Experimental and computational study of the assocation between vitamin B12 and Glutathione in type 2 diabetes

Abstract

Diabetes mellitus is a growing problem in large parts of India, where the population is vegetarian, and vitamin B12 deficient. We ask if prevalent vitamin B12 deficiency is related to the rising number of diabetic patients. We tested newly diagnosed Indian diabetic patients for correlation between their vitamin B12 and GSH, and found it to be weak. We then examined the theoretical dependence of GSH on vitamin B12 with a mathematical model of 1-carbon metabolism due to Reed and co-workers. We found that the lack of correlation is due to homeostasis of homocysteine despite large variation in the activity of methionine synthase, a co-enzyme of vitamin B12. We therefore studied the methionine cycle in the Reed-Nijhout model in greater detail: We first constructed a reduced methionine cycle model extracted from the full network, and then based on that we developed a simple analytically tractable ’stylized model’ that captures the essential topology. We find – counter-intuitively – that the flux responsible for homeostasis of homocysteine is actually peripheral to the methionine cycle. These results suggest (i) a natural explanation of why GSH is observed to be independent of vitamin B12, despite being downstream of it in the metabolic network, and (ii) that the clinically observed symptom of vitamin B12 deficiency, hyperhomocysteinemia, is not due to a simple “remethylation-block”, as is commonly argued.