In the laboratories of the Northwestern University One of the greatest mysteries of modern medicine has finally been solved: how metformin exerts its beneficial effects on metabolism. The discovery, published in Science Advances (I link it to you here), promises to revolutionize not only diabetes therapy, but also the development of new, more effective drugs.
For those who don't know what metformin is apart from its effects
Metformin is a very common drug used primarily to treat type 2 diabetes, which usually occurs in adulthood, especially in overweight people. Simply put, it helps the body better manage blood sugar. in three ways: reduces sugar production by the liver, improves sugar absorption by the muscles, and slows sugar absorption from the intestine.
It is considered the first-choice drug for type 2 diabetes (and not only) because, in addition to being effective, It has two important advantages: It does not cause weight gain and rarely causes dangerous drops in blood sugar. It is taken in tablet form with meals, and although it may cause some initial stomach upset, it is generally well tolerated by most people.
The Key to Metformin's Effects? It's in the Mitochondria
A team led by researchers from the Northwestern University has shown that the effects of metformin are mainly linked to a specific part of the mitochondria, the “engines” of our cells. The target is the mitochondrial complex I, which functions as a molecular engine to provide energy to cells. Metformin acts as a gentle brake on this system, modulating cellular metabolism.
To prove this theory, scientists took an innovative approach using genetically modified mice. They introduced a special protein called NDI1, originally found in yeast, in mouse cells. This protein acts as a backup generator that can continue to function even in the presence of metformin., allowing researchers to test whether blockade of mitochondrial complex I is indeed essential for metformin's effects.
Amazing results
Although millions of people already take metformin, understanding its exact mechanism has been a mystery. This study helps explain that metformin lowers blood sugar by interfering with the mitochondria in cells.
Professor Navdeep Chandel, Northwestern University Feinberg School of Medicine.
Mice treated with metformin showed significantly lower blood sugar levels after consuming glucose, as expected. However, mice with the NDI1 backup system were significantly less responsive to the hypoglycemic effects of metformin.
Beyond Diabetes
This finding is particularly significant because metformin has shown potential beyond the treatment of diabetes. Studies suggest that may help reduce cancer risk, decrease inflammation, and even improve longevity. Understanding exactly how metformin works could help researchers develop more targeted treatments for these conditions.
A unifying explanation
Colleen Reczek and his colleagues tested this theory in both mice fed regular chow and mice fed a high-fat diet to mimic the conditions that often lead to type 2 diabetes in humans. In both cases, the presence of NDI1 significantly reduced the effectiveness of metformin, but did not eliminate it entirely.
The study also helps explain why metformin’s effects can vary among people and why it works better when taken orally rather than injected. When taken as a pill, the drug primarily targets the gut and liver (key organs in controlling blood sugar) before reaching other parts of the body. This understanding could lead to the development of even more effective drugs to treat diabetes and other metabolic conditions.
Limitations and future prospects
The researchers noted that the genetically modified mice showed variable levels of NDI1 expression, which may have influenced the results. Additionally, because NDI1 cannot perfectly replicate all the functions of natural mitochondrial complex I, some differences in response may be due to these functional variations rather than the effects of metformin.
Further research will be needed to confirm these results, but the path is really convincing, and in any case… The “mystery” is solved.
