Acta Diabetologica (2018) 55:331–340
Impact of sirtuin‑1 expression on H3K56 acetylation and oxidative
stress: a double‑blind randomized controlled trial with resveratrol
· Gabriele Togliatto
· Roberto Gambino
· Valentina Ponzo
· Giusy Lombardo
· Rosalba Rosato
· Maria Felice Brizzi
Received: 13 November 2017 / Accepted: 29 December 2017 / Published online: 12 January 2018
© The Author(s) 2018. This article is an open access publication
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.
Keywords Resveratrol · Epigenetics · PBMC · Sirtuin-1
Chronic diseases, including obesity and diabetes mellitus
(T2DM), correlate with redox homeostasis imbalance.
Mitochondrial reactive oxygen species (ROS) generation
is considered the major regulator of hyperglycemia-medi-
ated epigenetic changes, including histone (H) posttrans-
lational modiﬁcations [1, 2]. In particular, H3K terminal
tail acetylation largely results in gene transcription after
genotoxic damage [3, 4]. Lo et al.  have recently shown
that the highest H3 acetylation level at the 56 lysine residue
(H3K56ac) is associated with proteins and transcription fac-
tors involved in T2DM signaling pathways in half of the
mature adipocyte genome. H3K56 is deacetylated by the
class III histone deacetylase (HDAC) sirtuins [3, 4]. One sir-
tuin family member, SIRT-1, was found persistently down-
regulated in T2DM patients  and has been associated with
mitochondrial ROS accumulation and increased p53 acety-
lation (p53ac) levels [7, 8]. Little data on the association
between SIRT-1 and H3K56ac have been provided [3, 4, 9].
Resveratrol, 3,5,4′-trihydroxy-trans-stilbene, activates
SIRT-1 and is a ROS scavenger . Its beneﬁts in human
disease are highly controversial since not all the beneﬁcial
properties described in preclinical studies have been con-
ﬁrmed by clinical trials [11, 12], and concerns about its
favorable eﬀects were recently raised by systematic reviews
and position statements [13–15]. We recently failed to detect
Managed by Massimo Porta.
* Maria Felice Brizzi
Department of Medical Sciences, University of Turin, Corso
Dogliotti 14, 10126 Turin, Italy
Department of Psychology, University of Turin, Turin, Italy