Scientists have uncovered a new dimension to how metformin, a decades-old diabetes drug, works. While it’s long been known that metformin primarily reduces glucose production in the liver or affects the gut, a new study reveals it also acts directly in the brain. Researchers from Baylor College of Medicine and collaborators found that the drug suppresses a protein called Rap1 in a specific brain region, the ventromedial hypothalamus (VMH). By doing so, metformin activates certain neurons that help lower blood sugar — and it does so even at very low, brain-targeted doses. To confirm the specificity, the team used genetically modified mice that lacked Rap1 in the VMH: when fed a high-fat diet and given metformin, their blood sugar levels did not improve, whereas other diabetes treatments (insulin, GLP-1 agonists) still worked. They also injected tiny amounts of metformin directly into the brains of diabetic mice and observed significant blood sugar reduction. The study identified SF1 neurons in the VMH as key players: metformin increased their electrical activity, but only when Rap1 was present. This finding could lead to more precise and effective diabetes treatments in the future.
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