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An effort has been made in this review to outline the origin of diabetes as a serious disease. A large number of studies are going on in order to understand the cause of this disease, both environmental as well as genetic factors have been found to be involved. We have tried to throw some light on inflammation in diabetes with special emphasis on interleukins and adipocytokines. Recently the involvements of cytokines and adipocytokines have been extensively studied and have been found to play an extremely important role in the manifestation of diabetes and its associated complications.
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Inflammation and Diabetes
Saxena M1* and Modi DR1
1Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareilly Road, Lucknow, India
*Corresponding author: Dr. Madhukar Saxena, Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareilly Road,
Lucknow-226025, India, Tel: 9839317441; E-mail: madhukarbio@gmail.com
Rec date: Aug 14, 2014, Acc date: Sep 23, 2014, Pub date: Sep 25, 2014
Copyright: © 2014 Saxena M et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
An effort has been made in this review to outline the origin of diabetes as a serious disease. A large number of
studies are going on in order to understand the cause of this disease, both environmental as well as genetic factors
have been found to be involved. We have tried to throw some light on inflammation in diabetes with special
emphasis on interleukins and adipocytokines. Recently the involvements of cytokines and adipocytokines have been
extensively studied and have been found to play an extremely important role in the manifestation of diabetes and its
associated complications.
Keywords: Inflammatory cytokines; Type 2 diabetes; Interleukins;
Adipocytokines; Tumor necrosis factor- α
Introduction
It has been postulated that type 2 diabetes mellitus (T2DM) is a
manifestation of the inflammatory host response. Increased
inflammatory activity plays a critical role in the development of
atherogenesis and rupture of atherosclerotic plaques. Inflammation is
an initial step of many diseases. Cytokines are a group of small soluble
or cell-membrane bound proteins or low molecular glycoprotein
messenger molecules with high potential secreted by WBCs and
various other cells in the body in response to a number of stimuli in
the regulation of inflammatory responses.
The balance of proinlammatory and anti-inflammatory cytokines is
essential for normal cellular function. Some polymorphic cytokine
genes have been shown to be associated with variation in cytokine
production in T2DM because it is caused due to dysfunction of
pancreatic β-cells. Due to destruction and inflammation in β-cells,
level of cytokines is slightly disturbed. It has already reported that
cytokines, chemokines and interleukins are involved in T2DM to
cause inflammatory and immune responses mediating the
pathogenesis of T2DM. Mediators of inflammation such as Tumor
Necrosis Factor–α (TNF- α), Interleukin (IL) -1β, IL-1Ra, IL-6, IL-18,
IL-10 and certain chemokines have been proposed to be involved in
the events causing Diabetes [1].
Interleukin-6 which is known to be the main stimulator of the
production of most acute phase proteins was shown to increase the
risk of diabetes. Other cytokines such as IL-1β or TNF-α are also
central mediators of inflammatory reactions. IL-18 is a potent pro-
inflammatory cytokine which plays a role in plaque destabilization and
prediction of cardiovascular disease (CVD) death in patients with
cardio artery diseases (CAD).
Tumor Necrosis Factor Alpha (TNF-α), IL-1β and
IL-1Ra
Pro-inflammatory cytokines Tumor Necrosis Factor-α (TNF-α) and
IL-1 could significantly contribute to the pathogenesis of T2DM.
Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine
that impairs insulin action and alters lipid metabolism. It was
suggested that the -238G>A and -308G>A polymorphisms of TNF-α
alter circulating free fatty acids and insulin resistance in obese subjects
with T2DM [2]. Vascular endothelial growth factor (VEGF) is a potent
multifunctional cytokine which plays a key role in the pathogenesis of
diabetic microvascular complications [3]. IL-1β and IL-1Ra shows
similar association in chronic inflammatory diseases as well as in
T2DM. TNF-α decreases tyrosine kinase activity of the insulin
resistant rodents and humans, suggesting that it is a possible mediator
of insulin resistance and diabetes [4-5].
IL-1β and IL-1Ra genotypes of the IL-1 cluster genes are associated
with diabetic nephropathy in Korean patients with T2DM [6]. The
-308A allele of the promoter polymorphism (G-308A) of the TNF-α
gene is a predictor for the conversion from Glucose tolerance to
T2DM. Furthermore, this polymorphism seems to have a gene-gene
interaction with the C-174C genotype of the IL-6 gene [7]. Studies
have provided increasing evidence that hepatocytes growth factor
(HGF) has a pathophysiological role in the development of the
diabetic complications. Serum HGF concentration may be a new
marker of atherosclerotic complications in T2DM patients [8].
Macrophages and T-lymphocytes are the first cells to appear in
pancreatic islets in the development of autoimmune diabetes. It has
been suggested that cytokines released by monocytes/macrophages
including IL-1β and TNF-α could have initial role in islet β-cell
damage. T2DM and atherosclerotic cardiovascular disease share many
antecedent factors that frequently coexist, which has given rise to the
concept of a common basis [9-10]. The cluster of risk factors, such as
uric acid and dyslipidemia are strongly related to fasting insulin
concentration of inflammatory markers in people with and without
T2DM. Inflammatory processes play a part in the cause of
atherosclerotic CVD [11]. The members of the IL-1 cytokine
superfamily IL-1α and IL-1β are strong inducers of inflammation. IL-1
Interdisciplinary Journal of
Microinflammation
Saxena and Modi, Interdiscip J Microinflammation
2014, 1:1
http://dx.doi.org/10.4172/ijm.1000110
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Interdiscip J Microinflammation
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receptor antagonist (IL-1Ra) acts in an antagonistic manner and serves
as a natural compensatory mechanism for the IL-1 induced disease
process [12]. In healthy individuals, IL-1Ra is detectable in plasma, in
contrast to usually undetectable levels of IL-1. White adipose tissue is
an important source of IL-1Ra. IL-1Ra levels are increased in human
obesity and may contribute to the development of insulin resistance
[13].
Interleukin-6
Interleukin-6 is a pro-inflammatory cytokine secreted by immune
cells, adipose tissue, muscles, and is able to accelerate or inhibit the
inflammatory processes [14-15]. It is also involved in
immunoregulatory actions and affects glucose homeostasis and
metabolism directly and indirectly by action on skeletal muscle cells,
adipocytes, hepatocytes, β-Cells of pancreas and neuroendocrine cells.
High circulating IL-6 levels have been associated with insulin
resistance and greater risk of T2DM [16]. It has been reported that the
common C-174G polymorphism in the promoter of the human IL-6
gene regulates its transcription in vitro with the G allele, showing
increased transcriptional activity both under basal condition and in
response to inflammatory stimuli such as lipopolysaccharides or IL-1
[17].
There is a significant correlation between adipose IL6 mRNA
expression and insulin resistance [18]. Several prospective studies have
associated increased plasma IL-6 levels with a higher risk of T2DM
and suggest that IL6 is a candidate gene for T2DM [19-20].
Interleukin-18
Interleukin-18 is a unique member of the Interleukin-1 family.
Although closely related to IL-1β in structure and in the requirement
of caspase-1 to cleave its precursor form into an active cytokine, the
IL-18 precursor is present in monocytes and macrophages of healthy
humans and mice, whereas the IL-1β precursor is absent in these same
cells [21]. Insulin-producing islet β-cells secrete IL-18 and
supernatants from stimulated islets induce IFN-γ in T cells in IL-18
dependent manner [22]. In humans, the gene for IL-18 maps to
chromosome 9, where a diabetes susceptibility locus, Idd2, resides
[23]. From previous studies, IL-18 levels have been associated with
adiposity and insulin resistance in obese premenopausal women. IL-18
concentration is increased by acute hyperglycemia in humans [24]. In
T2DM the level of IL-18 is elevated in case of diabetic children [25].
Interleukin-10
Interleukin-10 is also involved in obesity and has a role in the
regulation of immune system. Low levels of IL-10 production are
associated with hyperglycemia and T2DM [26]. It has been reported
that the presence of an A at position -1082 is correlated with low IL-10
production after stimulation of T-cells in vitro, while G at the same
position has been associated with high IL-10 synthesis [27]. It has been
demonstrated that the A/G mutation at position -1082 in the promoter
region of the IL-10 gene is probably associated with the incidence of
developing diabetes mellitus [28]. IL-10 stimulates antibody
production by B-lymphocytes and promotes their proliferation and
differentiation [29]. The predominance of the high IL-10 genotype in
T2DM is probably protective against the development of
inflammation, encouraging humoral immunity responses, delaying the
initiation of cytotoxic inflammatory reactions that mediate β-cell
destruction in pancreatic islets and driving their manifestations in
older age.
Adiponectin
Adiponectin is a serum protein produced and secreted exclusively
by adipose tissues. Adiponectin also known as adipocyte complement-
related protein of 30 KDa (Acrp30), is a hormone of adipocyte origin
that is involved in the homeostatic control of circulating glucose and
lipid level [30-31]. Adiponectin is a 147 amino acid protein that is
similar in sequence and structure to the C1q complement factor.
Unlike insulin and leptin, adiponectin levels in plasma remain
constant throughout the day and are not acutely affected by food
intake. Resistin is another hormone secreted by adipocytes that acts on
skeletal muscle myocytes, hepatocytes and adipocytes themselves,
where it is suggested to reduce insulin sensitivity leading to T2DM
(Figure 1). Leptin is the protein product of ob gene in mice and is
involved in appetite control. Visfatin is considered a new member of
the adipokine family. It is highly expressed in visceral fat and whose
level correlates with obesity. The action and identity of diabetes
susceptibility genes represent an important area for consideration of
disease mechanism.
Figure 1: Adipocytokines classification and functions leading to
type 2 diabetes.
Conclusion
In this review we have discussed the type 2 diabetes and its relation
with inflammation. Different environmental stresses, population
differences in activity and different diets clearly cause some genes to
manifest as a disease phenotype. The spectacular rise in rates of
diabetes among different populations as they adapt modern diet and
life style dramatically demonstrates the key role of environment,
insulin regulation and metabolic pathway. Many susceptibility genes
inhibit different pathways in the complex physiologic network that
cause T2DM. Our increased understanding of such phenomenon will
open new doors to understanding how common variants can alter
disease susceptibility and will be essential in understanding the
physiological importance of the genetic associations related to
inflammation and T2DM.
Citation: Saxena M, Modi DR (2014) Inflammation and Diabetes. Interdiscip J Microinflammation 1: 110. doi:10.4172/ijm.1000110
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Acknowledgements
Madhukar is thankful to Dr. D. S. Kothari post-doctoral fellowship
from university grant commission, New Delhi (BL/12-13/0317).
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Citation: Saxena M, Modi DR (2014) Inflammation and Diabetes. Interdiscip J Microinflammation 1: 110. doi:10.4172/ijm.1000110
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ISSN:ijm IJM, hybrid open access journal Volume 1 • Issue 1 • 1000110
... Adipose tissue, muscle fibres, and the liver all develop resistance to insulin in the complicated state of insulin resistance. Moreover, adipose tissue during obesity contains dendritic cells, mast cells, neutrophils, B cells, and T cells and is crucial for the development of inflammation in fat tissue and the effects of insulin (Saxena and Modi, 2014;Chen et al., 2015;Gupta, 2017;Artasensi et al., 2020;Wu and Ballantyne 2020;Zatterale et al., 2020). ...
... TNF-and IL-1 are the main cytokines that activate signalling pathways like the IKK/NF-B pathway in the pathogenic processes of insulin counteraction. This signalling pathway has increased activation in numerous tissues, such as adipose tissue in adiposis, and may promote insulin resistance via controlling the phosphorylation of insulin receptor substrate-1 by the IKK complex (Saxena and Modi, 2014;Chen et al., 2015). ...
... It is recognised as a phlogistic process intercessor that causes insulin resistance by disrupting glucose homeostasis and metabolism. High levels of circulating IL-6 are associated with insulin resistance in voluntary muscles, which increases the chance of developing diabetes mellitus (Saxena and Modi, 2014;Chen et al., 2015). ...
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