Impact of enteral arginine supplementation on lysine metabolism in humans: A proof‐of‐concept for lysine‐related inborn errors of metabolism

Abstract

Background Patients with lysine‐related inborn errors of metabolism (pyridoxine dependent epilepsy [PDE] and glutaric aciduria type 1 [GA1]), follow a lysine‐restricted diet with arginine‐fortified lysine‐free amino acid formula and additional oral arginine supplementation as a newer therapy for PDE. The rationale of arginine supplementation is based on arginine's ability to compete with lysine transport across cell membranes via shared transporter systems. Adequate doses of arginine required to competitively inhibit enteral lysine uptake has not been studied in humans. Objectives This proof‐of‐concept study investigates the effect of incremental enteral arginine doses on whole‐body lysine oxidation using an in‐vivo stable isotope tracer, L‐[1‐¹³C] lysine, in healthy humans. Methods Five healthy men completed 6 study days each consuming one dose of L‐arginine HCl per study day; range = 50‐600 mg/kg/d. Lysine intake was at DRI (30 mg/kg/d). Breath samples were analyzed for L‐[1‐¹³C] lysine oxidation to ¹³CO₂ using an isotope ratio mass spectrometer. Plasma amino acid concentrations were analyzed using an amino acid analyzer. Results Increasing doses of L‐arginine HCl caused a linear decrease in whole‐body lysine oxidation. Plasma arginine concentration increased, and plasma lysine concentration decreased below normal range with high arginine intakes. Discussion We provide the first empirical evidence of arginine‐lysine antagonism in response to increasing oral arginine doses. Results suggest 300‐600 mg/kg/d of L‐arginine HCl and lysine intake restricted to DRI is needed to reduce enteral lysine uptake and systemic lysine oxidation. This could potentially lead to a recommended dose for arginine in lysine‐related inborn errors of metabolism.