Metformin: Diabetic drug's surprising impact on brain For decades, metformin has been a cornerstone in managing type 2 diabetes, primarily known for its effects on the liver and gut. Now, groundbreaking research reveals a surprising role for the brain in metformin's action. Scientists have identified a specific protein, Rap1, in the brain's ventromedial hypothalamus, crucial for the drug's blood sugar-lowering capabilities. For 60 years, metformin has been the go-to medication to manage type 2 diabetes. It is known for lowering blood sugar, but there is no complete picture of how it really works. Scientists have now discovered its unexpected effect on the brain. Metformin works primarily by reducing glucose production in the liver and acting through the gut. However, researchers at Baylor College of Medicine and international collaborators have recognized a new player mediating clinically relevant effects of metformin: the brain. The findings are published in the journal Science Advances. "It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut. We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin," said corresponding author Dr. Makoto Fukuda, associate professor of pediatrics – nutrition at Baylor. The researchers focused on a small protein called Rap1, found in a specific part of the brain known as the ventromedial hypothalamus (VMH). They found that metformin’s ability to lower blood sugar at clinically relevant doses depends on turning off Rap1 in this brain region.#science_advances #baylor_college_of_medicine #ventromedial_hypothalamus #dr_makoto_fukuda #rap1
Metformin’s hidden brain pathway revealed after 60 years For over six decades, metformin has been a cornerstone treatment for type 2 diabetes, yet its exact mechanism of action remained unclear. A groundbreaking study led by researchers at Baylor College of Medicine, in collaboration with international partners, has uncovered a previously unknown pathway through which the drug influences blood sugar regulation in the brain. This discovery could lead to more effective diabetes therapies by targeting the brain’s role in the drug’s action. The research, published in Science Advances, challenges the long-held belief that metformin primarily works by reducing glucose production in the liver or modulating gut activity. Instead, the team found that the drug also acts directly in the brain, specifically in the ventromedial hypothalamus (VMH), a region critical for regulating whole-body glucose metabolism. By suppressing the activity of a protein called Rap1 in this brain area, metformin lowers blood sugar levels, offering a new perspective on its therapeutic effects. To investigate this, the researchers used genetically engineered mice lacking Rap1 in the VMH. When these mice were exposed to a high-fat diet—a model for type 2 diabetes—and treated with low doses of metformin, their blood sugar levels did not improve. In contrast, other diabetes treatments like insulin and GLP-1 agonists remained effective, highlighting the unique role of the brain in metformin’s action. Further experiments confirmed the brain’s involvement. When metformin was delivered directly into the brains of diabetic mice at doses thousands of times lower than typical oral doses, blood sugar levels dropped significantly.#science_advances #baylor_college_of_medicine #ventromedial_hypothalamus #rap1_protein #dr_makoto_fukuda
After 60 Years, Diabetes Drug Revealed to Unexpectedly Affect The Brain A long-standing diabetes medication, metformin, has been found to influence the brain in ways previously unknown, according to a study published in Science Advances. Researchers from Baylor College of Medicine in the U.S. identified a brain pathway through which the drug operates, adding to its known effects on the liver and gut. This discovery could pave the way for new treatments targeting the brain’s role in managing type 2 diabetes. For decades, metformin has been used to regulate blood sugar by reducing glucose production in the liver and improving insulin efficiency. However, its exact mechanism remained unclear until recent research suggested it also acts directly in the brain. The study focused on a protein called Rap1, which is active in a specific region of the brain known as the ventromedial hypothalamus (VMH). Experiments on mice revealed that metformin travels to the VMH, where it suppresses Rap1 activity, helping to counteract diabetes symptoms. When mice lacking Rap1 were tested, metformin had no effect on a diabetes-like condition, even though other drugs did. This finding strongly indicates that the drug’s anti-diabetic effects are partly mediated by the brain. The team also pinpointed specific neurons involved in this process, namely SF1 neurons, which become active when metformin is introduced to the brain. These neurons appear to be central to the drug’s mechanism, offering potential targets for more precise therapies. Direct injections of metformin into the brains of mice significantly lowered blood glucose levels, further supporting its role in the brain. While the drug’s effects on the liver and gut require higher concentrations, the brain responds to much lower doses.#science_advances #baylor_college_of_medicine #ventromedial_hypothalamus #rap1_protein #sf1_neurons
