AUTHOR=Karamshetty Varun , Acharya Jhankar D. , Ghaskadbi Saroj , Goel Pranay 

TITLE=Mathematical Modeling of Glutathione Status in Type 2 Diabetics with Vitamin B12 Deficiency

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=4

YEAR=2016

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00016

DOI=10.3389/fcell.2016.00016

ISSN=2296-634X

ABSTRACT=<p>Deficiencies in vitamin B<sub>12</sub> and glutathione (GSH) are associated with a number of diseases including type 2 diabetes mellitus. We tested newly diagnosed Indian diabetic patients for correlation between their vitamin B<sub>12</sub> and GSH, and found it to be weak. Here we seek to examine the theoretical dependence of GSH on vitamin B<sub>12</sub> with a mathematical model of 1-carbon metabolism due to Reed and co-workers. We study the methionine cycle of the Reed-Nijhout model by developing a simple “stylized model” that captures its essential topology and whose kinetics are analytically tractable. The analysis shows—somewhat counter-intuitively—that the flux responsible for the homeostasis of homocysteine is, in fact, peripheral to the methionine cycle. Elevation of homocysteine arises from reduced activity of methionine synthase, a vitamin B<sub>12</sub>-dependent enzyme, however, this does not increase GSH biosynthesis. The model suggests that the lack of vitamin B<sub>12</sub>–GSH correlation is explained by suppression of activity in the trans-sulfuration pathway that limits the synthesis of cysteine and GSH from homocysteine. We hypothesize this “cysteine-block” is an essential consequence of vitamin B<sub>12</sub> deficiency. It can be clinically relevant to appreciate that these secondary effects of vitamin B<sub>12</sub> deficiency could be central to its pathophysiology.</p>