Tissue-specific alterations of methyl group metabolism with DNA hypermethylation in the Zucker (type 2) diabetic fatty rat.

BACKGROUND Altered methyl group and homocysteine metabolism were tissue-specific, persistent, and preceded hepatic DNA hypomethylation in type 1 diabetic rats. Similar metabolic perturbations have been shown in the Zucker (type 2) diabetic fatty (ZDF) rat in the pre-diabetic and early diabetic stages, but tissue specificity and potential impact on epigenetic marks are unknown, particularly during pathogenesis. METHODS ZDF (fa/fa) and lean (+/?) control rats were killed at 12 and 21 weeks of age, representing early and advanced diabetic conditions. Blood and tissues were analysed with respect to methyl group and homocysteine metabolism, including DNA methylation. RESULTS At 12 weeks, hepatic glycine N-methyltransferase (GNMT), methionine synthase, and cystathionine β-synthase (CBS) activity and/or abundance were increased in ZDF rats. At 21 weeks, GNMT activity was increased in liver and kidney; however, only hepatic CBS protein abundance (12 weeks) and betaine-homocysteine S-methyltransferase mRNA expression (21 weeks) were significantly elevated (78 and 100%, respectively). Hepatic phosphatidylethanolamine N-methyltransferase expression was also elevated in the ZDF rat. Homocysteine concentrations were decreased in plasma and kidney, but not in liver, at 12 and 21 weeks. In contrast to hepatic DNA hypomethylation in the type 1 diabetic rat, genomic DNA was hypermethylated at 12 and 21 weeks in the liver of ZDF rats, concomitant with an increase in DNA methyltransferase 1 expression at 21 weeks. CONCLUSIONS The pathogenesis of type 2 diabetes in the ZDF rat was associated with tissue and disease stage-specific aberrations of methyl group and homocysteine metabolism, with persistent hepatic global DNA hypermethylation.