Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consum
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RESEARCH
Open Access
Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consumption of a Methionine-rich diet Nayoung Han1, Jung-woo Chae2, Jihyun Jeon2, Jaeyeon Lee2,3, Hyun-moon Back2, Byungjeong Song2,4, Kwang-il Kwon2, Sang Kyum Kim2 and Hwi-yeol Yun2*
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-SpeaksNONMEM (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. Keywords: Methionine metabolism cycle, Homocysteine, Mathematical model, Methionine-rich diet, Type 2 diabetes mellitus (T2DM)
* Correspondence: [email protected] Nayoung Han and Jung-woo Chae contributed equally to this work as the first author. Sang Kyum Kim and Hwi-yeol Yun contributed equally to this work as the corresponding author. 2 College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original autho
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