Low-dose metformin in the brain: A focused review of its novel mechanism of glucose lowering in type 2 diabetes

Metformin remains the first-line pharmacological therapy for type 2 diabetes mellitus (T2DM). While its glucose-lowering effects have primarily been attributed to peripheral actions, evidence indicates that it also crosses the blood-brain barrier (BBB) and can exert anti-diabetic effects from within the central nervous system (CNS). This focused review discusses metformin's central actions and how they might integrate with established peripheral mechanisms of glucose-lowering. We synthesized recent mechanistic studies conducted in murine models using systemic and intracerebroventricular metformin administration, brain-specific genetic loss- and gain-of-function approaches, neuronal activation mapping, electrophysiology, and pharmacological interrogation of autonomic and metabolic pathways. The evidence reviewed indicates that clinically relevant low concentrations of metformin in the brain engage a ventromedial hypothalamus (VMH)-steroidogenic factor 1 (SF1) neuron-Ras-proximate-1 (Rap1) signaling axis, which is essential for its glucose lowering action. Notably, metformin inhibits Rap1 in VMH SF1 neurons to reduce hyperglycemia. This central mechanism appears specific to metformin and is not shared by other approved antidiabetic agents. Current data also imply that the CNS effects of metformin operate in conjunction with peripheral pathways including hepatic AMP-activated protein kinase (AMPK) signaling and gut-derived glucagon-like peptide-1 (GLP-1) secretion, to produce its overall metabolic effect. Collectively, these findings support a model in which metformin lowers glucose through an orchestrated integration of a central Rap-1 dependent mechanism and peripheral metabolic actions. Additionally, the recognition of a central component to metformin's pharmacology expands the mechanistic framework of this cornerstone therapy and may inform future therapeutic strategies targeting integrated brain-metabolic pathways in T2DM.