Insulin in methionine and homocysteine kinetics in healthy humans: plasma vs. intracellular models

Abstract

-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...

Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline

“…In these young female rats, plasma homocysteine enrichment achieved plateau within 3 h of a primed infusion, compatible with rate constants of 1.5-1.7/h, a half-life of Ͻ30 min estimated from the observed ILR, and an assumed homocysteine content in total body water based on plasma concentration. A similar rapid equilibration (3 h) was observed in some human studies (38) but not others (19).…”

“…These objectives were tackled by stable isotope procedures based on isotopomer analysis. The first involved infusion of bis-[1-13 C,methyl-2 H 3 ]methionine (36,38), whereas the second utilized [1-13 C]homocysteine in combination with [U- 13 C]methionine. The study involves virgin female rats to provide basal information before examination of changes in maternal and fetal metabolism during pregnancy in response to dietary imbalances that impact on the methionine cycle.…”

Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract

“…In this study, the relative plasma [ 13 C]homocysteine/ [ 13 C]methionine enrichments were considerably higher than recent reports in humans under postabsorptive (37,38) and insulin-stimulated conditions. Theoretically, in tissues with the enzymatic capacity for transmethylation the intracellular enrichment of [ 13 C]methionine and [ 13 C]homocysteine should be similar, assuming that there is one common intracellular pool.…”

Hyperhomocysteinemia and Type 2 Diabetes in Côte d'Ivoire

“…Our study has showed a significant glycemia in the hyperhomocysteinemic diabetics compared to control group, suggesting possible synergistic interactions between the diabetes and the hyperhomocysteinemia. The studies linking the insulin resistance to plasma homocysteine levels are discordant [23]. Although the physiological mechanisms linking the insulin resistance to the hyperhomocysteinemia are not elucidated, it was observed that plasma homocysteine concentrations were frequently increased with the insulin resistance [23], suggesting a link between the hyperhomocysteinemia and the insulin resistance.…”

“…The studies linking the insulin resistance to plasma homocysteine levels are discordant [23]. Although the physiological mechanisms linking the insulin resistance to the hyperhomocysteinemia are not elucidated, it was observed that plasma homocysteine concentrations were frequently increased with the insulin resistance [23], suggesting a link between the hyperhomocysteinemia and the insulin resistance. The diabetes via its free radicals potentiates the deleterious effects of the hyperhomocysteinemia on the vascular endothelium [24].…”