Glycine Supplements Cut Liver Enzymes and Triglycerides in Severe Obesity

Glycine is the smallest amino acid but plays outsized roles in human metabolism — serving as a precursor for glutathione (GSH), a substrate for phase II detoxification via acylglycine conjugation, and a primary donor of single-carbon units to the 1-carbon cycle. Individuals with severe obesity are known to have significantly lower circulating glycine, partly due to slower de novo synthesis, and this deficiency may impair all three pathways, potentially worsening oxidative stress, toxin accumulation in the liver, and dysregulated methylation reactions. Despite these mechanistic links, glycine supplementation had not previously been tested in a severely obese cohort.

This single-arm, exploratory clinical trial (ClinicalTrials.gov NCT04658134) enrolled 19 adults with severe obesity (mean BMI 38.3 kg/m²) and treated them with oral glycine at 100 mg/kg/day for two weeks. Compliance was high (93% of prescribed doses consumed), and no adverse effects were reported. Comprehensive metabolic panels, amino acid profiles, urinary acylglycines, GSH, and 1-carbon cycle metabolites were measured before and after treatment.

Glycine supplementation significantly raised plasma glycine by approximately 49 µmol/L (from 138 to 186 µmol/L, p<0.001), directly reversing the deficiency state. Urinary excretion of four acylglycines — isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine — all increased significantly, indicating that the glycine conjugation detoxification pathway was enhanced, likely improving the liver's ability to clear potentially hepatotoxic metabolic byproducts. Clinically, plasma triglycerides fell significantly, as did alanine transaminase (ALT) and aspartate transaminase (AST), while the glutamate-serine-glycine (GSG) index — an indirect biomarker of MASLD severity — also improved, collectively suggesting reduced hepatic stress.

In the 1-carbon cycle, plasma serine, homocysteine, cysteine, and folate all rose significantly, indicating that increased glycine availability accelerated flux through this pathway. Interestingly, GSH concentrations were unchanged, suggesting that two weeks may be insufficient to detectably rebuild the GSH pool, or that other limiting factors constrain GSH synthesis in this population. Body weight, body composition, blood pressure, cholesterol fractions, HbA1c, fasting glucose, fasting insulin, and insulin resistance indices (HOMA-IR, Matsuda index) were all unchanged, consistent with the short intervention window.

These results position glycine supplementation as a potentially safe and accessible dietary intervention for improving liver health in severe obesity, particularly MASLD, by simultaneously enhancing detoxification capacity and 1-carbon metabolism. The authors call for larger, randomized controlled trials — ideally with liver biopsy or imaging endpoints — to confirm these preliminary findings and clarify optimal dosing and duration.