Diabetes Drug Affects Brain (new study confirms)

A widely prescribed diabetes medication has been shown to lower blood glucose levels in part by acting directly on the brain, according to research from Baylor College of Medicine.

Metformin, used for more than 60 years as a first-line treatment for type 2 diabetes, suppresses a protein called Rap1 in a specific region of the hypothalamus known as the ventromedial hypothalamus, or VMH.

This action activates a subset of neurons there and contributes to the drug's glucose-lowering effects at clinically relevant doses.

The findings, published July 30, 2025, in the journal Science Advances, challenge the long-held view that metformin works primarily by reducing glucose production in the liver and altering gut function.

Researchers led by Makoto Fukuda, associate professor of pediatrics and nutrition at Baylor, tested the role of the brain using genetically modified mice fed a high-fat diet to model type 2 diabetes.

Mice lacking Rap1 in the forebrain or specifically in VMH steroidogenic factor 1 (SF1) neurons showed no blood sugar reduction from low-dose metformin, even though other diabetes drugs such as insulin and GLP-1 receptor agonists continued to work normally.

Direct injection of tiny amounts of metformin into the brains of diabetic mice produced a clear drop in blood glucose at doses thousands of times smaller than those given orally.

Electrophysiology experiments on brain slices confirmed that metformin increases the electrical activity of VMH SF1 neurons, but only when Rap1 is present.

Without the protein, the neurons did not respond and the glucose-lowering benefit disappeared.

The study also showed that metformin crosses the blood-brain barrier at therapeutic concentrations and that the brain responds to far lower drug levels than the liver or intestines require.

“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,” Fukuda said in a statement from Baylor College of Medicine. 

“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,” added further.

The results establish a neural mechanism for metformin’s action at standard therapeutic doses.

Forced activation of Rap1 in the VMH raised blood glucose and blocked the drug’s benefits, while loss of Rap1 in those neurons mimicked metformin’s effects.

Higher, suprapharmacological doses of the drug bypassed the brain pathway and worked through peripheral mechanisms, consistent with earlier observations.

The discovery adds to existing evidence that metformin crosses into the central nervous system and may explain some of its broader reported effects, including potential benefits on brain aging.

Fukuda noted that the same Rap1 signaling could play a role in those outcomes and said future work will examine that possibility.

The study itself was conducted entirely in mouse models, and human confirmation of the brain pathway has not yet been reported.

The work identifies the VMH Rap1 pathway in SF1 neurons as a critical mediator of metformin’s antidiabetic action and points toward the possibility of new therapies that target this brain circuit more precisely.

Source: https://www.bcm.edu/news/how-does-metformin-lower-blood-sugar.