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For decades, physicians and scientists have thought that metformin, a biguanide drug that is prescribed for millions of people worldwide for type 2 diabetes (T2D), mainly targets the liver to suppress glucose production. A Northwestern University-led study in mice has now found that this “wonder drug” instead acts primarily on the gut, and prevents glucose levels from rising in the blood by driving glucose utilization inside cells lining the intestine.

The research found that metformin slows mitochondrial energy production in gut cells by inhibiting mitochondrial complex I in the intestinal epithelium. This then “co-opts” the intestines to function as a glucose sink, forcing the intestine to metabolize extra sugar. The study also found that another biguanide drug, phenformin, and the structurally unrelated supplement berberine, which is known as “nature’s Ozempic,” appear to engage the same pathway in the gut as does metformin.

The preclinical findings could help to explain several gut-related clinical effects in people who take metformin and suggest that modulating mitochondrial metabolism in the gut may represent an effective strategy for controlling blood sugar. “Metformin essentially helps the intestine suck the glucose out of the bloodstream, which further highlights that the gut plays a major role in regulating blood sugar levels,” said corresponding author Navdeep Chandel, PhD, professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

Chandel is senior and co-corresponding author of the researchers’ published paper in Nature Metabolism, titled “Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.” Chandel is also the David W. Cugell, MD, Professor of Medicine (Pulmonology and Critical Care), Biochemistry and Molecular Genetics, and an investigator with the Chan Zuckerberg Initiative. The study’s first author is Zach Sebo, PhD, a postdoctoral fellow in the Chandel lab who will soon start his own research group at the University of Kansas School of Medicine.

Metformin is the most widely prescribed medication for type 2 diabetes and the biguanide class drug approved by the FDA, the authors wrote. However, they noted, “Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear.”

The body relies on glucose as a fast and versatile fuel, but too much glucose can lead to insulin resistance and ultimately damage blood vessels and organs. The newly reported study builds on findings from previous work in Chandel’s lab, which found that metformin lowers blood sugar by blocking a specific part of the cell’s energy-making machinery, mitochondrial complex I, a key enzyme in cellular respiration. The research reported in Nature Metabolism extends that work by pinpointing the specific tissue targeted by metformin.

The study used a mouse model genetically engineered to express a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to inhibition by metformin. By expressing NDI1 specifically in intestinal cells, those gut cells resisted metformin’s effects. In these mice, the drug’s ability to lower blood glucose was significantly reduced, demonstrating that inhibition of mitochondrial complex I in the gut is a key driver of its therapeutic action. “In this study, we show how metformin exerts multiple clinical effects through selective inhibition of mitochondrial complex I in the intestinal epithelium,” they wrote.

Metformin is currently the only FDA-approved biguanide drug, but the team found that another biguanide, phenformin, which had previously been used to control blood glucose but was then withdrawn, also lowered blood glucose through the same mechanism. The findings suggest that directing drugs or supplements to the gut could be an effective strategy for controlling blood sugar, Chandel said. Sebo added, “Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works.”

The study revealed unexpected parallels with berberine, a popular plant-derived OTC supplement that is often used to control blood sugar. Berberine has recently gained attention on social media as “nature’s Ozempic,” though experts caution that evidence is still limited, and it should not be used as a substitute for approved medications. The study by Chanel and colleagues has now found that berberine appears to engage the same pathway as metformin in the intestine. “Thus, we identify mitochondrial complex I in intestinal epithelium as a shared and essential therapeutic target for metformin, phenformin, and berberine,” the authors stated.

“Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested,” Chandel said. “If you’re going to use berberine, you may as well use the real deal.”

The study results may help to explain clinical observations among people who take metformin. According to Chandel, individuals who take metformin tend to have lower blood sugar after meals, and the study suggests that metformin turns the gut into a “sponge” that soaks up extra sugar. Individuals taking metformin also tend to have lower levels of circulating citrulline, which is made only by mitochondria in small intestine cells. If metformin inhibits mitochondria, citrulline production drops. Taking metformin also increases levels of GDF15, a hormone linked to reduced appetite and weight loss. The gut senses energy stress and sends out GDF15, which tells the brain to eat less and adjust metabolism.

“In addition to enhanced intestinal glucose utilization and blood glucose clearance, this mechanism accounts for metformin-induced citrulline depletion, improved postprandial glycaemia, and elevated lactoyl-phenylalanine (Lac-Phe) and growth differentiation factor 15 (GDF15) levels—all of which are definitive clinical outcomes caused by metformin treatment,” the authors wrote in summary.

“People have always wondered how one drug can do 10 things,” Chandel said. “Well, it can do that if the drug is hitting a big node in a cell, and hitting mitochondria in a cell is a big node. So, if you can get into those cells and inhibit mitochondria, it’s going to have huge effects.”

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