Metformin Slows Mitochondrial Energy Production, Promotes Glycemic Control

Type 2 diabetes drug slows mitochondrial energy production in gut cells, forcing gut to metabolize excess sugar

For decades, physicians and scientists thought metformin, the leading Type 2 diabetes medication taken by millions worldwide, mainly targets the liver to suppress glucose production. But a new Northwestern study in mice, published in Nature Metabolism, has found this “wonder drug” instead focuses primarily on the gut, acting to prevent glucose levels rising in the blood by driving glucose utilization inside cells lining the intestine.

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 study found metformin slows mitochondrial energy production in gut cells, forcing the intestine to metabolize extra 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.

The study builds off findings from previous work in Chandel’s lab, which found metformin lowers blood sugar by blocking a specific part of the cell’s energy-making machinery called mitochondrial complex I, a key enzyme in cellular respiration. The new study furthers that work by pinpointing the specific tissue targeted by metformin. The findings suggest directing drugs or supplements to the gut could be an effective strategy for controlling blood sugar, Chandel said.  

Chandel also is the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonology and Critical Care, 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.

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

Parallels with berberine, ‘nature’s Ozempic’

The findings also reveal unexpected parallels with berberine, a popular plant-derived, over-the-counter supplement 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 found berberine appears to engage the same pathway as metformin in the intestine.

“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.”

Gut-related clinical observations from metformin users explained

Lastly, the findings help explain the following clinical observations of people who take metformin. According to Chandel, people on metformin:

• Tend to have lower blood sugar after meals. Metformin turns the gut into a “sponge” that soaks up extra sugar.
• Have lower levels of circulating citrulline, which is made only by mitochondria in small‑intestine cells. If metformin inhibits mitochondria, citrulline production drops.
• Have increased 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.

“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.”

More about how the study worked

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 resist 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.

Other Northwestern study authors include Ram Chakrabarty, PhD; Rogan Grant, PhD; Karis D’Alessandro, PhD; Alec Koss, Jenna Blum; Shawn Davidson, PhD, assistant professor of Medicine in the Division of Pulmonary and Critical Care; and Colleen Reczek, PhD, research assistant professor of Medicine in the Division of Pulmonary and Critical Care.

Funding for the study was provided by the National Institutes of Health (grants R35CA197532, P01HL154998-03 and P01AG049665), the National Heart, Lung, and Blood Institute of the NIH (grants T32HL076139-11 and T32HL076139-21), the Northwestern University Pulmonary and Critical Care Division Cugell Predoctoral Fellowship, the Cellular and Molecular Basis of Disease (grant T32GM008061), the NRSA Training Program in Signal Transduction and Cancer (grant T32CA070085), 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 (grant T32HL07139), the Medical Sciences Training Program (grant T32GM008152) and the Stand Up 2 Cancer Convergence 3.1416.