GABA as an Overlooked Mediator of Metformin Action: GABA-mediated Neuropsychiatric and Hepatoprotective Activities of Metformin.

BACKGROUND: According to treatment guidelines, metformin is the first-line medication for type 2 diabetes. The neuropsychiatric and hepatoprotective activities of metformin, mediated by modulation of gamma-aminobutyric acid (GABA) signalling pathways, have recently attracted the attention of researchers. SUMMARY: The objective of this narrative review is to compile the most recent data from original research on the GABA-mediated effects of metformin in a range of disorders. Original articles were searched from various electronic databases using relevant search terms. According to animal studies on rodent models of anxiety, metformin increases the intracellular level of AMP-activated protein kinase and GABAergic neurotransmission in the hippocampus and medial prefrontal cortex, resulting in anxiolytic effects. Similarly, metformin increased the levels of GABA and lowered the levels of glutamate in the hippocampus of diabetic epileptic rats. This action was associated with reduced neuroinflammation and apoptosis and improved cognitive function and seizure outcomes. Additionally, an open-label clinical trial with people who have Fragile X syndrome demonstrated that metformin is potentially an effective treatment, and it might improve GABA-mediated inhibition of the cortex as a mechanism. Moreover, beyond the neuropsychiatric action in the central nervous system, metformin reduced ferroptosis in a mouse model of hepatic ischemia/reperfusion injury, with GABA identified as a key microbiota-derived metabolite involved in hepatoprotection. KEY MESSAGE: Animal and human studies showed that GABAergic signalling pathways are involved in neuropsychiatric and hepatoprotective activities of metformin. However, the available literature is still fragmented and mainly based on animal studies, suggesting the need for more detailed mechanistic studies and human studies.