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Solving the mystery of metformin mechanisms

Project summary

Mechanism of action of metformin in hepatocytes: inhibition of glucotoxicity

Metformin has been in widespread use for over 50 years, but like many drugs, doctors still do not understand exactly how it works. Professor Agius’ student will explore metformin’s inhibition of cellular stress caused by high blood glucose, to see if this is one of its key effects. Their findings could help to inform the design of new Type 2 diabetes medications.

Background to research

Metformin is the most commonly prescribed drug for the treatment of Type 2 diabetes. It helps to lower blood glucose (by preventing the production of glucose in the liver), has relatively few side effects and is relatively inexpensive. However, despite widespread use for over 50 years, the drug’s exact mechanisms of action are unclear. In recent years new drugs were predicted to improve on metformin – only to fail in clinical trials. Studies at Newcastle University have shown that metformin helps to prevent the cellular stress caused by high levels of glucose and fat in the liver – a problem known as ‘glucotoxicity’. 

Research aims

With funding from Diabetes UK, a student supervised by Professor Loranne Agius will investigate the mechanisms by which metformin takes effect in people with Type 2 diabetes and confirm that one of its key actions is to protect the liver from glucotoxicity. Doses of metformin that are comparable to those administered to humans will be radioactively labelled and given to rat liver cells in the lab. This will enable the researchers to work out if metformin blocks the expression of genes that are important for the storage and release of glucose and fat via specific pathways.

Potential benefit to people with diabetes

This study will lead to improved knowledge of the molecules targeted by metformin, which could in turn help to explain why experimental new drugs have failed in clinical trials and, ultimately, contribute to the development of a new generation of drugs to improve the management of Type 2 diabetes

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