Running head: The Epigenetics of methylation status of DNA

Running head:  The Epigenetics of methylation status of DNA
in Type 1 diabetes

Utilization of Epigenetics of Alterations in Methylation Status of DNA as an
Advantageous Method to Early Detection in Type I Diabetes.

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            The literature review on three peer-reviewed
articles, presenting the methylation status of cell-specific DNA, is discussed
in this paper to speculate the potential benefit of using the methylation
status to predict the early stage of development of Type 1 Diabetes. The
article was written by Zhang, Lin, Han, Xie, & Li (2017) asserted that the
unmethylated insulin DNA was a confident biomarker in detecting the risk and
the initial onset of Type 1 diabetes throughout their review of other research
studies. The research study on mice and human cells, identifying the methylated
status of amylin DNA as a unique phenomenon corresponding to beta cell
destruction in an early development of Type 1 diabetes, was discussed (Olsen,
et al., 2016). Lastly, the discussion included another control study done on
tumor necrotizing factor (TNF) alpha promoter methylation status in the small
number of Chilean patients with Type 1 diabetes. 

Type 1 Diabetes

            Type 1 diabetes,
which is categorized as an autoimmune disease destroying beta cells in pancreas
caused by the activation of inherited diseases (Zhang, Lin, Han, Xie, & Li,
2017), is a multifactorial disorder that both gene and environmental factors
contribute to its development (McCane & Huehar, 2014).  Due to the genetic and environmental factors
simultaneously influencing the disorder, the complexity of the disease’s
progression makes it difficult to predict the onset and its course.
Additionally, the disorder contributes to a variety of cardiovascular diseases
and several microvascular complications that affect various organs in the body.
Furthermore, recent studies have revealed that Type 1 diabetes accords with
other endocrine autoimmune diseases such as Hashimoto’s disease and Graves’
disease (McGill, 2016), and some cancers (McGill, 2016).  The study by Carstensen et al. (2016), which
used the diabetes register database in five countries, reported the prevalence of
9149 persons diagnosed with common cancers among persons with Type 1 diabetes.  Because the disorder not only complicates its
own physiological pathway but also has the potential to contribute to other
diseases, early detection or precedence of this disorder is crucial for disease
manipulation and prevention.      

Epigenetics of
Methylation in Type 1 Diabetes

            The modern science knowledge reveals
the prospect of manipulating the course of a wide variety of diseases by
linking them with the epigenetic mechanism at molecular level.  Epigenetics is the study of science, in which
molecular pathways modify the inherited gene expressions without altering the
original genetic sequences of nucleotides in DNA (McCane & Huether, 2014). Many
studies have underscored that methylation mechanism is unique to tissues and the
differentiated methylation process of each cell may be specific. Methylation is
generally emphasized on its property of silencing gene’s expression, which
occurs with the addition of methyl group to cytosine base in the targeted DNA
molecule (McCane & Huether, 2014). However, the methylation mechanism in
particular cell causes some specific genotypes to become activated or silenced at
the nucleotide level (Arroyo-Jousse, Garcia-Diaz, Codner, & Perez-Bravo,
2016). The dynamics in DNA methylation, as one of the forms of epigenetics corresponding
with the changes in regulation activity and the influence on transcription
factors in DNA (Zhang, Lin, Han, Xie, & Li, 2017), is questioned if it can
be a vital utilization to foresee the development of Type 1 diabetes.         

Methylation status of TNF
alpha promoter gene

            As stated above, Type 1 diabetes is
categorized as an autoimmune disease leading to a destruction of beta cells in
the pancreas (Heinonen, Moulder, & Lahesmaa, 2015). This knowledge is
noteworthy to consider when examining the human-induced inflammatory system in
search of a clue to predict the precedence and/or the early onset of Type 1
diabetes. The pro-inflammatory cytokines and TNF alpha are known to be secreted
in the serum of the patients with high risk of Type 1 diabetes along with the
beta cell inflammation (Heinonen et al., 2015). Under this observation, it was
hypothesized that the interaction of homocysteine, folate, and TNF alpha
concentrations in the blood triggers the hypomethylation in the TNF alpha gene
promoter (Arroyo-Jousse, Garcia-Diaz, Codner, & Perez-Bravo, 2016).  Arroyo-Jousse and the research colleagues engaged
25 subjects, who were patients with Type 1 diabetes and healthy individuals
without Type 1 diabetes and other autoimmune diseases as a control group (Arroyo-Jousse,
et al., 2016). The higher level of homocysteine resulted in higher serum TNF
alpha concentration in patients with Type 1 diabetes, and this established some
correlation between serum homocysteine and TNF alpha concentration. However, the
correlation between TNF alpha gene promoter and serum protein concentration
found in patients in Type 1 diabetes was not a convincing evidence to concur
with the established hypothesis (Arroyo-Jousse, et al., 2016). The study expressed
its limitations by mentioning that not all the transcription binding sites in
the TNF alpha gene promoter site were taken into consideration in their study (Arroyo-Jousse,
et al., 2016). In this study of a board stance, it seems that there are
limitations because some physiological variables of each subject may exist but
are concealed.  For example, the
methylation of gene expressions of DNA may vary depending on the course of the
disease. In their study of subjects diagnosed with Type 1 diabetes, the extent
of beta cell damage in each subject was not stipulated. Additionally, the study
is limited since such a small number of subjects cannot account for the general
population at risk; thus, future studies with a larger number of subjects are

Unmethylated Insulin and
Amylin DNA

            The destruction of beta cells is supposed
to precede the development of Type 1 diabetes a considerable length of time
with the understanding that about 65% of that destruction in pancreases is normally
found at the time of diagnosis of Type 1 diabetes (Zhang, Lin, Han, Xie, &
Li, 2017). The recognition of epigenetic process of the unique methylation
pattern of insulin gene DNA in beta cells can suggest an early detection of
Type I Diabetes (Zhang, et al., 2017). Given that the beta cells may be damaged
coincidently with autoimmune destruction, the unmethylated insulin is then freed
into blood circulation (Zhang, et al., 2017). The unmethylated insulin DNA is
found primarily in the beta cells when compared to other tissues, and the
presence of unmethylated insulin in the blood, extracted from cell-free DNA, is
a significant indicator of beta cell destruction, and therefore suggesting the onset
of Type 1 diabetes (Zhang, et al., 2017). Through the compilation of evidence
from reviewing numerous research results, Zhang and the colleagues (2017) concluded
that the unmethylated insulin DNA status in the blood is the most positive
signal of impending Type 1 diabetes (Zhang et al., 2017).  Most of the studies in their review discovered
the congruent evidence of the elevated unmethylated status of insulin DNA in
the group with Type 1 diabetes compared to the group without.  One of the studies Zhang et al. (2017)
reviewed was the research done by comparing the methylated status of insulin
DNA among the subjects with newly diagnosed with Type 1 diabetes and were highly
at risk with a set criteria of having “two or more biochemical autoantibodies,
abnormal glucose tolerance test results and normal HbA1c levels” (Zhang et al.,
p. 3, 2017). The same group of researchers performed a subsequent study of the
subjects at risk at the later time and divided these subjects “into progressors
(who developed TID after a 3-to 4-years period) and nonprogressors (who did not
develop TID over a similar time interval)”. The result of study disclosed the
higher level of unmethylated insulin DNA circulating in the blood of
progressors (Zhang et al., p. 4, 2017). This result supports the assertion that
unmethylated status of insulin DNA is a strong positive indicator and adds to
the assertion’s validity.  

            With the aforementioned acknowledgment
about the phenomena of unmethylated insulin DNA status, a control study on mice
and human cells were conducted and quantified the demethylated amylin cell-free
DNA (Olsen, et al., 2016).  Olsen et al.
(2016) explain that the gene expression of amylin is specific to beta cells and
the methylated status is a valuable sign of the beta cell destruction, which leads
to the releasing of the amylin cell-free DNA into the blood of patients with Type
1 diabetes.  As a result, the study recommends
the demethylated amylin cell-free DNA accompanied by the unmethylated insulin
DNA testing in order to uncover the beta cell destruction for the impending
onset of Type 1 diabetes. 


            The use of methylation status of
various gene expressions of DNA to detect the early stage of Type 1 diabetes has
been discussed, and this confers an attempt to decisively reserve beta cells in
any means of prevention. The discoveries support the use of methylation status
of DNA from the destruction of beta cells as the indicator to identify the
precedence or early onset of Type 1 diabetes. The study also points out that
the samples can be non-invasively and conveniently drawn from the blood of the
patient (Zhang, et al., 2017).  The gene
expressions in Type 1 diabetes is affected by multiple factors such as family
history, diet, lifestyle, and environmental factors (McCane & Huether,
2014).  Many studies suggest that the
mitochondrial oxidative stress influenced by dietary factor can affect the
genetic expressions of insulin resistance and beta cell destruction (Xu, Cheema, Zarini, Li, T., &
Huffman, 2017). All the studies have the limitation in controlling the
variables of familial, dietary, and environmental factors.  Despite
lacking the control of variables and having a small number of study subjects,
it is plausible that differentiated methylation can be used to detect Type 1
diabetes.  To establish the validity of
this concept, further investigation is essential.       


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