Abnormal methyl group metabolism and epigenetic regulation in the Zucker (type 2) diabetic fatty rat

Abstract

Methyl group metabolism and DNA methylation have been shown to be altered in a streptozotocin‐induced model of type 1 diabetes. The Zucker diabetic fatty (ZDF) rat exhibits similar perturbations of methyl group metabolism, but DNA methylation status and the expression of epigenetic regulatory proteins have not been characterized in this model of type 2 diabetes. Because epigenetic regulation could be linked to secondary complications associated with type 2 diabetes, we chose to examine methyl group metabolism, including DNA methylation, in the liver and pancreas, as well as the heart and kidney. At 12 wk of age, 6 ZDF and 6 lean rats were sacrificed for blood and tissue analysis. As expected, ZDF rats were diabetic (2X increase in glucose and insulin) and exhibited marked hypohomocysteinemia. Glycine N‐methyltransferase (GNMT), a regulator of transmethylation, was divergently regulated in different tissues. In ZDF rats, hepatic GNMT activity and abundance were increased, whereas pancreatic activity was decreased. No change was noted in renal GNMT activity and abundance, or cardiac GNMT abundance, despite a lack of activity. In contrast to type 1 diabetes, hepatic DNA was hypermethylated in ZDF rats. Mechanistically, it appears that expression of epigenetic regulatory proteins (i.e. DNA methyltransferases and methyl CpG binding proteins) was abnormal in diabetic animals as well. (Support: Amer. Heart Assoc.)Grant Funding SourceAmerican Heart Association