By Elodie Vaz | Published on May 20,
2026 | 4 min read
For decades, metformin
has been regarded as a drug that acts primarily on the liver to reduce glucose
production. But a new study conducted by Northwestern University and published
on May 8 in Nature Metabolism challenges this paradigm: the true site of
its action may actually be the intestine. In mice, researchers show that the
drug works by directly modifying the energy metabolism of intestinal cells,
effectively turning the intestine into a “glucose sponge.”
Type 2 diabetes is
characterized by chronic hyperglycemia linked to progressive insulin
resistance. When the body can no longer properly use glucose, it accumulates in
the bloodstream, increasing the risk of vascular, renal, neurological, and
cardiovascular complications. For several decades, metformin has been the
first-line treatment used to control excessive blood sugar levels.
Until now, the scientific
consensus held that the molecule mainly reduced hepatic glucose production.
However, several clinical observations remained difficult to explain, including
its pronounced effect after meals, its ability to reduce appetite, and its
multiple metabolic effects.
Rethinking metformin’s
mechanism of action
The aim of this new study
was precisely to identify the tissue truly responsible for metformin’s
therapeutic effects. The work builds on previous research from Navdeep
Chandel’s laboratory, which had already shown that the drug inhibits
mitochondrial complex I, an enzyme essential for cellular respiration and
energy production.
The key question,
however, remained unanswered: in which organ does this inhibition produce the
metabolic effects observed in patients? “Metformin essentially helps the
intestine absorb glucose from the blood, which further highlights the
intestine’s major role in blood sugar regulation,” explained Dr. Navdeep
Chandel, senior author of the study and professor of biochemistry and molecular
genetics at the Feinberg School of Medicine, in a press release.
To answer this question,
the researchers used a mouse model expressing a yeast enzyme, NDI1, capable of
mimicking mitochondrial complex I while remaining resistant to inhibition by
metformin.
This enzyme was expressed
specifically in the intestinal cells of the mice, rendering only the intestine
insensitive to the drug. The researchers then observed the effects on blood
glucose levels in treated animals.
The results showed that
when intestinal mitochondria could no longer be inhibited by metformin, the
drug’s glucose-lowering effect was significantly reduced. These findings
demonstrate that the intestine may be a major — if not central — site of the
molecule’s therapeutic action.
Intestinal
mitochondria at the heart of blood sugar control
The study shows that
metformin slows mitochondrial energy production in intestinal mucosal cells.
This energy deficit then forces the cells to consume more glucose in order to
maintain their metabolic activity.
In other words, the
intestine actively captures circulating sugar, thereby reducing blood glucose
levels after meals. This discovery also helps explain several phenomena long
observed in patients taking metformin.
Researchers notably
reported reduced circulating levels of citrulline, a molecule produced
exclusively by the mitochondria of the small intestine, as well as increased
levels of GDF15, a hormone associated with reduced appetite and weight loss.
“We’ve always wondered
how one drug could have ten different effects,” said Dr. Chandel. “Well, it’s
possible if it targets a key component of the cell, and targeting mitochondria
is a key component.”
The study also highlights
unexpected similarities with berberine, a dietary supplement widely promoted on
social media. According to the authors, berberine appears to use the same
intestinal metabolic pathway as metformin.
The researchers
nevertheless urge caution. “Metformin is supported by decades of clinical
evidence, whereas supplements like berberine are far less studied,” Dr. Chandel
emphasized.
A new therapeutic
target?
Beyond metformin itself,
this study opens the door to a new therapeutic approach centered on the
intestine and intestinal mitochondria. According to Professor Zach Sebo, these
findings invite researchers to reassess established models: “Our study suggests
that revisiting assumptions about metformin’s mechanism of action could lead to
a better understanding of how it works.”
Read next: Liver,
sugar, and pills: who's in control?
About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on
human life. A registered nurse since 2010, she spent twelve years at patients’
bedsides before exchanging her stethoscope for a notebook. She now investigates
the links between environment and health, convinced that the vitality of life
cannot be reduced to that of humans.
