment of diseases associated with age-related metabolic dysfunction, consistent with MRC's strategic research priority "Living a long and healthy life"

Planned Impact

This proposal forms part of a continued effort to maximise the impact of the group's research. In the work leading up to the current proposal the group has moved away from experimental signalling compounds that are of specialist interest only, to embrace therapeutically useful agents whose mechanism is incompletely understood. The aim of this application is to learn more about the action of one of these agents on cell physiology, which promises to illuminate a path towards the development of better therapeutic agents in the future. Dysregulation of insulin signal transduction is increasingly understood to affect organismal ageing in organisms from C.elegans and Drosophila to mammals, research that fits well with MRC's current strategy to support research towards living a long and healthy life. The current proposal will contribute towards MRC's portfolio in this area by enabling the identification either of cellular signalling mechanisms and/or chemical agents that can then be investigated in vivo for utility in prolonging lifelong health and wellbeing

Given sufficient long-term support, a portfolio of research in this area is likely to have several beneficiaries who will benefit as outlined below:

(i) Biotech and pharmaceutical companies, who could develop any new agents or targets that we identify. A successful example of this is Sirtris in the US, a company focussed on discovering and developing proprietary drugs with the potential to treat diseases associated with aging which was recently sold to GSK for nearly $1 Billion. There is clearly an outstanding opportunity for the UK to improve its competitiveness in this area, given the breadth and depth of relevant experience in UK labs. If a similar biotech company developed in the UK, this would also provide employment opportunities for appropriately qualified PDRAs coming through these UK labs.

(ii) The general public, UK government and NHS will ultimately benefit from agents capable of prolonging the 'healthspan.' Longevity is increasing rapidly in the UK and elsewhere but this will only provide benefit to individuals and be affordable in terms of taxation and health care if the extra years are healthy years.

Publications

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Forteath C (2023) Amino acid homeostasis is a target of metformin therapy. in Molecular metabolism

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Quan X (2015) The copper binding properties of metformin--QCM-D, XPS and nanobead agglomeration. in Chemical communications (Cambridge, England)

 
Description Citation in Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology.
Geographic Reach Europe 
Policy Influence Type Citation in clinical reviews
Impact The clinical review will lead to increases in survival and quality of life in heart failure through influence on future prescribing guidelines. Heart failure is a very significant healthcare problem with significant morbidity, mortality and few treatment options
 
Guideline Title 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD
Description Influence of metformin research programme on clinical guidelines
Geographic Reach Europe 
Policy Influence Type Citation in clinical guidelines
Impact CVD is the largest cause of morbidity and mortality in most of Europe and refinement of guidelines is improving treatment all of the time
 
Description Programme Director Biomedical Research (Diabetes)
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact I am leading the expansion of Dundee's ground-breaking science teaching that I pioneered in Kuwait, exploiting state-of-the-art blended learning strategies to deliver an exciting, unique and truly innovative science taught postgraduate experience. The MSc is part of CMDN's flagship international Kuwait-Scotland collaboration with the Dasman Diabetes Institute in Kuwait, conceived by Professor Andrew Morris and now led by Professor Mairi Scott. The outcomes and impact of the MSc go far beyond teaching, as it is a key foundation of the planned Kuwait-Scotland PhD programme, which will in turn lead to further bilateral research collaboration.
URL https://learning.health.org.kw/
 
Description BHF project grant
Amount £202,642 (GBP)
Funding ID PG/18/79/34106 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2019 
End 05/2022
 
Description Project grants
Amount 54,080 د.ك.‏ (KWD)
Funding ID RC-14015002 
Organisation Dasman Diabetes Institute 
Sector Charity/Non Profit
Country Kuwait
Start 11/2014 
End 11/2016
 
Description Relative contributions of fructose bisphosphatase-1 (FBP1) and other possible mediators to the anti hyperglycaemic action of salicylate
Amount £252,097 (GBP)
Funding ID 19/0006045 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2020 
End 05/2023
 
Description The Cunningham Trust studentship
Amount £82,000 (GBP)
Organisation The Cunningham Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 09/2018
 
Description studentships
Amount £87,909 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 09/2016
 
Description CARDIOLINC Yvan Devaux 
Organisation Cardiolinc Network
Country Luxembourg 
Sector Learned Society 
PI Contribution Research collaborations with other CARDIOLINC members
Collaborator Contribution Academic collaborative network on cardiovascular research
Impact None yet
Start Year 2017
 
Description Local visits: school visit (Monifieth), Diabetes UK local group meeting (Dundee) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I attended a school careers day (2015) to describe to the school children what a biochemist does

Members of my lab have attended a Diabetes UK local group meetings (2015) to discuss our research
Year(s) Of Engagement Activity 2015
 
Description Press release 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact TV and radio broadcasts following publication of article in Circ Res
Year(s) Of Engagement Activity 2016
 
Description Press release 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Press release following award of research prize in Nov 2016
Year(s) Of Engagement Activity 2016