Antidiabetic effect of drug metformin linked to iron homeostasis

Researchers have discovered how the frontline Type 2 diabetes drug metformin may work to help cells better take up and use glucose. Their study, published in the journal Cell, may also explain other potential beneficial effects of metformin for prevention of a variety of chronic diseases, including cancers.

To show that metformin appeared to make the cells act as if they are starved for the essential mineral iron, biochemists used a new method to simultaneously probe how all of a cell's biochemical processes respond to the presence of a drug. The team showed that metformin has a global effect on iron distribution in cells, resulting in alteration of essential biochemical processes.

"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 it's cells at once," said the senior author. "Today there are several ways to do this, but our method, called protein-fragment complementation assays (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.

hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation.

Authors demonstrate that hdPCA accurately predicts the effects of two longevity and health span-affecting drugs, the immunosuppressant rapamycin and the type 2 diabetes drug metformin, on cellular pathways. They also discovered an unsuspected global cellular response to metformin that resembles iron deficiency and includes a change in protein-bound iron levels.

"We'd chosen to use metformin, mostly because it was an interesting test case, having no clear mechanism of action,"added the study's first author. "The lead to effects of metformin on iron homeostasis was a bonus of this study. A connection between iron metabolism and diabetes was already suspected but no-one had ever showed a specific antidiabetic effect of metformin in living cells connected to iron homeostasis."

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.