Exogenous GABA as a natural epigenetic modifier for managing glycemic memory and diabetic nephropathy by modifying the epigenetic axis

Background Glycemic memory contributes to the progression of diabetic nephropathy (DN) despite glycemic control. This study investigates γ-aminobutyric acid (GABA), a natural compound with 82.5% structural similarity to metformin, for its potential in mitigating glycemic memory and DN.Methods Structural similarity and molecular docking identified GABA as a SIRT1-targeting metformin analog (binding affinity: 5.8 kcal/mol), supported by ADME profiling. In vitro assays assessed antioxidant activity (DPPH IC50: 141.09 µg/mL), cytotoxicity (MTT assay), oxidative stress markers, and histone H3 acetylation. In vivo, high-fat diet-fed Sprague-Dawley rats underwent dietary reversal and GABA treatment (100/200 mg/kg) to evaluate metabolic, renal, hepatic, oxidative, and epigenetic effects.Results GABA maintained >90% cell viability at 5 µM, with no cytotoxicity up to 150 µM. It reduced oxidative markers and restored histone acetylation in vitro. In vivo, 200 mg/kg GABA treatment significantly reduced cholesterol (44.44%), triglycerides (28.64%), and LDL (40.80%), while increasing HDL by 103.65%. At 100 mg/kg, GABA lowered blood urea (30.43%), creatinine (4.65%), uric acid (75.00%), bilirubin (53.57%), SGOT (54.24%), SGPT (39.52%), and ALP (60.58%), with histopathological improvements in renal tissues.Conclusion GABA exhibits antioxidant, hepatoprotective, and renoprotective properties, highlighting its potential as a therapeutic agent for glycemic memory-associated DN.