-Methionine is a sulfur-containing amino acid that is reversibly converted into homocysteine. Homocysteine is an independent cardiovascular risk factor frequently associated with the insulin resistance syndrome. The effects of insulin on methionine and homocysteine kinetics in vivo are not known. Six middle-aged male volunteers were infused with L-[methyl-2 H3, 1-13 C]methionine before (for 3 h) and after (for 3 additional hours) an euglycemic hyperinsulinemic (150 mU/l) clamp. Steady-state methionine and homocysteine kinetics were determined using either plasma (i.e., those of methionine) or intracellular (i.e., those of plasma homocysteine) enrichments. By use of plasma enrichments, insulin decreased methionine rate of appearance (R a; both methyl-and carbon Ra) by 25% (P Ͻ 0.003 vs. basal) and methionine disposal into proteins by 50% (P Ͻ 0.0005), whereas it increased homocysteine clearance by ϳ70% (P Ͻ 0.025). With intracellular enrichments, insulin increased all kinetic rates, mainly because homocysteine enrichment decreased by ϳ40% (P Ͻ 0.001). In particular, transmethylation increased sixfold (P Ͻ 0.02), transsulfuration fourfold (P ϭ 0.01), remethylation eightfold (P Ͻ 0.025), and clearance eightfold (P Ͻ 0.004). In summary, 1) physiological hyperinsulinemia stimulated homocysteine metabolic clearance irrespective of the model used; and 2) divergent changes in plasma methionine and homocysteine enrichments were observed after hyperinsulinemia, resulting in different changes in methionine and homocysteine kinetics. In conclusion, insulin increases homocysteine clearance in vivo and may thus prevent homocysteine accumulation in body fluids. Use of plasma homocysteine as a surrogate of intracellular methionine enrichment, after acute perturbations such as insulin infusion, needs to be critically reassessed.clearance; transsulfuration; transmethylation; euglycemic clamp METHIONINE, A SULFUR-CONTAINING AMINO ACID that is abundant in meat and other animal proteins, is converted intracellularly to homocysteine through transmethylation with a methyl acceptor (4). Homocysteine, i.e., the demethylated form of methionine, is not normally present in the amino acid sequences of proteins, but it can accumulate in blood as well as in intracellular fluids in a number of conditions, such as arteriosclerosis (21), renal failure (33), Alzheimer's disease (2), neural tube defects (17), and others.Although not yet included in the cluster of factors associated with the insulin resistance syndromes (30, 36), homocysteine is usually increased in many of these conditions, such as type 2 diabetes, in particular with kidney insufficiency and/or proteinuria (35), obesity (13), and hypertension, particularly associated with diabetes (19). Thus a disturbance in the regulation by insulin of methionine/homocysteine metabolism can be suspected.Physiological hyperinsulinemia inhibited whole body leucine and phenylalanine appearance from endogenous body proteins in a dose-response fashion (7,27). Insulin also either decreased or did not a...