Aberrations of methyl group and homocysteine metabolism during the progression of diabetes in the ZDF rat

Abstract

Altered methyl group and homocysteine (Hcy) metabolism was tissue‐specific, non‐transient, and preceded hepatic DNA hypomethylation in STZ‐induced type 1 diabetes. Similar perturbations occur in the Zucker (type 2) diabetic fatty (ZDF) rat, but the tissue specificity and effect of disease progression are unknown. ZDF and lean rats were killed at 12 and 21 wk of age. At 12 wk, hepatic glycine N‐methyltransferase (GNMT), methionine synthase, and cystathionine β‐synthase (CBS) activity/abundance were increased, whereas plasma Hcy was decreased in ZDF rats. At 21 wk, GNMT was induced in liver and kidney. In liver only, there was a trend toward increased CBS protein abundance (78%, p = 0.080) and betaine‐Hcy methyltransferase mRNA expression (~100%, p = 0.098). Phosphatidylethanolamine methyltransferase activity tended to be lower in ZDF liver (p =0.071) despite an increase (p < 0.05) in mRNA expression. Hcy levels were decreased in plasma and kidney, but not in liver, at 12 and 21 wk. Elevated glutathione concentrations in liver and kidney at 12 wk, and in kidney at 21 wk, suggests altered regulation of redox homeostasis. Hepatic genomic DNA was hypermethylated at 12 and 21 wk, with a trend toward increased DNMT1 mRNA expression (p = 0.08) at 21 wk. In summary, alterations of methyl group and Hcy metabolism, redox status, and epigenetic regulation result during the progression of type 2 diabetes. Support: Am. Heart Assn.