It's long been thought that the type-2 diabetes drug taken by an estimated 20 million Americans was doing its heavy lifting in the liver, suppressing the production of glucose to regulate blood sugar. But new research has uncovered it's actually working its magic in the gut – which opens the door to the possibility of finding new compounds that perform the same function.
Metformin has been increasingly studied for its health impacts beyond glucose regulation, including its use as a weight-maintenance tool for people discontinuing GLP-1 treatment, shielding cells from age-related inflammation, and even mimicking the biological benefits of exercise in men with prostate cancer who are unable to be physically active. Other studies have found signs that it can reduce osteoarthritic joint pain, protect the brain from cognitive decline and, overall, prolong overall health longevity and lifespan.
While studies are in their early stages, it does seem to be associated with a wide range of health benefits, and much of the research aligns with an emerging body of evidence that the gut-brain axis plays a pivotal role in our health and how we age.
The new study adds to this, because metformin's hard work takes place in the gut – where Northwestern University scientists found it slows down the cellular machinery powering energy production – the mitochondria – and in turn forces the gut to metabolize excess sugar, regulating glucose levels.
“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,” says corresponding author Navdeep Chandel, a professor at Northwestern University's Feinberg School of Medicine.
In the study, the scientists used human metabolomic data and a mice model to uncover new mechanistic details about how the drug works in the gut, suppressing citrulline synthesis, which is a metabolite made only by mitochondria in the small intestine, and also increasing growth differentiation factor 15 (GDF15) – a stress-response hormone-like protein that, in its simplest terms, signals along the gut–brain axis to suppresses appetite and manage energy stability throughout the whole body.
"Despite [metformin's] extensive use, the mechanisms underlying many of its clinical effects, including attenuated postprandial glucose excursions, elevated intestinal glucose uptake, and increased production of lactate, Lac-Phe and GDF15, remain unclear," the scientists write in the study, "Here, we map these and other clinical effects of metformin to intestine-specific mitochondrial complex I inhibition.
"This inhibition co-opts the intestines to function as a glucose sink, driving uptake of excess glucose and converting it to lactate and Lac-Phe," they continue. "Notably, the glucose-lowering effect of another biguanide, phenformin, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism."
Ultimately, this all supports the evidence the scientists demonstrate in their work – that metformin works its power in the gut, opening the door not just to other existing drugs being used for intestinal blood-sugar regulation, but potentially to developing new compounds that focus on this part of the body's energy production biochemistry.
"We further determined that phenformin, another biguanide, and berberine, a natural compound used as an over-the-counter treatment for type 2 diabetes, lower blood glucose through the same mechanism," the team writes. "Thus, we identify mitochondrial complex I in intestinal epithelium as a shared and essential therapeutic target for metformin, phenformin, and berberine."
The study was published in the journal Nature Metabolism
Source: Northwestern University
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