Diabetes drug metformin 'could aid Alzheimer's'

Behind the Headlines

Friday July 6 2012

Will Alzheimer's disease be cured by metformin?

Today’s Daily Express headline claims that a “2p diabetes pill could hold key to Alzheimer’s cure”. The headline accompanies a story about a potential new use for the drug metformin.

The story is based on a study that examined the effect metformin had on promoting the growth of new nerve cells in the brain. The headline is misleading as the research is promising but only preliminary research into treating Alzheimer’s.

The first stage of the research successfully showed that metformin can stimulate the development of both mice and human stem cells into nerve cells in a laboratory setting. The second stage tested the effects of metformin in a real-life setting on mice. Researchers found that when mice were injected with the drug, new nerve cells developed in the area of the brain responsible for learning and memory. The mice were also better at navigating a ‘water maze’ test.

What is metformin?

Metformin is a diabetic drug currently licensed for use in the first-line management of type 2 diabetes. It works by decreasing the body’s production of glucose, and increasing the body’s sensitivity to insulin, causing cells to take up glucose.

This is potentially exciting as current treatments for Alzheimer’s can slow the progression of disease but cannot reverse it. If the same effects seen in mice were also seen in humans it may lead to an improvement in symptoms such as memory loss.

However, what is effective when injected into mice brains is not necessarily safe and effective when given to people in tablet form. To find out if oral metformin offers a viable treatment option for people with Alzheimer’s, let alone a “cure”, will require many more years of research.

To learn more about stem cells, read the Behind the Headlines special report, Hope and hype: an analysis of stem cells in the media.

 

Where did the story come from?

The study was carried out by researchers from Canada and the US and was funded by the Canadian Institute of Health Research, the McEwen Center for Regenerative Medicine, the Canadian Stem Cell Network and the Three to Be Foundation. The study was published in the peer-reviewed scientific journal Cell.

The news generally gives a fair representation of this research. However, the Express fails to spell out that using metformin to treat Alzheimer’s or other neurological conditions is a long way off.

 

What kind of research was this?

This was laboratory research that centred upon the nerve stem cells that build the brain while an embryo develops. Previous study by the same researchers identified a chemical pathway that is involved during embryonic development and that causes early nerve stem cells in the developing brain to develop into mature nerve cells. Other work by a fellow researcher also found that the diabetes drug metformin activated this same chemical pathway in liver cells. They, therefore, thought that if this pathway in the liver was activated by metformin, then it might also activate the same pathway in the brain.

Theoretically, if the brains of adults contain these early stem cells, then it may be possible for metformin to use them to help the brain to recover or be repaired. This is described by the researchers as ‘recruiting’ the cells. This would make metformin an appropriate candidate drug to test in this area.

 

What did the research involve and what were the results?

What is a water maze test?

A water maze test comprises a pool of water, with a single platform (sometimes more than one platform) placed just below the surface of the water.

 

Usually the platform and the pool are white, making the platform difficult to see. Mice are placed in the pool and swim around until they find the platform.

 

Researchers usually time how long their test mice take to find the platform, but they may also film the mice to examine their searching pattern or technique. This can be an important indicator of their behavioural functions. Usually, mice are tested over and over again to see if they learn where the platform is.

 

If the mice fail to find the platform after a certain time they are usually removed to prevent them from drowning.

The first stage of this laboratory research involved nerve stem cells taken from mice. The researchers successfully put these nerve stem cells into a culture with metformin and successfully demonstrated that the stem cells would develop into mature brain nerve cells. They then tried to replicate this finding with human nerve stem cells. In the laboratory, the researchers first generated nerve stem cells from human ‘pluripotent stem cells’ (the earliest stage of stem cell, which can develop into any cell type in the body). The researchers again cultured these human nerve stem cells with metformin and showed that they could develop into mature brain nerve cells.

The third stage in the research involved testing metformin on live mice. After injecting the mice with metformin, they took samples from their brains to see if the drug had caused development of nerve cells in the area of the brain important for learning and memory (the hippocampus). To test whether giving metformin made any difference to the function of the mice’s brains, they tested their performance in a water maze, comparing mice that had been injected with metformin for 38 days, with mice that had not received the drug.

 

How did the researchers interpret the results?

The researchers concluded that metformin activates the pathway that is essential for the normal development of mature nerve cells in the brain from nerve stem cells. They say that it does this in both rodent and human cells that have been cultured in a laboratory. Metformin also enhances nerve cell development in the brains of live mice, and enhances their learning performance in a water maze. From this, the researchers concluded that their findings suggest that metformin, with its ability to enhance nerve cell development, could potentially be used to treat some neurological diseases.

 

Conclusion

This research centres on how mature nerve cells in the brain develop from stem cells during embryonic development. Building on previous research findings, the researchers showed that metformin could enhance the development of mature nerve cells from stem cells. This gives us tantalising clues about how it might potentially be used to treat people. The theory for this is that if our brains contain these early stem cells and they could be ‘recruited’ by metformin, then this could allow for brain recovery or repair from a range of neurological conditions.

So far, the action of metformin on the way human brain cells develop has only been tested in the laboratory. In real life it has only been shown to work in mice. The researchers successfully demonstrated that when mice were injected with metformin they developed new nerve cells in the area of the brain important for learning and memory. They also then showed that these mice had improved performance in a water maze. However, what effect oral metformin has on brain cells in living people, and whether this translates into any improvement on brain function and memory is completely unknown at this stage.

The current work has not specifically focused on the potential for use in Alzheimer’s disease. However, the researchers highlight that there has been prior interest in using metformin in individuals with early stage Alzheimer’s disease. This is because it has been observed that many of these people who develop Alzheimer’s disease are also diabetic and, therefore, if their bodies are producing too much insulin, this may be involved in the breakdown of nerve cells in the brain. Therefore, the researchers speculated that people with Alzheimer’s disease could potentially benefit from metformin.

As Dr Eric Karran of Alzheimer’s Research UK told the Express: “This well-conducted piece of research reveals a possible new biological effect for metformin, but work is still needed to determine how relevant the findings may be for Alzheimer’s disease”.

The main message is that metformin is currently only licensed for use in type 2 diabetes. It is not possible to tell, based on this research, whether it would be appropriate for use in people with Alzheimer’s disease or have any effect in halting or reversing the disease process.

 

Analysis by NHS Choices. Follow Behind the Headlines on twitter.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

2p diabetes pill could hold key to Alzheimer’s cure. Daily Express, July 6 2012

Links to the science

Wang J, Gallagher D, DeVito LM, et al. Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation. Cell Stem Cell. 2012;11:23-35

'Video abstract'

Study lead, Dr Freda Miller describes the metformin research (MOV, 32.63Mb).   

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