After 60 years: “Now we finally understand how this medicine works”

Disease and treatment 24. okt 2018 2 min Clinical Professor, Professor Niels Jessen Written by Morten Busch

For 60 years, metformin has been doctors’ first-line drug for treating people with type 2 diabetes. However, no one has known precisely how it works. An international research team with Danish participation has now discovered how metformin works. This pioneering discovery will help not only the 400 million people with diabetes but also potentially people with other conditions.

When people swallow a pill, the medicine inside has been thoroughly tested to ensure that it works as intended and has no serious side effects. Nevertheless, scientists do not always know how medicine works. This can be a problem for people taking several types of medicine, because predicting the effects is more difficult. A new study has finally discovered the how the diabetes drug metformin works.

“Metformin behaves differently to many other drugs. One reason is that only a few organs absorb it, and it is not metabolized in the body. People simply excrete it in their urine once it has worked. Precisely tracking where and how it works has therefore been difficult. Our new research shows that metformin works by targeting energy-sensitive proteins in the liver, and this interaction reduces the liver’s production of glucose,” explains co-author Niels Jessen, Professor of Clinical Pharmacology, Aarhus University and Head of Research, Steno Diabetes Center Aarhus.

Clear effect

Previous research has shown that metformin works by suppressing the production of glucose by the liver, thereby reducing the symptoms of type 2 diabetes. However, because metformin passes unaltered through the body, determining precisely how this happens has been difficult. One of the many theories was that metformin affects the liver’s energy balance and thereby slows down the production and release of glucose.

“To test this theory, we tried to see what would happen if we removed one of the key components of the liver’s energy metabolism: an enzyme called FBP1. We therefore slightly modified the enzyme so that it was no longer sensitive to adenosine monophosphate (AMP) that usually suppresses FBP1, causing it to produce and release less glucose.”

This also enabled the researchers to examine whether FBP1 and AMP are actually essential for the effects of metformin. If the theory was correct, metformin would continue to alter the energy balance so that more AMP would be produced and, since the mutated FBP1 enzyme would be insensitive to AMP, metformin would no longer be able to reduce the production and release of glucose.

“We demonstrated this effect in the laboratory, so it was very exciting to see what would happen when we treated mice that had the altered enzyme with metformin. The effect was clear, substantially impairing the ability of metformin to reduce high blood glucose.”

Unknown effects create anxiety

Based on the experiments, the researchers concluded that metformin works by creating mild energy stress in the liver, which increases the quantity of AMP, which then suppresses FBP1 and thereby the production and release of glucose. Even though the researchers definitely cannot rule out other effects of metformin, this new study is a milestone in understanding this type of diabetes treatment.

“Although we still do not understand precisely how metformin creates energy stress, the discovery of the specific influence on one of the liver’s proteins is pioneering and will be very important for using metformin to treat people in the future.”

The new knowledge will help to solve one of the specific challenges associated with modern medicine: people often take several different types of medicine simultaneously. If doctors do not understand how an individual drug works, predicting how the drugs will interact will also be very difficult.

“Unknown effects make doctors anxious. We can now predict these effects better, and this will clearly improve treatment because we can now ensure that we can dose and combine different types of medicine correctly.”

This knowledge will also assist in developing precision medicine (sometimes called personalized medicine), in which the medicine is tailored based on the genetic profile of an individual. Knowing which genetic version of FBP1 a person has will enable doctors to predict whether metformin will work and what dose to prescribe.

“This is a good example of the importance of funding basic research. Metformin is a 60-year-old drug with a long-expired patent, so no company is interested in researching how the drug works. This type of research is only enabled if public research is funded through independent research grants. And this research has now resulted in being able to develop more targeted and effective medicine with fewer side-effects.”

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase” has been published in Nature Medicine. Niels Jessen is Head of Research of Steno Diabetes Center Aarhus, which has been partly funded through a donation from the Novo Nordisk Foundation.

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