5 Minutes
Background: Metformin’s surprising effects beyond glucose control
Metformin is the most widely prescribed medication for type 2 diabetes and has been used clinically for more than six decades. Beyond lowering blood glucose, observational and laboratory studies have linked metformin to reduced inflammation, lower cancer incidence, and protection against cardiovascular disease. Despite this broad protective profile, the drug’s full mechanism of action remains incompletely understood — a gap that has limited efforts to develop next-generation therapies with similar or improved benefits.
New clinical evidence: Metformin shifts copper, iron and zinc levels
Study design and methods
Researchers at Kobe University led by endocrinologist Wataru Ogawa conducted a clinical comparison of roughly 200 patients with diabetes treated at Kobe University Hospital. About half of the participants were receiving metformin while the other half were not. The team measured serum concentrations of several biologically important metals — notably copper, iron and zinc — and evaluated clinical markers associated with metal deficiency or excess. Their findings were published in BMJ Open Diabetes Research & Care.
Key results
The study reports statistically significant differences in blood-metal profiles between metformin-treated patients and controls. Patients taking metformin showed reduced serum copper and iron levels alongside higher zinc concentrations. According to Ogawa, these shifts are substantial because lower copper and iron and increased zinc have previously been associated with improved glucose tolerance and reduced risk of diabetes complications. The Kobe University paper represents the first clinical demonstration in humans that metformin use correlates with altered systemic metal levels.
Why metal binding matters: biochemical and therapeutic implications
Chemical and preclinical studies have suggested that metformin can interact directly with certain metal ions, particularly copper. Metal-binding can influence enzyme activity, oxidative stress, and cellular signaling — processes implicated in metabolic regulation, inflammation, and tumor biology. If metformin’s binding to metals changes their bioavailability or distribution, this could help explain some of the drug’s pleiotropic effects beyond glucose lowering.
The study also highlights a translational angle: imeglimin, a newer diabetes drug approved in Japan and structurally related to metformin, is thought not to bind metals in the same way. Comparative investigations between metformin and imeglimin could therefore disentangle which clinical benefits are tied to metal interactions versus other molecular mechanisms.
Implications for future drug development and patient care
Ogawa and collaborators emphasize that association does not equal causation. They call for controlled clinical trials and targeted animal experiments to test whether the metal shifts are a direct cause of metformin’s benefits, or secondary effects of improved metabolic control. If a causal relationship is established, it may be feasible to design drugs that deliberately modulate copper, iron and zinc homeostasis to prevent diabetes complications, enhance glucose tolerance, or reduce cancer risk.
From a clinical perspective, routine monitoring of trace metals could become relevant for patients on long-term metformin therapy if follow-up studies confirm clinically meaningful deficiencies or imbalances. Therapeutic strategies might include dietary counseling, targeted supplementation, or new agents that mimic metformin’s desirable metal-related effects without unwanted interactions.
Expert Insight
Dr. Maya Reynolds, a clinical pharmacologist and science communicator (fictional), comments: "This study fills an important translational gap. Laboratory work has long hinted that metformin forms complexes with transition metals. Showing corresponding shifts in human blood adds weight to the hypothesis that metal homeostasis contributes to the drug’s multifaceted benefits. The next step is intervention trials to see whether correcting or mimicking these metal changes can reproduce the protective effects in patients who cannot take metformin or who are at high risk for complications."
Conclusion
The Kobe University study provides the first clinical evidence that metformin use is associated with reduced copper and iron and increased zinc in blood serum. These metal shifts offer a plausible biochemical explanation for some of metformin’s broad health benefits, from metabolic protection to potential anti-cancer effects. Confirmatory trials and mechanistic studies are now needed to determine causality and to translate these insights into safer, more targeted therapies for diabetes and its complications.
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