EPIGENETIC ALTERATIONS IN PATIENTS
WITH TYPE 2 DIABETES MELLITUS
Karachanak-Yankova S1,a, Dimova R2,a, Nikolova D1, Nesheva D1, Koprinarova M3,
Maslyankov S4, Tafradjiska R5, Gateva P6, Velizarova M7, Hammoudeh Z1, Stoynev N2,
Toncheva D1, Tankova T2, Dimova I1,*
*Corresponding Author: Ivanka Dimova, Associate Professor, Department of Medical Genetics, Medical University
Sofia, Zdrave str. 2, 1431 Sofia, Bulgaria. Tel: +359-2-91-72-735. E-mail: ivanka.i.dimova@ gmail.com
page: 15
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INTRODUCTION
Type 2 diabetes mellitus (T2DM) is characterized
by hyperglycemia arising from insulin resistance
combined with relative insulin deficiency. As
hyperglycemia becomes chronic, it leads to oxidative
stress, which is one of the central mechanisms for
glucose toxicity. It is the proximate cause of retinopathy,
kidney failure, neuropathies, and macrovascular
disease in diabetes [1].
The genetic basis for developing T2DM has
been recognized for a long time. The concordance
of T2DM in monozygotic twins is ~70.0% compared
with 20.0-30.0% in dizygotic twins and a sibling of an affected individual has about three times higher risk
for developing the disorder than the general population
[2].
The decades of research into the genetic causes
of T2DM have culminated with a succession of large
genome-wide association studies. Despite their power
and cost, they have identified genetic variants that
increase T2DM risk by only 10.0-30.0% [3-5].
The incidence of T2DM has increased dramatically
over the past decades [6], which is a too short
period for accumulation of considerable alterations in
the human genome. Therefore, it is likely that environmental
factors, such as diet and sedentary lifestyle,
might play a significant role in the development of
the disease.
The role of epigenetic factors in the gene environment
interactions pointed to epigenetics as a
possible molecular link between environmental factors
and T2DM. Previous studies have shown that
epigenetic mechanisms can predispose individuals
to the diabetic phenotype. Conversely, the altered
homeostasis in T2DM, such as prolonged hyperglycemia,
dyslipidemia and increased oxidative stress
could also cause epigenetic changes associated with
the development of disease complications [7].
The operational definition of epigenetics proposes
three successive signals for the establishment of
the epi-genetic state: an environmental signal (i) that
triggers a second intracellular signal, (ii) to establish
the exact chromatin location where the modification
will take place, and (iii) a third sustaining signal
that helps maintain this modification. The epigenetic
make-up changes during intrauter-ine and early
postnatal development, as well as throughout adult
life [8].
A classic example of epigenetic transcriptional
regulation is the covalent post replicative methylation
of DNA at the fifth position of the cytosine ring
of CpG dinucleotides. DNA methylation is a highly
dynamic process in development and disease. It is
strongly associated with gene silencing and decreased
gene expression [9]. The functional significance of
DNA methylation alterations became apparent with
their recognition as critical contributors to the pathogenesis
of cancer, acting by silencing of tumor suppressor
genes [10]. There is convincing evidence
that DNA methylation is performed by DNA methyltransferases
(DNMTs). DNMT1 is essential for maintaining
DNA methylation patterns in proliferating
cells as it methylates CpG dinucleotides in the newly
synthesized strand and DNMT3a and DNMT3b are
necessary for de novo meth-ylation during embryonic
development [11].
The biological consequences of DNA methylation
are mediated by a family of methyl-CpG binding
domain (MBD) proteins. Among these, only MBD2
seems to be specific for methyl-CpG sites alone. It
directs a multi subunit complex containing nucleosome
remodeling and histone deacetylase activities to
methylated DNA, thus leading to gene silencing [12].
Taking into account the role of epigenetics in
the pathogenesis of type 2 diabetes mellitus, we have
per-formed analysis of MBD2 expression levels in
T2DM patients and controls. Considering also that
altered metabolic homeostasis and increased oxidative
stress in T2DM can trigger epigenetic changes
that can lead to disease complications, we calculated
the fractions of DNA methylation of 22 genes related
to stress and toxicity in groups of healthy controls
and T2DM patients with different duration of the
disease, newly-diagnosed and with disease duration
of less and more than 5 years.
Based on the obtained results, we answered
the following questions: i) are there any MBD2 expression-
related changes in DNA methylation in the
pathogenesis of T2DM; ii) what is the role of the
epigenetic changes in 22 genes related to stress and
toxicity in T2DM pathogenesis and progression; and
iii) are these changes related to the increased risk of
oncological disorders in T2DM patients.
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