Metformin is more than 60 years old as the main pillar of type 2 diabetes care. It is famous because of lowering blood sugar, mainly by decreasing the level of glucose in the liver, and is prescribed to millions of people across the globe. In addition to action as an antidiabetic, metformin is associated with anti inflammatory effects, anti cancer effects, anti obesity effects, and cardiovascular protective effects. However, another secretive quality of this medication has remained a mystery to researchers since the early years of study; namely, its affinity to metals such as copper, iron and cobalt.
A study published in BMJ Open Diabetes Research and Care in 2025 has now provided a strong evidence that indeed metformin does alter the circulation of metals in the blood of diabetes patients with type 2 diabetes.
This updated intuition can redefine our perception of the positive and the negative possibilities of using the most popular drug used in the entire world to control diabetes.
Why Metals Matter with Diabetes
Human health depends on trace metals like copper, iron and zinc. They are involved in the enzyme activity, formation of red blood cells, immunity and even energy metabolism. In diabetes, the imbalance in metal is well reported:
Copper: It is frequently high in diabetics, which is associated with ineffective blood sugar regulation and complications.
Iron: Deficiency and overload may lead to an aggravation of glucose metabolism and cardiovascular health.
Zinc: An essential part of insulin storage and release, and generally low in diabetics.
Because metformin is also known to chelate or bind metals, researchers believed that it might have such a direct effect on these vital mineral levels. Clinical evidence in humans was so far limited.
The Study Design
The study was a cross-sectional study of 189 adults diagnosed with type 2 diabetes at Kobe University in Japan. Out of them, 93 were receiving metformin at least six months and 96 were not.
The researchers compared the blood concentrations of copper, iron, zinc and vitamin B12 among the two groups and some related markers like ceruloplasmin, ferritin, transferrin and homocysteine.
The aim was rather straightforward yet effective: to find out whether long-term use of metformin can change the dynamics of metals in humans.
Key Findings
The results were striking:
Lower Copper Levels
There was a significant decrease in copper in metformin users (16.0 umol/L vs 17.8 umol/L in non users).
A copper carrying protein called ceruloplasmin was also reduced.
This trend indicates a picture that is similar to latent copper deficiency.
Lower Iron Levels
In metformin users serum iron and ferritin (iron storage protein) were lowered.
The evidence of reduced iron availability was an increase in transferrin and unsaturated iron binding capacity.
Higher Zinc Levels
Remarkably, zinc was greater in users of metformin (13.3 umol/L vs 12.5 umol/L).
The action is not well understood but possibly secondary actions of impaired copper absorption.
Vitamin B12 Deficiency
In line with previous studies, the level of vitamin B12 was lower in metformin users significantly.
Homocysteine, a B12 deficiency marker was increased.
Effect of Metformin in Singular Therapy.
The statistical modeling proved that even after the correction on the age, sex, BMI, and other medications, the use of Metformin itself predicted the lower level of copper and iron.
Why These Findings Matter
There are significant clinical and scientific implications of these discoveries:
Theoretical Benefits of Metformin: Reduction of copper can be a real benefit to metformin anti-inflammatory and anti-cancer effects as high copper concentrations are associated with oxidative stress and diabetic complications.
Possibility of Nutrient Deficiencies: Conversely, the long-term losses of copper, iron and vitamin B12 may cause unrecognized deficiencies, anemia or neurological issues.
Personalized Medicine: The relationship between metal levels and patients being on metformin could be useful in determining those who may suffer side effects and still benefit the therapeutic effect of metformin.
Limitations to Consider
It was observational, which means that it demonstrates associations but not cause and effect. Results may be affected by diet, supplement intake and personal differences. Furthermore, the levels of cobalt, which is one of the main parts of vitamin B12, could not be detected in most of the samples.
Nevertheless, this is the best evidence so far that metformin has an effect on the human metal metabolism as they are the largest sample and this was carefully analyzed by the statistics.
Future Directions
The researchers note that, another diabetes drug, imeglimin, which is structurally related to metformin, but which lacks good metal binding properties, has recently been approved in Japan. A comparison of its impacts on copper, iron and zinc can also help explain whether the advantages of metformin are in part due to its chelating action.
The clinical guidelines can eventually suggest regular tests of vitamin B 12, copper, and iron in patients under long-term metformin treatment- just like today, there exists advice to test the kidney and the vitamin B 12 levels.
Conclusion
Metformin is not only a drug that lowers blood sugar. This work discloses that it quietly rebalances the metal of the body reducing copper and iron and increasing zinc. Such changes could be used to take into consideration its preventive properties against inflammation, cancer, and diabetes complications, yet the awareness on the presence of hidden nutrient deficiencies should be created.
To patients and clinicians, the message is the same: metformin is still one of the basics of diabetes treatment, yet monitoring the presence of important mineral levels can help to guarantee that the benefits of the treatment are maximized, and undesired side effects are reduced to a minimum.
Reference
Otowa-Suematsu N, Sakaguchi K, Yamada T, et al. Association of metformin treatment with changes in metal dynamics in individuals with type 2 diabetes. BMJ Open Diabetes Research & Care. 2025;13:e005255. doi:10.1136/bmjdrc-2025-005255