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Current Research in Translational Medicine xxx (2019) xxx–xxx

Available online at

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General review

Role of HDAC inhibitors in diabetes mellitus

Rashita Makkara , Tapan Behla,* , Sandeep Arorab
a
Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
b
Department of Pharmacy, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India

A R T I C L E I N F O A B S T R A C T

Article history: Objective: The role of histone deacetylases has come out as an emerging remedy in control and treatment
Received 13 April 2019 of various metabolic disorders and cancers. This review highlights their intricate role in diabetes mellitus
Accepted 21 August 2019 as well as its associated complications.
Available online xxx
Key findings: Through recent studies and reports the role of various epigenetic markers in treatment of
diabetes mellitus has been revealed. HDAC enzyme regulates the structure of chromatin and transcripts
Keywords: genes in the nucleus synthesizing various proteins that control metabolic activities in the body. It mainly
Histone deacetylases
acts by removing an acetyl group from its precursor protein thereby modulating gene expression and
Insulin resistance
Acetylation
regulates the metabolic enzyme acetylation in mitochondria and cytosol.
Transcription Summary: The present review focus on the intrinsic role of HDAC inhibitors as an emerging remedy for
β-cell destruction diabetes and its complications demonstrating their use in preventing resistance of β-cells towards
Gene expression insulin, destruction of β-cells and provide protection against cytokine mediated attack on pancreatic
cells.
© 2019 Elsevier Masson SAS. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Role of HDACs in etiology of diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
HDAC inhibitors and insulin signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
HDAC inhibitors and activity of β-CELLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
HDACs as treatment approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Introduction making it an essential hallmark of the disease [1]. The WHO last
reported the prevalence of diabetes in October 2018 [2]. The
Diabetes mellitus allocates a group of chronic diseases where number of people affected with the disease has reached to 422
aberrancies in substrate metabolism occur in response to relative million from 108 million in 1980 and the numbers are supposed to
or absolute lack of insulin with pronounced long term complica- double every ten years. The prevalence of disease has also reached
tions. The disease may be due to inherited or acquired deficiency of upto 8.5% from 4.7% among the individuals above 18 years in 1980.
insulin synthesis or its inability to bind to receptor and produce The low and middle income countries are more exposed to
effective results. Various body systems particularly the nerves and diabetes and it has become one of the major causes of blindness,
blood are highly damaged due to increased levels of glucose stroke, lower limb amputations, kidney failure and heart attacks.
Diabetes has also been stamped to be the 7th leading cause of
death in 2016 by WHO [3,4]. The long recognized causes of type I
diabetes include destruction of β-cell and autoimmune islet
* Corresponding author.
E-mail addresses: tapanbehl31@gmail.com, tapan.behl@chitkara.edu.in (T. Behl) inflammation though it is still debated whether molecular
. mechanisms involve predominantly inflammatory cytokine

http://dx.doi.org/10.1016/j.retram.2019.08.001
2452-3186/© 2019 Elsevier Masson SAS. All rights reserved.

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10.1016/j.retram.2019.08.001
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mediated β-cell destruction or classical cytotoxic T-cell mediated
killing or both. A number of mechanisms explaining destruction of
β-cells have been proposed like glucolipotoxicity, islet amyloid
polypeptide deposition mediated disruption of membrane and
inflammation of islets. Later, a unified hypothesis was proposed
that explained the cause of β-cell destruction by induction of
inflammatory mediators in pancreatic islets that further activate
pathways in β-cells resembling those in type 1 diabetes (T1D) [5,6].
The inventory processes for developing novel treatment
approaches has undergone a revolutionary turn which has aided
study and targeting of newer protein molecules with exceptional
outcomes. A drug developer is no less than an artist as targeting
specific proteins with respect to disease pathology to achieve
higher degree of effective treatment with minimal possible side
effects is not a job of left hand. The recent trend of drug
development has turned to epigenetic modifications in gene
expressions of the diseased patient which aims at targeting
proteins involved in pathogenesis of the disease. The manner in
which DNA is packaged profoundly influences the transcription of
genes in eukaryotic cells. The stable and potentially reversible
alteration in gene expressions of an individual without any
permanent change in DNA sequence with inheritance property
is called epigenetic modifications [7]. Waddington originally
defined epigenetics as a firm reason for programmed changes
during development of embryo due to interactions between genes
and their products bringing out a phenotypic change. The bridge
between environment and genetics is epigenome while determin-
ing the final phenotype on modification of gene expressions
without any alteration in DNA sequence is epigenetic code. By
targeting the specific gene directly, the phenotype of the disease
can be changed through epigenetic modifications in response to
pathological and environmental conditions like diet, exercise,
toxins, inflammation, oxidative stress and metabolic changes. The
epigenetic modifications show a phenomenal role in genomic
imprinting, stable inheritance of gene expression, embryonic
development, cell differentiation and identity, inactivation of X
chromosome, immune cell functioning, and responses to environ-
mental signals at cellular levels [8]. One such emerging epigenetic
modification that is being investigated recently is Histone
modification. It has managed to obtain exceptional results in
treatment of severe life threatening diseases including cancer and
metabolic disorders [9]. Gene transcription processes in cells of
eukaryotes depend highly upon the chromatin confirmation.
Nucleosome is the basic unit of chromatin constituting four core
dimers of histones namely H2A, H2B, H3 and H4 which are doubly
folded around the DNA in the form of an octamer. The covalent
modifications undergo in the basic N-terminal tail of histone
proteins which recruit factors responsible for transcription via
changes in structure causing packaging of chromatin and regulate
gene expression [10]. The remodeling of chromatin through
acetylation, phosphorylation, methylation and various other
posttranslational modifications in histones is the fundamental
phenomenon in eukaryotic cell biology highlighting diverse
approaches for treatment in response to physiological and
pathological conditions. The histone acetyl transferase (HAT)
and histone deacetylase (HDAC) as their name suggests acetylate
and deacetylate histone proteins respectively [11,12]. The HAT
enzyme undergoes posttranslational histone acetylation by
transferring an acetyl group from acetyl coenzyme A to the
e-NH3 groups of internal residues of histone proteins. Acetylation
forms decondensed chromatin called ‘euchromatin’ by neutraliz-
ing the positive charge on tail of N-terminal residues of lysine. This
decreases the propensity of positive terminal residues towards
DNA activation, increasing access of DNA towards transcription
factors and RNA polymerase by unfolding nucleosomes and causes
gene activation. In contrast to HAT, the enzyme HDAC acts by
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/
10.1016/j.retram.2019.08.001
removing acetyl group from histone lysine residues and restores
the persisting positive charge on terminal tails of Nitrogen
therefore increasing their likeliness for DNA. The tails displace
transcription factors and forms a repressive structure of chromatin
hence suppress transcription [13]. The mammalian HDACs can be
divided into two families and four classes. The first family includes
category of HDACs that are classically Zinc ion dependent while
the other family is nicotinamide adenine dinucleotide (NAD)
dependent HDACs.
The Zn dependent family of HDACs includes:
Class I HDACs: It comprises of HDAC isoforms 1, 2, 3 and 8.
These HDACs are localized and found exclusively in the nucleus
and are related to Rpd3 yeast enzyme with homology shared in
catalytic pocket.
Class II HDACs: It is advanced into two categories which is Class
IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10). It covers two
homology regions, in Nitrogen terminal regulatory area and
Carbon terminal area of catalysis. The HDACs circulate between
nucleus and cytosol with certain recruitment of protein complexes
and deacetylation sites occur.
Class IV HDACs: They comprise only one member i.e. HDAC 11. It
is found in both nucleus as well as cytoplasm.
The NAD+ dependent family of HDACs include:
Class III HDACs: They are also called the silent information
regulator 2. The HDAC enzymes are dependent on NAD+ under
presence of which acetyl groups are removed from residues of
acetylated lysine. This class includes homology of yeast Sir 2, which
in presence of cofactor NAD acts as a vital protein for silencing
certain genes and catalyze their action. They are also called
Sirtuins. Till now seven members have been noted in the family of
protein sirtuin localized in mitochondria, nucleus and cytoplasm of
the cell [14].
The deacetylation action of HDAC 6 is higher on 5th and 8th
lysine residue of histone 4 while HDAC 1 and 3 have been tested for
their efficacy to deacetylate the lysine residues containing four
core histones on varied levels [15,16] (Table 1).
HDAC inhibitors through hyperacetylation of non histone and
nucleosomal histone proteins regulate expression of genes. Most of
the HDACs are large multiprotein complex regulated and do not
activate enzymatically without interacting with other proteins.
NuRD/Mi2, coREST, Sin3, and N-CoR and SMRT, the nuclear
receptor corepressors are some of the multiprotein complexes
required in the activation of HDAC proteins. The SMRT and N-coR
nuclear receptor complexes enzymatically activate HDAC3 where-
as the other complexes i.e. the Sin 3, CoREST and NuRD/Mi2
complexes stimulate the activity of HDAC1and HDAC2 deacetylase.
Class IIa HDACs recruit HDAC3 comprising N-CoR/SMRT active
complexes and are inactive HDACs. HDACs and its inhibitors
predominantly control cell proliferation, differentiation, apoptosis
and also modulate cell cycle by regulating cellular reactions [17,18].
HDACs have multiple actions as they target numerous cellular
pathways and produce resultant responses.
HDACs bind to nuclear receptors and regulate signaling of
hormones by modulating their release. This indicates its use in
management of diabetes mellitus as HADCs stimulate release of
insulin.
The α-tubulin proteins are expressed in the cytosol of the cells.
HDAC 6 is highly specific and binds to α-tubulin and actin proteins
which control the stability and functioning of microtubules. The
acetylation state of actin is highly modulated by HDAC6 thereby
blocking its fibrillar action and affects actin dependent motility.
Angiogenesis is also prevented by use of HDAC inhibitors as
angiogenic markers like VEGF and HIF-1α are targeted by HDACs
The role of HDACs in modulating inflammation by suppressing
outburst of inflammatory mediators has already been discussed in
the article.
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Table 1
An overview of HDACs.

CLASS NAME LOCATION Co - FACTOR EXPRESSING TISSUES USES

CLASS I HDAC 1 Nucleus Zn2+ DEPENDENT Widespread Inflammation, Insulin resistance
HDAC 2
HDAC 3 Nucleus/Cytoplasm
HDAC 8 Nucleus
CLASS II (a) HDAC 4 Nucleus/Cytoplasm Heart, Brain Hyperglycemia, Insulin resistance,
HDAC 5 Smooth muscle Decreased insulin production
HDAC 7 Placenta, Pancreas, Heart
HDAC 9 Smooth muscle, Brain
CLASS II (b) HDAC 6 Kidney, Liver, Heart Glucose intolerance, Hyperglycemia
HDAC 10 Spleen, Kidney, Liver
+
CLASS III SIRT 1 Nucleus, Cytoplasm NAD DEPENDENT White adipose tissue Enhanced insulin signaling
SIRT 2 Cytoplasm Testes, Heart, Brain Impaired insulin signaling
SIRT 3 Mitochondria Brown adipose tissue Enhanced insulin signaling
SIRT 4 Islets of pancreas Impaired insulin signaling
SIRT 5 Liver Enhanced insulin signaling
SIRT 6 Nucleus Impaired insulin signaling
SIRT 7 Enhanced insulin signaling
CLASS IV HDAC 11 Nucleus Zn2+ DEPENDENT Heart, Smooth muscle, Brain, Inflammation
Kidney

HDACs suppress tumor growth by binding to p53, p21 and
cyclin proteins and alter cell cycle of the body.
Diabetes mellitus
The main source of energy for most of the cellular functions is
glucose. An increased level of circulating glucose in body post meal
stimulates pancreatic β cells to release insulin. Insulin plays an
important role in glucose homeostasis. It undergoes autophos-
phorylation on binding with transmembrane receptors and
phosphorylates the intercellular protein substrates including
insulin receptor substrate – 1 and 2 (IRS-1 and IRS- 2). The
phosphorylated IRS subsequently activates phosphoinositide 3-
kinase (PI3K/AKT) pathway. These phosphorylated products
stimulate activation of several enzymes and proteins and translo-
cate glucose transporter 4 (GLUT 4) to cell membrane from
intracellular cell vesicles. An array of metabolic events is
demonstrated by another important pathway in insulin signaling
called mitogen activated protein kinase (MAPK) pathway [19]. Over
the last century drastic behavioural and lifestyle changes have
produced conditions of insulin resistance where amidst the
presence of abundant amount of insulin, it is no longer able to
bind to its receptor causing prohibition of any further series of
events [20].
Diabetes can be categorized into two principal forms:
Type I diabetes: formerly known as insulin dependent diabetes,
is a condition where pancreas fails to synthesize insulin hence
disturbing homeostasis of glucose in body. It is frequently observed
in children and adolescents and is termed juvenile diabetes.
Type II diabetes: also known as non-insulin dependent
diabetes, is a condition in which the body fails to respond to
pre-existing insulin. About 90% of diabetic cases worldwide are
accounted to be T2D and predominantly targets adults [21].
Mutations in one or more genes by genetic-environmental
interactions trigger onset of diabetes making it a complex disease.
Both the types of diabetes are genetically distinct where type I
diabetes is believed to happen due to variations in immune
regulatory genes highlighting its autoimmune nature and exposing
individuals to T-cells driven β-cell destruction and chronic
inflammation whereas in contrast genome wide association scans
(GWAS) suggested type II diabetes as a disease where alterations in
genes evoke changes on β-cell function and impairs its compensa-
tion to increased demands of insulin [1]. The immune and
metabolic pathogenesis of both types of diabetes seems to
converge on common extracellular inflammatory stressors despite
their dissimilar genetic background and these stressors induce
intracellular signaling in islet cells. The most commonly reported
intracellular stressors is IL-1β which is secreted from activated
mononuclear cells that prohibit functioning of β-cell and cause cell
death on prolonged exposure due to their selective β-cell toxicity
[22,23].
The molecular performance of HDAC was assumed to be limited
to deacetylation as indicated by their name but recent advances in
phylogenetic analysis suggested their role in regulating perfor-
mance in a broader range of non histone proteins. In terms of
posttranslational mechanisms the impact of acetylation is no less
than phosphorylation increasing demand of HDACi as a treatment
approach for an expanding range of diseases. The original goal of
HDAC inhibition was transcriptional control over oncogene net-
works in cancer cells but their indications as novel treatment in
other diseases including neurodegenerative and inflammatory
diseases is growing exceptionally. The master transcription factor
nuclear factor (NF-kB) in inflammation is now recognized to be
regulated by acetylation. In the current review the prospects of
inhibition of HDAC as a novel approach for treatment of diabetes
will be reviewed. It also incorporates an outline of genetic
associations relating to etiology of diabetes and HDACs and
evaluating its potential as an oral therapy in treatment of disease
and its associated complications depending upon the pathological
events [24,25].
Role of HDACs in etiology of diabetes
A combination of environmental and genetics factors contrib-
ute in the etiology of diabetes making it complex. Though T1D and
T2D are considered to be genetically distinct, an association
between the 6q21 chromosomal region has been identified by
genome wide association scans (GWAS) studies where HDAC 2 is
also located signifying the latter’s role in both the diabetes. The
epigenetic and environmental factors significantly contribute in
the etiology of the disease making it a polygenetic disorder.
Simmons and Pinney reported that an unfavorable fetal milieu due
to exposure of fetus to intra uterine growth retardation (IUGR)
affects the development of β-cells due to modification in muscular
transport of glucose by glucose transporter 4 (GLUT 4) and varying
key regulatory genes like pancreatic and duodenal homeobox
factor 1 (Pdx1) thereby advancing to T2D. Loss of acetylation of
histone recruits HDAC1 which complexes Pdx1 a proximal

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promoter to the Sin3A corepressor hence reducing the expression
of Pdx1after IUGR. The HDAC1/Sin3 complex formed propagates
epigenetic cycle and recruits histone demethylase which inhibits
the transcription of Pdx1 thereby causing loss of histone 3 lysine 4
trimethylation (H3K4me3). Inhibition of HDACs reverses this effect
by methylation and dimethylation of H3K9 which lodges the
promoter Pdx1 in its transcriptionally inactive state [26]. The
transcription of Glut4 is inhibited as a result of lack of histone
acetylation in adult muscle tissue of Glut 4 promoter as mediated
by HDAC1 and HDAC4 thereby repressing the peripheral uptake of
glucose and producing insulin resistance thus contributing to T2D.
The remodeling of chromatin in incretin hormones such as glucose
dependent insulinotropic peptide 1 and glucagon-like peptide 1
has already been induced as a therapeutic approach in treatment of
T2D which has led to greater association with the transcription
factors due to in vitro global acetylation of H3 histones [27,28].
HDACs and histone acetylation are also useful in treatment of rare
kinds of autosomal diabetes namely “maturity onset diabetes of
the young” (MODY) and its seven dissimilar subtypes based on the
mutations in genes apart from their clinical relevance in treatment
of T1D and T2D. The genes encode nearly all transcription factors
which are involved in the production of insulin and development
of pancreas except for insulin and glucokinase. Some of these
include hepatocyte nuclear factor (HNF)- 1α, -1β and -4α which
produces hepatic gluconeogenesis and transcription of insulin,
neurogenic differentiation 1 (NeuroD1) and Pdx1. Histone acetyl
transferases (HATs) and HDACs by remodeling chromatin interact
with the transcription factors and regulate normal functioning
suggesting their important role in pathogenesis of diabetes [29].
HDAC inhibitors and insulin signaling
The signaling of insulin is vital in maintaining the glucose
homeostasis in body as a decline in its signaling inhibits hepatic
steatosis in liver and containment of gluconeogenesis with
reduced uptake of glucose in muscles. Insulin signaling also
regulates the mass of β-cells which is directly involved in onset and
progression of diabetes [30]. The Fig. 1 below describes the
pathway for insulin signaling. On binding to insulin receptor, the
autophosphorylation and phosphorylation of insulin receptor
substrate (IRS) family members occurs causing release and action
of insulin. The IRS proteins post phosphorylation bind and activate
phosphatidylinositol 3-kinase which further stimulate protein
kinase Akt phosphorylation ultimately translocating glucose
transporter (GLUT 4) to the plasma membrane from intracellular
vesicles and mediating uptake of glucose. The myocyte enhancer
factor (MEF)-2 and GLUT 4 enhancer factor (GEF) are chief
Fig. 1. signaling pathways associated with HDACs.
Please cite this article in press as: R. Makkar, et al., Role of HDAC inhibitors in diabetes mellitus, Curr Res Transl Med (2019), https://doi.org/
10.1016/j.retram.2019.08.001
regulators that control translocation of GLUT 4 by binding to its
translational elements [31]. The obstruction in release of insulin
may occur at several stages. There are two mechanisms that
control the signaling of insulin in β-cells through HDACs, firstly
through epigenetic control while secondly through IRS2 expres-
sion and activity regulation via protein acetylation [32]. The role of
IRS2 has been reported to be very crucial in proliferation of β-cells
of pancreas hence identifying and employing a precise isoform of
HDAC can be a valuable approach as therapy forT2D [33]. The
HDAC1 located in nucleus acts via acetylation of histone in the
promoter region of IRS2 while the cytoplasm localized HDAC
acetylates the lysine residues in IRS2 and leads to modification of
proteins [34]. The expression of different isoforms of HDACs
differed in the brain with altered activity in kidneys of diabetic
patients. The differentiation of β-cells of pancreas was reported to
be controlled by HDAC 4, 5 and 9. An increased expression of
HDAC1 was encountered from pancreatic cells isolated from
children with T1D with decrease in HDAC2 and HDAC3 expres-
sions. The secretion of insulin is suppressed by histone acetylation
and promoted expression of Tcf7l2 with increased articulation of
HDAC7 in pancreatic cells of T2D patients. The acetylation of lysine
in SREBP 1a and p53 inhibits ubiquitination while acetylation of
lysine in PGC1α and FOXO promotes autophosphorylation. The
phosphorylation of tyrosine in neuronal cells seems to diminish on
IRS2 post translational modification due to acetylation of lysine in
IRS2 with no reports β cells of pancreas [35,36]. The patients
receiving HDAC inhibitors as therapy for treatment of cancer have
been reported to fabricate hyperglycemia as its consequence
indicating its role in signaling of insulin in some organs with
impairment of tolerance to glucose. Hence through these findings
the need to pick more selective HDAC inhibitors can be
suggested necessary to provide protective effect for insulin
signaling [37,1] (Fig. 2).
HDAC inhibitors and activity of β-CELLS
The factors mediating transcription play crucial role in
development of pancreas by differentiation of endocrine and
exocrine. The etiology of type-1 diabetes is highlighted by the
understanding of mechanism of apoptosis of β-cells induced by
inflammatory cytokines. The molecules with capability to suppress
this apoptotic processes can be efficiently employed as therapy for
preventing β-cells from hypersensitive reactions and immune
responses. Various studies have reported the protective actions of
HDAC inhibitors in preventing destruction of β-cells [38]. The
determination of precise isoform of HDAC which is responsible for
survival of β-cells is fundamental to its therapeutic application as
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Fig. 2. Mechanism of Insulin Signaling.
broad spectrum HDAC inhibitors may have toxic effects and fail to
restore significant β-cell functions like secretion of insulin as
stimulated by levels of glucose [39]. Genetic and chemical
inhibition of HDAC3 has been found to suppress the apoptosis
of β-cell line of rats. The selective HDAC 1, 2 and 3 inhibitors
embarked better protective effects in β-cell line as compared to
broad spectrum HDAC inhibitors like SAHA indicating additional
side toxicities induced by inhibition of various isoforms of HDAC.
MS-275 a selective HDAC inhibitor he genetic knock down of
HDAC3 stimulated secretion of insulin in response to glucose levels
and restores it [40]. The development of endocrine progenitors of
NGN3+ was enhanced on treatment with HDACi. The epithelial cells
in pancreas contain precursors for PDX1+ which augments
development of various cell types of pancreas besides NGN3+
cells. On enhancing proliferation of precursors of PDX1+ by FGF 10
or mesenchyme the progenitors of endocrine NGN3+ are intensi-
fied. On initiating treatment with HDACi no increase in the
production of PDX1+ precursors was noticed indicating role of
HDACi and FGF 10 in enhancing the endocrine progenitors NGN3+
in alternate ways except for poorly growing cells of NGN3+ making
it independent of proliferation of cells. Also the relationship
between the β-cell signaling of transforming growth factor in
differentiation of pancreatic cells is being investigated. A
possibility of HDACi to inhibit the promoter NGN3+ cells directly
as mechanism of action is being explored for its therapeutic
efficiency. The presence of non histone substrates of proteins in
HDACi regulates expression of genes and also controls death and
proliferation of cells. The acetylated forms of these substrate
Fig. 3. HDAC inhibitors and β-cell destruction.
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10.1016/j.retram.2019.08.001
5
proteins accumulate on HDACi treatment modifying their func-
tions [41,42]. The targets in pancreas that can are involved in
etiology of DM are also under investigation for contributing better
in expression and regulation of Ngn3. Hence through various
studies the role of HDACs in proliferation of β-cells has been stated
evident as they have direct effects on fate regulation of endocrine
cells [1] (Fig. 3).
HDACs as treatment approach
Various HDACi have recently been approved by FDA e.g.,
Panobinostat is under phase IV clinical trials and has also been
approved by FDA in 2015 for its use in management of multiple
myeloma and cutaneous T-cell lymphoma (CTCL)
Some of the HDACi under clinical trials include:
Valproic acid is under phase III clinical trials for its use in
cervical and ovarian cancer. Tacedinaline, another HDACi is under
phase III trials for its use in management of multiple myeloma and
lung cancer. Mocetinostat is under phase II clinical trials for its use
in management of Follicular and Hodgkin lymphoma and acute
myeloid leukemia. Rocilinostat has been recently developed and is
under phase I trials for its use in treatment of multiple myelomas.
Many other HDAC inhibitors drugs like Mocetinostat, Abexinostat,
Practinostat are under phase II clinical trials and are being studied
for their beneficial effects in treatment of Follicular and Hodgkin
lymphoma and acute myeloid leukemia, Sarcoma and lymphoma
and Recurrent or metastatic prostate cancer respectively.
Some of the HDACs used in management of diabetes mellitus
include:
Vorinostat (SAHA) was the first HDAC inhibitor to be approved
by FDA in 2006 for its use in treatment of cutaneous T-cell
lymphoma. Apart from its use in myeloma, SAHA is also being
examined for its therapeutic role in management of diabetes
mellitus as its is reported to increase expression of insulin even in
low concentrations of glucose. Sodium butyrate (NaB) and
Trichostatin A (TSA) are other HDACi that are simultaneously
being examined for their use in diabetes mellitus. TSA is believed to
increase insulin release by stimulating expression of β-cells and
stimulating GLP-1 proteins. TSA also improved the transdiffer-
entiation of bone marrow stem cells into insulin-producing cells
Sodium butyrate (NaB) stimulates early events of pancreatic
specification in embryonic stem (ES) cells by promoting their
differentiation into insulin-producing cells.
Valproate has been used commonly in treatment of bipolar
disorders and other CNS disorders. A typical side effect associated
with Valproate was hyperinsulinemia. It was found that the
function is attributed to inhibition of HDACs by Valproate. Hence,
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valproate is also under study for evaluation of its effect in
management of diabetes mellitus.
Various other HDACi like Romidepsin, Panabiostat have been
approved by FDA for management of lymphomas and their role in
diabetes is yet under investigation.
Conclusion
HDACs are indulged in multiple biological system pathways and
contribute majorly in pathogenesis and development of diabetes
mellitus even through genetic basis. HDACs promote development,
proliferation and differentiation of β-cells and regulate their
functioning by preventing inflammatory cell damage, improve
resistance of insulin and prevent microvascular complication of
diabetes at later stages. Altogether it can be summoned that HDACi
can be initiated as promising therapy for preventing and treating
diabetes and its clinical utility is under examination as there is still
a lot to be learned about its mechanism.
Declaration of Competing Interest
The author(s) declare no conflict of interest.
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