Scientists Discover Metformin Doesn’t Work the Way We Thought

How wonder drug works

By Kristin Samuelson, Northwestern University

For years, researchers believed metformin, the most widely used medication for type 2 diabetes, worked mainly by reducing glucose production in the liver. 

However, a new study from Northwestern University using mice suggests the drug’s primary target is actually the gut. Researchers found metformin lowers blood sugar by increasing glucose use in cells that line the intestine, helping prevent excess sugar from building up in the bloodstream.

Glucose is an essential source of energy for the body, but chronically high levels can contribute to insulin resistance and damage to blood vessels and organs. The study indicated that metformin reduces mitochondrial energy production in intestinal cells, forcing those cells to burn more glucose.

“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, professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

The study was published in Nature Metabolism.

New Clues About How Metformin Works

The new findings build on earlier research from Chandel’s laboratory showing that metformin lowers blood sugar by blocking mitochondrial complex I, a critical component of the cell’s energy production system. The latest work identifies the intestine as the main tissue responsible for this effect. According to Chandel, the results suggest that targeting the gut with future drugs or supplements could become an effective way to control blood sugar.

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 lead author, Zach Sebo, is a postdoctoral fellow in the Chandel laboratory who will soon launch his own research group at the University of Kansas School of Medicine.

“Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works,” Sebo said.

Berberine and “Nature’s Ozempic” Comparisons

The study also uncovered similarities between metformin and berberine, a plant-derived supplement commonly promoted for blood sugar control. Berberine has gained popularity online as “nature’s Ozempic,” although experts warn that evidence supporting its use remains limited and it should not replace approved medications. Researchers found that berberine appears to activate the same intestinal pathway as metformin.

“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.”

Clinical Clues Reveal Metformin’s Gut-Driven Effects

The findings may also explain several well-known effects seen in people taking metformin. According to Chandel, patients using metformin often:

• Experience lower blood sugar after meals. Metformin makes the intestine act like a “sponge” that absorbs extra glucose.
• Have lower levels of circulating citrulline, which is a compound produced only by mitochondria in cells of the small intestine. When metformin suppresses mitochondrial activity, citrulline production decreases.
• Have increased levels of GDF15, a hormone linked to appetite suppression and weight loss. Scientists believe the gut responds to energy stress by releasing GDF15, which signals the brain to reduce food intake and adjust metabolism.

Engineered Mice Reveal Metformin’s Mitochondrial Mechanism

“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.”

To test the mechanism, researchers used genetically engineered mice that produced a yeast enzyme called NDI1. This enzyme mimics mitochondrial complex I but cannot be blocked by metformin. When NDI1 was expressed specifically in intestinal cells, those cells became resistant to the drug’s effects. In these mice, metformin lost much of its ability to lower blood sugar, providing strong evidence that blocking mitochondrial complex I in the gut is central to how the medication works.

Reference: “Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control” by Zachary L. Sebo, Ram P. Chakrabarty, Rogan A. Grant, Karis B. D’Alessandro, Alec R. Koss, Jenna L. E. Blum, Shawn M. Davidson, Colleen R. Reczek and Navdeep S. Chandel, 8 May 2026, Nature Metabolism.
DOI: 10.1038/s42255-026-01530-y

Funding for the study was provided by the National Institutes of Health, the National Heart, Lung, and Blood Institute of the NIH, the Northwestern University Pulmonary and Critical Care Division Cugell Predoctoral Fellowship, the Cellular and Molecular Basis of Disease, the NRSA Training Program in Signal Transduction and Cancer, the Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research, the Schmidt Science Fellows, in partnership with Rhodes Trust, the Simpson Querrey Fellowship in Data Science, the Training Program in Lung Sciences, the Medical Sciences Training Program and the Stand Up 2 Cancer Convergence 3.1416.