Mathematical modeling of glutathione status in type 2 diabetics with vitamin B 12 deficiency

Abstract

Deficiencies in vitamin B 12 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 12 and GSH, and found it to be weak. Here we seek to examine the theoretical dependence of GSH on vitamin B 12 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 12 -dependent enzyme, however, this does not increase GSH biosynthesis. The model suggests that the lack of vitamin B 12 -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 12 deficiency. It can be clinically relevant to appreciate that these secondary effects of vitamin B 12 deficiency could be central to its pathophysiology.