Researchers have discovered a mechanism that may explain how the frontline Type 2 diabetes drug, metformin, works to help cells better take up and use glucose. The findings, published in Cell, could also help explain metformin’s action in preventing a variety of chronic diseases, including cancers.
In an international collaboration, scientists at the Crick and the University of Montreal developed a new method that probes how all of a cell’s biochemical processes respond to a particular drug at the same time. The technology measures changes in the binding properties of all proteins to each other simultaneously. This enables scientists to identify molecular signatures that reveal how drugs influence cells.
The team applied this technique to two metabolic drugs, for one with a known mechanism of action, the immunosuppressant, rapamycin, and for one with no known mechanism of action, metformin.
They found that metformin makes yeast cells act as if they are starved of the essential mineral iron. Further analysis revealed that metformin has a global effect on iron distributions in cells, which has a knock-on impact on iron-dependent biochemical processes.
Building on earlier findings
Previous work at the Crick showed that glucose metabolism - which is affected by metformin - evolved because of iron-dependent reactions. Evidence from other labs also suggested a connection between iron metabolism and diabetes. But this new study is the first time that a concrete connection between the drug, metformin, and iron homeostasis in living cells has been shown.
“This discovery opens up new opportunities in molecular medicine to develop new ways to prevent and treat not only Type 2 diabetes, but also cancers and chronic diseases that have shown responsiveness to metformin in recent years,” said Markus Ralser, co-author of the paper and head of the Molecular Biology of Metabolism Lab at the Crick.
Senior author, Stephen Michnick from the University of Montreal said: “If you want to know what a drug or any other molecule is doing in the body, you need to survey everything going on in its cells at once. Today there are several ways to do this, but our method called hdPCA, has the merit of being extremely simple to perform and interpret, non-invasive and inexpensive; it can be done in almost any lab.”
The method can be deployed to rapidly predict and confirm how a drug might affect cells and simultaneously, identify any liabilities the drug might have if introduced into humans.
Further cell and animal studies will have to be done to pin down how important iron-starvation mimicking effects of metformin are to glucose metabolism and how this mechanism might be better exploited to improve diabetes treatments.