Abstract
BackgroundAlthough alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). The aim of the current study was to predict changes in plasma methionine and homocysteine concentrations after simulated consumption of methionine-rich foods, following the development of a mathematical model for MMC in Zucker Diabetic Fatty (ZDF) rats, as a representative T2DM animal model.MethodThe model building and simulation were performed using NONMEM® (ver. 7.3.0) assisted by Perl-Speaks-NONMEM (PsN, ver. 4.3.0). Model parameters were derived using first-order conditional estimation method with interactions permitted among the parameters (FOCE-INTER). NCA was conducted using Phoenix (ver. 6.4.0). For all tests, we considered a P-value < 0.05 to reflect statistical significance.ResultsOur model featured seven compartments that considered all parts of the cycle by applying non-linear mixed effects model. Conversion of S-adenosyl-L-homocysteine (SAH) to homocysteine increased and the metabolism of homocysteine was reduced under diabetic conditions, and consequently homocysteine accumulated in the elimination phase.Using our model, we performed simulations to compare the changes in plasma methionine and homocysteine concentrations between ZDF and normal rats, by multiple administrations of the methionine-rich diet of 1 mmol/kg, daily for 60 days. The levels of methionine and homocysteine were elevated approximately two- and three-fold, respectively, in ZDF rats, while there were no changes observed in the normal control rats.ConclusionThese results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods.
Highlights
Alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM)
These results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods
A study performed in type 1 DM (T1DM) patients revealed an association between homocysteine levels and diabetic complications [7], and recent systematic review with a meta-analysis studies concluded that high levels of homocysteine may be associated with type 2 DM (T2DM) progression [8] and the development of vascular complications of diabetes [9]
Summary
Alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). As a universal key intermediate in the MMC, homocysteine is not obtained from the diet, but is remethylated to methionine, or converted to cysteine by the trans-sulfuration pathway It is well-known that elevated homocysteine levels are associated with the early development of cardiovascular diseases [4], especially increasing the risk in patients with diabetes mellitus (DM) [5, 6]. 0we hypothesized that long-term administration of a high-methionine diet to T2DM rats with normal renal function may create metabolic changes, culminating in an elevated level of circulating homocysteine To verify this hypothesis, mathematical modeling of methionine metabolism was required to predict the levels of homocysteine derived from given amounts of methionine
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