Study Reveals Metformin's Brain Mechanism for Blood Sugar Control
New research reveals metformin regulates blood sugar through brain pathways involving the Rap1 protein in the hypothalamus. The study shows suppressing Rap1 in the brain prevents metformin from lowering blood sugar in diabetic mice. These findings could lead to new diabetes treatments targeting this brain pathway.
A study has uncovered a brain-related pathway for how metformin — the first-line treatment for diabetes for over 60 years — regulates blood sugar, opening the door to more targeted therapies. Researchers identified the Rap1 protein in the hypothalamus as key to metformin's brain effect, with suppressing Rap1 in the brain stopping metformin from lowering blood sugar in diabetic mice.
The research shows that metformin regulates blood sugar by acting on brain pathways, not just liver or gut. "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," the author stated. "We looked into the brain as it is widely recognised as a key regulator of whole-body glucose metabolism."
While diabetes medications are not considered as targeting the brain, the study, published in the journal Science Advances, shows that metformin has been influencing brain pathways all along. "These findings open the door to developing new diabetes treatments that directly target this pathway in the brain," the researcher said.
Researchers focussed on Rap1, a protein located inside the brain's ventromedial hypothalamus, which is critical for regulating satiety and sensing glucose. They found that suppressing activity of Rap1 in the specific brain region helped metformin reduce blood sugar in a meaningful manner.
The team tested the result by observing genetically engineered mice who lacked Rap1 in the ventromedial hypothalamus. The mice, placed on a high-fat diet to model type 2 diabetes, were treated with low doses of metformin and their blood sugar levels did not improve. However, other diabetes treatments such as insulin and GLP-1 agonists remained effective.
The brains of the diabetic mice were then delivered metformin directly. Even at doses thousands of times lower than those typically taken orally, the treatment led to a marked reduction in blood sugar levels. "We also investigated which cells in the VMH (ventromedial hypothalamus) were involved in mediating metformin's effects. We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they're directly involved in the drug's action," the researcher explained.
Analysing brain tissue samples, the researchers measured electrical activity of the SF1 neurons — metformin increased activity in most of them, but only when Rap1 was present. Among mice that lacked Rap1 in SF1 neurons, the diabetes drug was seen to have no effect, demonstrating that Rap1 is required for metformin to activate the brain cells and regulate blood sugar.
"This discovery changes how we think about metformin. It's not just working in the liver or the gut, it's also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels," the researcher stated.
Metformin's use in humans for treating diabetes was first reported in 1957 in France.