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Scientists have uncovered evidence that metformin’s effects may begin in an unexpected place: the intestine.
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.
Scientists have uncovered evidence that metformin’s effects may begin in an unexpected place: the intestine.
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.
Credit: Kristin Samuelson, Northwestern University
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.”
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.”
Credit: Kristin Samuelson, Northwestern University
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.
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.
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Given to a pile of people and didn't even know how or why it worked. For me berberine grows in the front yard.
ReplyDeleteBarberries
2. Contain beneficial plant compounds
Barberries are rich in berberine, a unique plant compound that may be associated with several health benefits.
Berberine is a member of the alkaloid family, a group of compounds known for their therapeutic effects
Studies have shown that it acts as a powerful antioxidant, combating cell damage caused by reactive molecules called free radicals
Also, berberine may help reduce blood sugar and cholesterol levels, slow the progression of certain cancer cells, fight infections, and have anti-inflammatory effects
What’s more, barberries contain other compounds that may have health benefits, such as other alkaloids and organic acids. Yet, most research has focused on berberine