How a widely used diabetes drug actually works

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Doctors have used the drug metformin to treat type 2 diabetes for more than half a century, but despite its prevalence, researchers don’t have a clear understanding of how it works. Now, Yale researchers have elucidated the mechanism behind metformin and related drugs for type 2 diabetes, and debunked a previously held theory about how they work. The team, including lead author Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (endocrinology) and professor of cellular and molecular physiology, and first author Traci LaMoia, a graduate student in Shulman’s lab, have published their findings in PNAS on March 1.

“Metformin is the most common medication used to treat diabetes,” Shulman says. “It’s important to understand how it works so we can potentially develop even better drugs to treat type 2 diabetes.”

Exploring the Mysteries of a Diabetes Drug

Studies in humans have shown that metformin inhibits the process of gluconeogenesis, which is the way the liver makes glucose from non-glucose precursors such as amino acids and lactate. How he accomplishes this, however, has been a mystery.

Mitochondria in cells generate energy through the electron transport chain, which consists of four protein complexes that release energy through a series of reactions. Most scientists previously thought that metformin worked by inhibiting Complex I, the first and largest mitochondrial complex that creates the hydrogen ion gradient. However, Shulman’s group has previously demonstrated that metformin inhibits complex I only at pharmacological concentrations much higher than what is generally prescribed.

To further test this hypothesis, the team performed a series of experiments on both liver slices and mice. Using a complex I inhibitor known as piercidin A, they found that this mechanism did not reduce hepatic gluconeogenesis. “Using a highly specific complex I inhibitor, we show that inhibiting complex I does not lower blood glucose in both in vitro and in vivo studies,” says Shulman.

Progress through research

Through previous studies, Shulman’s lab team had identified inhibition of the mitochondria-associated enzyme glycerol phosphate dehydrogenase, which converts glycerol to glucose, as a potential mechanism of action for metformin. Now, in the current study, they were able to show through another series of experiments that metformin, along with the related drugs phenformin and galegine, actually inhibited the conversion of glycerol to glucose both in vitro and in vivo. and that they did so by an indirect mechanism by inhibiting the activity of complex IV.

“Taken together, these studies show that metformin does not lower blood sugar through inhibition of complex I activity, but rather lowers blood sugar through inhibition of complex IV activity, which in turn results in an inhibition of glycerol phosphate dehydrogenase activity and a reduction in the conversion of glycerol to glucose,” says Shulman.

Why it’s important to know

It is not uncommon for drugs to be approved for clinical use even though researchers do not understand how they work, whether they are found to be safe and effective. But Shulman says research into misunderstood drugs like metformin is allowing scientists to develop more beneficial treatments. Taking metformin, for example, can lead to unpleasant side effects such as gastrointestinal upset, leading many patients to stop taking it. Shulman hopes his team’s research can lead to the development of diabetes drugs with the safe efficacy of metformin but better tolerance.

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