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.