Yale Researchers Continue to Unravel the Mystery of Metformin

Yale researchers have further elucidated the mechanism of metformin, a widely used type 2 diabetes medication that, despite its long history of being safe and effective, works in a way that has remained elusive to scientists.

On March 1, Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, published his lab’s findings on how metformin works to suppress gluconeogenesis through inhibiting Complex IV activity. Now, a different study led by Yingqun Huang, MD, PhD, professor of obstetrics, gynecology & reproductive sciences, builds upon Shulman’s findings and further illuminates how the drug works. Her team published its findings in Proceedings of the National Academy of Sciences on March 28. “Our research not only discovered a new mechanism of metformin, but also identified potential therapeutic molecular targets,” says Huang.

Metformin findings build on one another

Shulman’s findings over recent years supporting an oxidation-reduction (redox)-dependent mechanism of metformin—in which cytosolic redox is increased—intrigued Huang’s lab. But while Shulman’s lab has focused on how inhibition of the mitochondrial enzyme Complex IV promotes an increased cytosolic redox state and inhibition of gluconeogenesis [glucose production from glycerol, lactate and amino acids]Huang is interested in how increased redox changes hepatocytes [liver cells] further downstream—a mechanism researchers are now debating.

In 2020, Huang’s lab published a paper in NatureCommunications that found that the expression of a gene known as TET3 was increased in mice and humans with diabetes. In turn, the expression of a specific fetal isoform of the HNF4A gene was also increased. In healthy adult lives, the adult form of HNF4A is exclusively expressed. In patients with diabetes, however, the fetal isoform is chronically increased because TET3 is also chronically increased. This fetal isoform also increases gluconeogenesis by regulating key enzymes involved in the process.

“In our published paper two years ago, we identified that the upregulation of TET3 and the HNF4A fetal isoform in humans and mice with diabetes contribute to unabated gluconeogenesis in the liver,” says Da Li, professor at China Medical University and co-author on both studies. Now, through its latest work, Huang’s lab has discovered that when metformin induces an increase in cellular redox, this in turn increases let-7, a small microRNA molecule. When let-7 increases, it binds to and downregulates TET3, suppressing the HNF4A fetal isoform and also gluconeogenesis— mproving diabetes

“In the livers of diabetes, let-7 is depressed,” explains Di Xie, associate research scientist in Huang’s lab and first author of the study. “Metformin brings let-7 back to normal levels and inhibits gluconeogenesis.”

Improved diabetes medications are a goal

Unabated glucose production from the liver is one of the key mechanisms of diabetes. Through better understanding how metformin works to suppress gluconeogenesis, Huang hopes her work will lead to more effective drugs with fewer side effects. The study also identified potential therapeutic targets including let-7. Scientists could potentially use a vector such as a mild virus known as adeno-associated virus, for example, to specifically deliver a let-7 mimic to the liver of patients with diabetes to enhance let-7 expression and treat the condition. Huang hopes to develop such a vector for delivering therapeutics like a let-7 mimic in future research.

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