Metformin targets the gut instead of the liver to lower glucose
· News-Medical"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'
"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, Rogan Grant, Karis D'Alessandro, Alec Koss, Jenna Blum, Shawn Davidson and Colleen Reczek.
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