Overview

• Metformin’s glucose-lowering effect at standard clinical doses depends on inactivating the Rap1 protein in the ventromedial hypothalamus.
• Within that brain region, SF1 neurons become more active in response to metformin only when Rap1 is present.
• Direct intracerebral injections of metformin in diabetic mice lowered blood sugar at doses thousands of times smaller than those required orally.
• Mice engineered without Rap1 in their ventromedial hypothalamus did not respond to low-dose metformin but retained normal glucose control with insulin and GLP-1 therapies.
• These insights open the door to developing brain-targeted diabetes treatments and investigating whether the same pathway underlies metformin’s neuroprotective effects.