Metformin: a medical mystery

The discovery of a bacteria at a wastewater treatment plant ignited an investigative journey into the clinical mechanisms of a pharmaceutical used to treat diabetes.
February 27, 2024

Metformin, one of the most prescribed medications in the world, is finding its way into our wastewater. The pharmaceutical designed to treat diabetes effectively lowers blood sugar, but in the end, most of the drug goes straight down the toilet. It begs the question: if people don’t metabolize the majority of it, what’s the mechanism behind its clinical success? 

“Metformin has been around for 50 years, but nobody really knows how it works,” says Larry Wackett, a Distinguished McKnights Professor in the Department of Biochemistry, Molecular Biology and Biophysics (BMBB). “Of course, there are theories.” 

Wackett, who typically uses his expertise in biochemistry to tackle environmental issues, initially became interested in Metformin so he could learn how to eliminate it from wastewater, where it poses a risk to public health and the environment. But when his grad student, Lambros Tassoulas, approached him to look at Metformin with an eye to health implications, he was hooked. Together they discovered that Metformin has a unique inhibitory effect on an enzyme in the human gut, providing novel clues to the mystery behind Metformin’s medical effectiveness.

Step one: a bacteria with Metformin-degrading properties

Their research launched after colleagues at Hamline University found a Metformin-degrading bacteria at St. Paul’s wastewater treatment plant. “They have what they call ‘activated sludge,’” says Wackett. “It’s basically an intestine that's digesting all the products that go into these wastewater treatment plants.” 

CBS alum and Hamline faculty Betsy Martinez-Vaz took the sludge and deprived it of nitrogen to see if it contained any bacteria that would target Metformin as food, which is how they discovered Pseudomonas mendocina. Martinez-Vaz and Wackett’s team published this work in Frontiers in Bioengineering and Biotechnology nearly two years ago.

As Wackett and Tassoulas began the arduous process of identifying the enzyme in the bacteria responsible for breaking down Metformin, they wondered — could we find this enzyme in human’s digestive systems? And more importantly, if this enzyme is in humans, could it be part of the Metformin mechanism that lowers blood sugar in diabetes sufferers? 

As it turns out, probably not. A large database showed no records of the enzyme being recorded in human studies. But it did pose an interesting possibility.

A chemical twin saves the day

“Tassoulas thought maybe there are other enzymes in our gut microflora that work on molecules resembling Metformin,” says Wackett. And since previous studies linked the mechanisms of Metformin to our gut bacteria, it prompted Wackett and Tassoulas to investigate the molecules (and associated enzymes) that exist within us.

Enter: agmatine and agmatinase. Agmatine occurs naturally in humans and has similar chemical qualities to Metformin. Coincidentally, it’s often sold as a supplement and can have similar therapeutic effects to Metformin when administered orally. But agmatinase, an enzyme in our gut, works to convert agmatine into byproducts like urea. Ever heard of urea crystals? Think: kidney stones.

Wackett’s team did a little experimenting to see how Metformin interacted with agmatinase. Basically, Metformin competes with agmatine to bind to agmatinase. In that way, it “inhibits” or prevents agmatinase activity – like converting agmatine into its more morbid-sounding byproducts (i.e. urea).

“Maybe it just acts as an inhibitor. That's its main action,” says Wackett. “I wouldn't say it's like, it's proof [that this is the main mechanism of Metformin]. But we have all these things that are suggestive this could be contributing or may be a major effect of Metformin in the gut.”

It certainly adds a piece to the puzzle. Wackett is happy for the study to be out in the world so he can get back to solving the wastewater crisis. “If Metformin isn’t going away, maybe wastewater treatment plants could also use this knowledge to improve their degradation processes,” says Wackett. “Also, Metformin is going to be around for a long time. It’d be good to understand more of how it works.” — Adara Taylor