Impact of sirtuin-1 expression on H3K56 acetylation and oxidative stress: a double-blind randomized controlled trial with resveratrol supplementation

AIMS: Sirtuin-1 (SIRT-1) down-regulation in type 2 diabetes mellitus (T2DM) has been associated with epigenetic markers of oxidative stress. We herein aim to evaluate whether an increase in SIRT-1 expression affects histone 3 acetylation at the 56 lysine residue (H3K56ac) in T2DM patients randomly selected to receive either resveratrol (40 mg or 500 mg) or a placebo for 6 months. The primary outcome is changes in the H3K56ac level by variation in SIRT-1 expression and the secondary outcome is the evidence of association between SIRT-1 level, antioxidant markers (TAS), and metabolic variables. METHODS AND RESULTS: At baseline, peripheral blood mononuclear cell H3K56ac values among the SIRT-1 tertiles did not differ. At trial end, SIRT-1 levels were significantly higher in patients receiving 500 mg resveratrol. At follow-up, patients were divided into tertiles of delta (trial end minus baseline) SIRT-1 value. Significant reductions in H3K56ac and body fat percentage were found in the highest tertile as were increased TAS levels. A multiple logistic regression model showed that the highest delta SIRT-1 tertile was inversely associated with variations in H3K56ac (OR = 0.66; 95% CI 0.44-0.99), TAS (OR = 1.01; 95% CI 1.00-1.02), and body fat percentage (OR = 0.75; 95% CI 0.58-0.96). CONCLUSIONS: We provide new knowledge on H3K56ac and SIRT-1 association in T2DM. These data suggest that boosting SIRT-1 expression/activation may impact redox homeostasis in these patients. ClinicalTrials.gov Identifier NCT02244879.