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Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consumption of a Methionine-rich diet

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Authors
Han, Nayoung; Chae, Jung-woo; Jeon, Jihyun; Lee, Jaeyeon; Back, Hyun-moon; Song, Byungjeong; Kwon, Kwang-il; Kim, Sang Kyum; Yun, Hwi-yeol
Issue Date
2018-02-10
Publisher
BioMed Central
Citation
Nutrition & Metabolism, 15(1):14
Keywords
Methionine metabolism cycleHomocysteineMathematical modelMethionine-rich dietType 2 diabetesmellitus (T2DM)
Abstract
Background
Although 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.

Method
The 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.

Results
Our 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.

Conclusion
These results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods.
ISSN
1743-7075
Language
English
URI
http://hdl.handle.net/10371/139580
DOI
https://doi.org/10.1186/s12986-018-0247-1
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College of Pharmacy (약학대학)Research Institute of Pharmaceutical Sciences (종합약학연구소)Journal Papers (저널논문_종합약학연구소)
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