Metformin has been a foundation treatment for type 2 diabetes for more than sixty years, yet researchers are still uncovering new details about how it works.
A recent study suggests that, at the doses used in clinic, one of metformin’s key actions may take place in the brain rather than only in the liver or intestine.
Metformin is usually the first tablet offered to people who are newly diagnosed with type 2 diabetes.
It has a long safety record, is inexpensive and has a low risk of causing low blood sugar.
The standard explanation has been that metformin lowers glucose by reducing glucose release from the liver and by making the body more sensitive to insulin, with some additional effects in the gut.
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Yet those explanations have never fully captured the complexity of the drug.
It has also been linked with slower ageing, reduced risk of some cancers and better brain health in some studies, which has led researchers to ask whether there might be additional pathways at work.
The new brain first mechanism
Scientists at Baylor College of Medicine have investigated how low, clinically relevant doses of metformin act in the brains of mice with a diabetes like condition.
They focused on a region called the ventromedial hypothalamus, which plays a central role in controlling appetite, energy use and glucose balance.
In this area of the brain they had previously identified a protein called Rap1 that influences glucose metabolism. In the latest study, the team showed that metformin travels into this brain region and switches off Rap1 in a specific group of nerve cells known as SF1 neurons.
When Rap1 is inhibited in these cells, blood glucose levels fall.
The researchers then bred mice that lacked Rap1 in this part of the brain.
In those animals, metformin no longer lowered blood sugar at the usual doses, even though other diabetes drugs still worked.
When they forced Rap1 to stay switched on, metformin again lost its effect.
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Taken together, these findings provide strong evidence, in animals, that low dose metformin exerts an important part of its glucose lowering action through this brain pathway. At much higher doses, which are less relevant to routine care, metformin can still act through other routes in the body.
Why this matters
Understanding that metformin works, at least in part, through specific brain circuits helps to explain why modest doses can have such reliable effects on glucose control. It opens up several possibilities.
First, drug developers may be able to design new treatments that more precisely target the Rap1 pathway in the hypothalamus.
That could lead to medicines that improve glucose control with fewer side effects.
Second, it may help to shed light on some of the other reported benefits of metformin, such as slower decline in brain function with age and possible links with longer life.
If the same brain cells and proteins are involved in ageing pathways and glucose control, this could be an important bridge.
Large human studies have already suggested that metformin users may have a lower risk of early death compared with people using some other diabetes medicines, though this sort of work is always open to hidden confounding factors.
What this means for people with type 2 diabetes
For now, this research does not change how metformin is used in clinic. The doses, timing and combinations with other medicines remain driven by existing guidelines and by your individual circumstances.
These studies do, however, reinforce a few key points.
- Metformin remains an important first choice for many people with type 2 diabetes
- It likely has more than one mechanism of action, which may help explain its wide range of benefits
- There is active work under way to understand how its brain effects might be harnessed for future treatments
Metformin can still produce side effects, especially in the gut, and is not suitable for everyone. It needs adjustment in kidney disease and sometimes has to be stopped before certain scans and procedures.
If you have questions about whether it is right for you, or how it fits alongside newer drugs such as GLP 1 and SGLT 2 treatments, it is worth discussing options with your diabetes team.
