Possible protective effect of procainamide as an epigenetic modifying agent in experimentally induced type 2 diabetes mellitus in rats

Abstract

Background: Diabetes mellitus (DM) is a metabolic disease that is associated with disturbed carbohydrates, lipids and protein metabolism due to insulin deficiency and/or impaired insulin action. Recently epigenetic mechanisms were shown to be involved in endocrine cell differentiation and islets function. Procainamide which is a cardiac antiarrhythmic drug has been recently classified as one of the epigenetic drugs targeting DNA methylation.
Aim: The present study was designed to evaluate the effect of procainamide as a demethylating epigenetic agent on streptozotocin-induced type 2 diabetes mellitus in rats.
Methods: Fifty adult male albino rats of weight ranging from 150 to 200 g were included in this study. Rats were divided into five groups (each of 10 rats) as follows: group I: served as a normal control group, group II: diabetic rats that received 1 ml gum acacia 2% orally, daily for 4 weeks, group III: diabetic rats that received procainamide (20 mg/kg body weight)/day, orally for 4 weeks, group IV: diabetic rats that received metformin (300 mg/kg/day), orally for 4 weeks, group V: diabetic rats that received both procainamide and metformin in the same previous doses for 4 weeks. The following parameters were assessed in rats of all studied groups: fasting blood glucose level, serum insulin level, serum tumor necrosis factor alpha (TNF-a) (as a proinflammatory cytokine as well as an indirect biomarker of DNA methylation) and DNA methyltransferase enzyme (DNMT) activity in pancreatic tissues (as a direct marker of DNA methylation).
Results: The present study revealed that combined administration of both procainamide and metformin produced a statistically significant reduction of fasting blood glucose levels as compared to untreated diabetic rats as well as diabetic rats treated by either procainamide or metformin alone. In addition, procainamide administration either alone or in combination with metformin resulted in a statistically significant rise of serum insulin levels. TNF-a levels were statistically elevated in diabetic untreated rats as well as those treated with metformin only while procainamide intake led to its statistical decrease. Also, procainamide administration produced a statistically significant reduction in the activity of DNA methyltransferase in pancreatic tissues reflecting its possible role as a demethylating agent that increases insulin expression and release by pancreatic cells.
Conclusion: The present work could provide a proof of concept that procainamide could be used as a possible therapeutic potential in type 2 diabetics as an epigenetic demethylating agent to increase insulin levels and it is better to be used in combination with oral hypoglycemic agent e.g. metformin to decrease insulin resistance.