International Journal of Health Sciences and Research

www.ijhsr.org ISSN: 2249-9571

Review Article

Immune Dysfunction in Diabetes Mellitus (DM)

Vinod Kumar Rajana

Junior Research Fellow, Department of Biotechnology, IIT Guwahati

ABSTRACT

Diabetes mellitus patients are more prone to infection and also the wound healing capacity is very
less. As the immune cells are well established mechanisms to protect us from pathogens. So, this
article tried to combine all the recent updates of the relevant scientific data that have been done till
now on ―The effect of diabetes mellitus on the immune cells‖. It has been well described that there is
no or less effect of diabetes mellitus on the adaptive immune system. But if it comes to innate immune
system diabetic mellitus affects the cellular functions like chemotaxis, phagocytosis, and killing of
pathogens by monocytes, macrophages, and neutrophils. Most studies showed that decrease in normal
cellular function, and alteration in enzyme activity and cytokine secretion in diabetic monocytes,
macrophages, and neutrophils when compared to control cells. Improvement in cellular functions can
be achieved by controlling diabetes mellitus. By understanding how the immune cells were altered in
diabetes mellitus further we can proceed by targeting therapeutically to achieve better results in
regulation of diabetic complication and improve the lifespan of diabetic patients.

Key words: Hyperglycemia, Insulin, Monocytes, Macrophages, Neutrophils, Advanced Glycation end
product (AGE)

INTRODUCTION diacylglycerol, protein kinase C(PKC)

Immune and metabolic systems are activation and oxidant formation (Ceolotto
interrelated and most fundamental et al. 2001). Complications in diabetes are
requirement for survival. Diabetes mellitus mainly caused by chronically elevated
(DM) is a clinical syndrome associated with inflammatory immunity as the major cause
metabolic disorder due to impairment in of morbidity and mortality of diabetic
insulin secretion or its action leads to patients (Sun et al. 2012). There may not be
hyperglycemia. Estimated worldwide any direct alteration in the adaptive
diabetics deaths are 4.6 million per year. immunity, but whereas in innate immunity,
(Espinoza-Jim&#xe9 et al. 2012).In future there is an alteration in its functions like
by 2030, it would reach 525 million. These cytokine response, chemotaxis,
statistics alert the whole world to focus on phagocytosis, and killing. (Xiu et al. 2014)
diabetes.(Xiu et al. 2014).Further Long term Virulence of microbes increases in
complication and immune compromise arise hyperglycemia and its increased microbial
in hyperglycemia condition (11.2mmol/l or adherence in diabetic while comparing with
220 mg/dl)(Boyanova and Mitov 2013) nondiabetic or normal cells. Ex;-candida
cause many problems in DM like Albicans (opportunistic pathogen) Also
atherosclerosis, nephropathy, Surgical site infection by staphylococcus
neuropathy,(Gyurko et al. 2006).It also has aureus is also frequently occurred as a
a role in other diseases like rheumatoid serious complication in diabetes. (Yano et
arthritis, osteoporosis, aging(Singh et al. al. 2012) due to alteration in immune cell
2014) through hyperosmolarity, function (Geerlings and Hoepelman

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 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

1999).These infectious complications have utilization and on its counter hormone

more effect on diabetic prognosis (Yates et insulin, glucagon.
al. 2009). In this respect diabetes considered
worldwide as a secondary immune 1. Immune Cells in Hyperglycaemia
deficiency next to malnutrition (Daoud et al. 1.1 Monocytes:
2009). Monocytes are developed in the
As indicated above only innate bone marrow from the myeloid progenitor
immune cells function is altered in cells and migrate to peripheral blood to
hyperglycemia, so among the innate reach specified tissue (Volkman and
immunity cell major role was played by, Gowans 1965).They have a very short
monocytes, macrophages, and neutrophils. lifespan and travel in blood for
As all these are originated from the same approximately 10-20 hr. before entering into
precursor they have some common features tissue.(Sunderkötter et al. 2004).
(V. Kumar and Sharma 2010). Interestingly i. TNF-α and its pathways:-
the approach of the Monocytes and macrophages from
Ongoing studies worldwide are not humans and mice of type 1 diabetes (TID)
solely on examining the role of altered express high levels of enzyme long-chain
immune cells in cause of disease but it acyl-CoA synthetase 1(ACSL 1) catalyzes
should also need to focus on the diabetic the thioesterification of fatty acids through
phenotypic effect on the immune system increased release of PGE2 (prostaglandin
itself (Daoud et al. 2009). E2)(Kanter et al. 2012) . In monocytes,
Initially, when there is an injury, CD33, a membrane receptor has the ability
neutrophils will invade first to the site of to inhibit the cytokine production through
injury to execute foreign particles and its immunoreceptor tyrosine-based
secrete cytokines (Henderson et al. 2003). inhibitory motif (ITIM). Ex vivo studies on
These cytokines recruit monocytes along T2D patient’s monocytes suggest that there
with neutrophils and macrophages is CD33 down-regulation and suppressor of
(Petrofsky and Bermudez 1999). These cytokine signaling protein-3 SOCS-3
cytokines also stimulate pro-inflammatory upregulation, whereas high expression
and anti- inflammatory responses (Duffield levels of IL-8, TNF-α, IL-12p70 via
2003) (Rao, Zhong, and Sun 2014). Mice ROS.(Gonzalez et al. 2012).
infected with pathogenic bacteria like non- Monocytic THP-1 cells and human
typhoidal Salmonella, Shigella, and Vibrio PBMC, results in high level (2 to 5 fold)
parahaemolyticus shows high mortality mRNA expression of cytokines TNF-α,IL1-
morbidity and bacterial load in streptozocin- β, and their receptors(TNFR,IL-1R)
induced hyperglycemic mice than normal CD27L,monocyte chemoattractant protein-1
(Koley et al.2016). Hyperglycemia activated (MCP-1) and inflammatory chemotactic
leukocytes are also involved in insulin gene inducible protein-10 (IP-10),β2-
resistance in T2D (de Vries et al. 2015). integrins and some metalloproteinase in
In this paper, we intend to review High Glucose than Normal Glucose. The
recent updates of the action of highest level of gene expression is shown in
immunological cells particularly monocytes, IL-12. Also proved that these are under the
macrophages and neutrophils in diabetes. control of pathways protein kinase C (PKC),
These cells generate cytokines and reactive p38 MAPK (p38), c- Jun-terminal kinase,
oxygen species (ROS) as the hallmark of and inhibitory kappa B kinase (Wen et al.
many diseases which are linked to metabolic 2006) In another study on THP-1 monocytic
and vascular disorder like diabetes are cells also showed rise in expression levels
caused by oxidative stress due to free of monocyte chemoattractant protein-1
radicle (Wiernsperger 2003). Which has (MCP-1), TNF-α, β (2)-integrin, interleukin-
intense effect on glucose consumption, 1β. Along with increase of transcription in

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MCP-1 gene and protein level and adhesion expression .In-vitro studies on monocytes
of THP-1 to endothelial. Specific inhibitors also showed same results as in vivo.
of oxidant stress, protein kinase C, ERK1/2, (Bernal-Lopez et al. 2013)
and p38 MAPK blocked the elevated levels Monocytes towards atherosclerosis:-
of MCP-1 by HG (Shanmugam et al. 2003) Lipopolysaccharide (LPS) activated
PGE2 and cytokine secretion of monocytes from T1D patient’s exhibits
monocytes has been regulated by the reduction in IL-6 and CCL2 secretion.
Extracellular signal-regulated protein These cytokines are induced through
kinases (ERK) pathway, is further activated MAPK/ ERK and P38 pathways. So LPS is
by mitogen-activated protein kinase (MEPK acting somewhere in these pathways.
or MEK) tyrosine and threonine Apolipoprotein E (Apo E) is effective in
phosphorylation and inactivated by protection of monocytes from lipid
mitogen-activated protein phosphatase-1 accumulation is also altered in monocyte.
(MPK-1) dephosphorylation. Ceolotto et al (Wehrwein et al. 2006) In hyperglycemia
in-vivo in human monocyte experimental the HUVE, showed increased expression of
results clearly shown that there is significant protein and mRNA levels of CCL5 and also
increase in the activity of the ERK and increased monocyte adhesion (2.1-2.2 fold)
MEK kinases but not in the MPK-1 in through the P38 MAPK pathway. (Gao et al.
hyperglycemia it has a negative role in 2015)
pathophysiology of monocyte and Human monocytic cells when
macrophages As most of them are under exposed to high glucose enhanced the
NF-kB control so as expected there is secretion of resistin and TNF- α mRNA and
upregulated in NF-kB expression levels protein levels.(Tsiotra et al. 2013). HG and
(Ceolotto et al. 2001) PIT-1 decrease expression of PIP3 and at
IL-6 in intermediate monocytes and its the same time there is an increase in the
controversy:- concentration of ICAM (intercellular
When healthy individuals are adhesion molecule 1) in HUVEC and
induced acute hyperglycemia by IV infusion CD11a (lymphocyte function- associated
of dextrose and octreotide for 2 hr. Results antigen 1, LFA-1 subunit) in
in a decrease of IL-6 expression. Where as monocytes.(Manna and Jain 2014)
In vitro results of PBMC with high glucose ii. Insulin resistance by
also showed reduction in IL-6 and IL-17A hyperglycemia:-
expression levels. Among them, Studies on circulating monocytes of
intermediate monocytes show highest hyperglycemic patients reveal that there is
reduction. The path ways for the reduction high expression level of CD11c and lower
of IL-6 was identified as P38 MAPK expression levels of CD206 with respect to
expression not by phosphorylation using as normal glycemic control monocytes.CD11c
electro chemiluminescence assay and elevation correlates with increase insulin
SB203580 inhibitor (Spindler et al. 2016). resistance, obesity, triglyceridemia and low
CD16+ CD14+ is intermediate monocytes serum IL-10. They might undergo M1
which are more in T2D and secrets pro- inflammatory polarization in high glucose
inflammatory cytokines TNF-α and IL-1 β. condition (Torres-Castro et al. 2016).
(Terasawa et al. 2015) Taken together, all the above studies
The in vivo study on normal and have investigated the effect of
well (HbA1c ≤ 6.5) or poorly (HbA1c > 6.5) hyperglycaemia on monocytes. It was
controlled DM patients showed that clearly evident that there is an effect of
monocyte chemoattractant protein (MCP-1) cytokines on the proper functioning of
and IL-6 are upregulated, in diabetic monocytes and its role in inflammation,
patients than healthy subjects.. So control of proliferation, and adhesion leads to other
glycaemia might decrease only IL-6 complications like cardiovascular diseases

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atherosclerosis. But there are some hyperglycaemia or DM. The infiltration of

controversies in IL-6 upon which future macrophages might be due to the growth
research has to be concentrated. and proliferations are the cause for a
1.2 Macrophages:- diabetic lesion (Saini et al. 1996). Along
Macrophages derived from with hyperglycaemia, hyperlipidemia has
monocytes of myeloid progenitor cells in synergistic effect in stimulation of isolated
bone marrow have a crucial role in immune macrophage proliferation and accumulation
response and homeostasis i.e. immune of macrophages in atherosclerotic lesions by
regulation, host defense and wound ERK-mediated LDL oxidation glucose
healing(Xiu et al. 2014) (Rosenberger and pathway (Lamharzi et al. 2004).
Finlay 2003). Are involved in the first line ii. Epigenetic alterations and IL-6:-
of defense (Laskin et al. 2011) Those are In vitro studies, hyperglycaemia
broadly classified into classically activated leads to macrophage dysfunctioning on
macrophages and alternatively activated long-term exposure. Also significant
macrophages ((Espinoza- Jim&#xe9 et al. reduction in pro-inflammatory cytokines
2012).These both cells have opposite action TNF-α and IL-6 production, CD86 and
and have a major role in type 1 and type 2 CD54 expression but enhanced nitric oxide
diabetes. i.e. islet cell destruction (Kolb- (NO) secretion in F4/80(+) peritoneal
Bachofen and Kolb 1989) Microvascular exudate macrophages (PEMs) When treated
and atherosclerotic lesions ((Ross 1993). with IFN-γ and LPS from streptozotocin
Substantial increase in tissue macrophages (STZ) induced mice with diabetes for 4
is a common feature in all complications month. A similar change was shown in bone
nephropathy, atherosclerosis, neuropathy, marrow derived macrophages indicates that
retinopathy (Sun et al. 2012). The common there is involvement of epigenetic
progenitor cells monocytes after they enter alterations in macrophage precursors. These
into tissue compartments differentiated results are reversed by AKT and ERK
irreversible into macrophages. These inhibitors (Sun et al. 2012).
resident macrophages exhibit phenotypic Studies on the effect of epigenetic
differences from recruited macrophages. histone modification on the inflammatory
Resident macrophages differ in their cytokine production by THP-1 derived
morphology and function as they express macrophages in hyperglycaemia, reveals
germline encode nonclonal receptors most that inhibition of specific H3K9me3
studies of macrophages are on (PEMs) methyltransferase SUV39H1 by chaetocin
peritoneal exudate macrophages and (SPMs) in high glucose treated macrophages
splenic macrophages because PEMs are increases the expression levels of
easy to isolate and SPMs have inflammatory cytokines interleukin-6 (IL-6),
heterogeneous population and have IL-12p40, macrophage inflammatory
immune-modulatory effect (G. Liu et al. protein-1α (MIP-1α), and MIP-1β.
2006). Contrarily when High glucose treated
i. Proliferation:- macrophages under over expression of
The proliferation of the splenic SUV39H1 also increases the expression
macrophage (SPMs) and WEHI -3 cell lines levels inflammatory cytokines.(Li et al.
are more in the hyperglycemic environment 2016)
but not by osmolality. (5.6-30mM). It is So as a result of these experimental
concentration dependent in the presence of data the macrophage alteration by
CSF-1 (Y. J. Liu et al. 1995).The Colony AKT/ERK pathway and epigenetic histone
stimulating factor (CSF-1) enhances the modification might be one of the
proliferation and growth of mouse splenic mechanisms for alteration in inflammatory
macrophages as its CSF-1receptor (CSF-1r) cytokine secretion.
expression levels have three-fold increase in

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iii. Islet cell destruction:- iv. Microbicide property:-

The PEM as a source of The isolated peritoneal macrophages
inflammatory cytokines shown highest from streptozotocin-induced hyperglycemic
expression level for IL-12 (5.4 fold) in time mice show a low level of bacterial killing
(3-12h) and dose-dependent manner (10, and phagocytosis than normal mice infected
17.5, 25 mmoles/liter). IL-12 protein with pathogenic bacteria like non-typhoidal
accumulation and its mRNA expression (20 Salmonella, Shigella, and Vibrio
fold change) from mouse peritoneal parahaemolyticus. So as a result of a
macrophages (MPM) is also increased in disturbance of the innate immune function
high glucose in streptozotocin-induced type in the hyperglycemic mice might make
1 diabetic mice as well as type 2 diabetic diabetic individuals more prone to bacterial
db/db mice. These IL-12 signals T-cell to infection. (Koley et al. 2016)
become Th1 cell. Both Th1 and IL-12 cell v. Atherosclerosis:-
infiltration is vital importance in Studies on RhoA/ROCK activation
autoimmune diabetes and inflammation, of the macrophages by hyperglycaemia
interestingly research on mouse proved that using RAW 264.7 cell line in atherogenesis
reduction in IL-12 can reduce reveal that this RhoA/ROCK activation
atherosclerosis and inflammatory follows the JNK/ERK pathway but not
complications (Wen et al. 2006) As the through NF-kB pathway by using ROCK
protein kinase C, p38 MAPK (p38), c-Jun- inhibitor hydroxyl fasudil and Si RNA
terminal kinase, and inhibitory-kappa B silencing. As a result of macrophage
kinase activity were increased in MPM in activation releases more pro-inflammatory
the presence of HG. Also, the inhibitors of phenotypes.(Cheng et al. 2015).
these pathways reduce the HG-induced IL- Accumulation of cholesterol in arterial
12 expression in MPM. So it is expected macrophage is one of the causes for
that these pathways are involved in HG- atherosclerosis in diabetes. This cholesterol
induced IL-12 gene expression in transport was mediated by ATP- binding
streptozotocin (STZ) induced type I diabetic cassette transporter A1 (ABCA1) is the
mice and type II diabetic db/db mice. The roprotective protein. Their results showed
IL-12 has a major role in diabetic that high glucose activates ERK pathway
inflammations (Wen et al. 2006). The study and produce ROS. These generated ROS
on P38 MAPK activity in monocytes involved in degradation of ATP-binding
isolated from metabolic syndrome patients cassette transporter A1 (ABCA1) mRNA
show that MAPK could a promising target and protein level (Chang et al. 2013)
to prevent diabetic complication. (Jialal, (Spartano et al. 2014).
Adams- Huet, and Pahwa 2016) RAW264.7 macrophages when
IL-27 has a β cell protection stimulated with high glucose (15-25mM)
activity in diabetes was concluded based on along with LPS and normal glucose (5mM)
result that Islets proinsulin levels were with LPS. High glucose alone can’t able to
lower where as The islet infiltration by induce NO generation and cytokine release.
F4/80(+) CD11c (-) 7/4(-) macrophages, But in combination with LPS, high glucose
CD4 (+) T cells, and CD8 (+) T cells was induce NO generation by inducible nitric
increased in EBI3 (-/-) and WSX-1(-/-) mice oxide synthase (iNOS) expression and IL-1
compared with WT mice, but after β secretion at a higher rate than in normal
recombinant IL-27 administration these all glucose. it was through increased
results are reversed and also there is an phosphorylation levels of protein kinase C-
increase in islet proinsulin levels in WT and α (PKC-α), protein kinase C-delta (PKC-δ),
EBI3(-/-) mice.(Fujimoto et al. 2011) and p38 phosphorylation and NF-κB
transcriptional activity lead to inflammation

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and atherosclerosis in diabetes.(Hua et al. Due to inflammation, there is

2012). significant increase in IL-6 (2.9fold),
vi. M1 polarization:- chemokines response (KC 2.6 fold, MCP-1
Primary monocytes from healthy 2.6 fold, MIP-1α 4.4 fold) and superoxide
donors were differentiated into macrophages release by cytochrome c reduction where as
and exposed to normal glucose, high reduced chemotaxis towards FMLP and
glucose, and high mannitol as osmotic WKYMVm in Akita PMN(novel model for
pressure control. The results showed that hyperglycaemia) over wild type PMN.
high glucose macrophages have high Many of this function are linked with
expression levels of CD11c and nitric oxide NADPH oxidase and myeloperoxidase
synthase (NOS) whereas downregulation of enzyme (MPO) involving metabolic
IL-10 and arginase -1 in comparison with pathways. Polymorphonuclear neutrophils
normal glucose and osmotic pressure (PMN) damage tissue directly by
control. As a result it was concluded that superoxide protease, nitric oxide (NO)
high glucose has an effect on macrophages release and indirectly by TNF and IL-1 in
leads to M1-like inflammatory polarization inflammation. (Gyurko et al.2006).
in diabetes. (Torres-Castro et al. 2016) i. NADPH complex:-
In summary from the above studies, Superoxide production in
it was clear that there is a well-established polymorphonuclear neutrophils (PMN) is by
effect of hyperglycaemia on the macrophage the action of NADPH oxidase. It is made up
functional activity and phagocytosis through of membrane-bound (gp91phox and
different pathways. But further studies has p22phox) and cytoplasmic (p47phox,
to focus on understand and identify p67phox, and rac) components.
downstream signals which lead to different Phosphorylation of p47phox and its
pathways and how the pathways are translocation and assembly leads to NADPH
interrelated. This will give us the better oxidase activation. There is a pre-maturation
approach to understanding the mechanism and translocation of cytoplasmic p47phox in
and develop therapeutic target for cure or at neutrophils proves that the NADPH oxidase
least decrease disease progression and activity is more in diabetic neutrophils
complications. (Gyurko et al. 2006).
1.3 Neutrophil:- ii. NADPH action:-
Elie Metchnikoff discovered The NADPH oxidase is thought to
neutrophils in starfish larva while be the reason for the release of ROS by the
conducting studies on inflammation. These activity called oxidative burst. Its action on
cells are the first line of defense and act molecular oxygen generates superoxide
first.(V. Kumar and Sharma 2010) .Among anion O2-. Further this anion form into
the blood leucocytes 60-70% are hydrogen peroxide (H2O2), hypochlorous
granulocytes and among the granulocytes acid (HOCL) and MPO are principle
90% are neutrophils. The largest fraction of enzymes produced inside the neutrophil
white blood cells (WBC) is azurophilic granules. Interestingly the
polymorphonuclear neutrophils (PMN) results showed high MPO protein
(Walrand et al. 2006). Bone marrow is the expression level whereas decrease in MPO
places where the neutrophils originate from activity measured by HOCL production in
the pluripotent stem cells attain maturity diabetic neutrophils when compared to
within 8-10days. Functional properties of control. C.albicans phagocytosis activity
neutrophils include granular content, was measured by May-Grunwald-Giemsa
degranulation, adhesion, aggregation, staining showed lower in diabetic than
phagocytosis, chemotaxis and respiratory control. These indicate the importance of
burst activity (Bogomolski-Yahalom and HOCL production in MPO activity in the
Matzner 1995)

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killing and phagocytosis function of inhibition of MPO. So MPO has a crucial

neutrophils (de Souza Ferreira et al. 2012a). role in the NET formation and its deficiency
iii. MPO action:- make subject prone to candida Albicans
ROS is a measure of neutrophil infection (Metzler et al.2011). When
activation and phagocytosis. MPO catalyze neutrophilic cells were treated with 0,
H2O2 to HOCL, as its expression is more in 5,25mM of glucose and 25 mM mannitol
type II diabetes (T2D) might make them are analyzed by immunostaining for DNA,
more prone to cardiovascular disease. It was chromatin, and elastases. The NETs release
clearly evident when elevated MPO was quantified by Hoechst 33342. It
plasma levels are observed in cardio indicated that high glucose (25mM) has
syndrome patients (de Souza Ferreira et more circulating markers of NETosis and
al.2012a).While evaluating the expression NET release when compared to mannitol
levels of MPO by measuring HOCL (25mM) and normal. Plasma elastase,
formation, surprisingly MPO mRNA and mono- and oligonucleosome and dsDNA
protein expression levels are high but levels are high in T2D than a normal non-
HOCL generation is decreased in diabetic diabetic. (Menegazzo et al. 2015)
neutrophic ls when comparing control (de Neutrophil count is decreased in
Souza Ferreira et al. 2012a).The reduced T1D patients. So as to access the
HOCL formation is thought to be due to mechanism how the count is decreasing in
alteration in the enzymatic activity of MPO diabetes. They analyze the protein levels
by AGE formation. There is also being a and enzyme activity of neutrophil elastase
feedback mechanism on enzyme activity (NE) and proteinase 3(PR3) both are
and concentration. As HOCL is an neutrophil serine proteases present in
important member of ROS it causes neutrophil granules. Their study showed that
problem in pathogen immune system (de the NE and PR3 levels are more in
Souza Ferreira et al. 2012a). progressive increases with the more number
iv. NET and its Microbicide action:- and titer of antibody against the beta cell
Along with phagocytosis neutrophils antigen. These results are correlated with
are endowed with the special ability to the elevated level of NET and reduced
generate extracellular trap called neutrophil levels of endogenous serine protease
extracellular trap (NET)(Joshi et al. inhibitor α- antitrypsin in T1D. As a result,
2013).NET is constitutes of granule proteins these might act sensitive biomarkers for
and chromatin to kill pathogens(Brinkmann T1D at an early stage.(Wang et al.2014)
et al. 2004).NET releases after the cell v. Role of RAC2 in NET formation:-
membrane breaks which depends on the The null Rac2 mice show less
generation of ROS by NADPH oxidase. production of ROS and NO leads to failure
Chronic granulomatous disease patients in NET formation. It was confirmed by the
have NADPH gene mutation so they can’t supply of external ROS sources and L-
be able to form NET. These NET provide a NAME for NO inhibition. As the Rac2 is
microbicidal property to neutrophils (Fuchs involved in ROS production The formation
et al. 2007).As H2O2 is a substrate for MPO of NET essentially needs Rac2 as important
which is produced from the superoxide component via pathways involving ROS
generated by the NADPH oxidase system so and NO production was assessed in mouse
deficiency and dysfunction of MPO have a Rac1null and Rac2 null neutrophils with
mild to moderate effect on NET formation. wild-type neutrophils (Lim et al.
They observed the failure of NET formation 2011). The FcR/rac system depends on
in MPO-deficient donor patient’s NADPH oxidized system and increase TNF-
neutrophils. Whereas the results of partial α production. So diabetic hyperglycaemia
MPO-deficient donor make NET Delay in affects both phagocytic and cidal activity of
NET formation is seen in pharmacological neutrophils (de Souza Ferreira et al. 2012b)

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this rac and Cdc42 activate JNK and P38 neutrophils and lymphocytes isolated from
MAPK pathway (Caron and Hall 1998) T2D patient’s blood. The results showed
vi. Pathways and delayed response:- that there is a decrease in calcium
As the pathways are affected during mobilization in T2D than normal. So this
hyperglycaemia, DM patients are more calcium mobilization alteration in immune
susceptible to infection. The neutrophils cells might be one of the mechanisms of
NET formation and microbicidal activity are immune disturbance in diabetes (Kappala et
reduced in diabetes than normal. al. 2014)
Neutrophils from T2D show high-level vii. Synergistic effect of dyslipidemia:-
expression of IL-6 are responsible for Neutrophils or PBMC (peripheral
continuous active state which makes them blood mononuclear cells) when treated with
less response to LPS stimuli for long time. It RHQ (rhodamine-quinoline based
might also be by negative feedback chemodosimeter) for measuring endogenous
mechanism of NET formation in diabetic ROS and HOCL. The results showed that
neutrophils (Joshi et al. 2013). Diabetic rat HOCL and ROS generation is more in
peritoneal neutrophils exhibit delayed diabetic dyslipidemia neutrophils than
response when compared to normal might diabetic nondyslipidemia neutrophils and
be due to expose to chronic hyperglycaemia normal control. Due to more production of
for 30days or may be continuous exposure H2O2 and hyperactivity of myeloperoxidase
to hyperglycaemia makes them less enzyme (MPO) in diabetic dyslipidemia.
stimulus(de Souza Ferreira et al. 2012b). These results prove that dyslipidemia has a
Neutrophils when pretreatment with synergistic effect on the generation of ROS
PKCα/β inhibitor Go6976 or GF109203X and provoke diabetic patients into more
decrease NF-kB, TNF-α, production and complications (Ghoshal et al. 2016).
prevent LPS induced phosphorylation of viii. Proteins and complications:-
IKK αe /β, IkB- α, NF-kB and observed Glycated hemoglobin (HbA1c)
failure of activating P38 and JNK pathways. proportionally elevates the basal ROS
These data strongly supported production in post menopause females. As
interconnection of pathways and cytokine the neutrophil function is decreased they
production in neutrophil (Wen et al. 2006). may be more susceptible to infection. So
Peripheral blood mononuclear cells (PBMC) glycemic control is more important in post
of diabetic patients have decreased menopause females to prevent diabetic
stimulation response with mitogens complications.(Saito et al. 2013).
concanavalin a, phytohemagglutinin, Hyperglycaemia elevates the rate of
pokeweed mitogen when compared with myelopoies is makes the diabetic patients
healthy control patients. Also decrease in more prone to atherosclerosis. As measured
diabetic neutrophils, polymorphonuclear plasma levels of neutrophil produced
cells (PMNC) respiratory burst activity S100A8/S100A9 is proportionately
compared to normal. This effect might be increased with leukocyte counts in coronary
due to long-term in-vivo exposure to artery disease (Nagareddy et al. 2013). An
hyperglycaemia (Daoud et al. 2009). increase in the activities and its percentage
Calcium dependent processes such equivalence of neutrophil membrane-bound
as phagocytosis and chemotaxis of elastase (MLE), membrane-bound form of
neutrophil and lymphocytes are active in cathepsin B (MCB) and their respective
protection against microbial infections. intracellular proteases (ICE,ICB) of
While investigating the process of calcium neutrophils is observed in T2D compared to
mobilization under the effect of N-formyl- normal might have a role in diabetic
methionyl-leucyl-phenylalanine (f MLP), complications (Zurawska-Płaksej et al.,
Thapsigargin (TG), and hydrogen peroxide 2014).
(H₂O₂) on [Ca²⁺] (i) homeostasis in

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Studies on human chitinases and (PPR)(Shiny et al. 2013). People with

chitinase-like proteins i.e. neutrophil- insulin resistance had been reporting of
derived chitotriosidase (CHIT1), acidic suffering from coronary risk factors like
mammalian chitinase (AMCase) and hypertension, obesity, dyslipidemia and
chitinase 3-like protein 1 (YKL-40) of glucose intolerance are major causes of
whole blood isolated neutrophils in T2D. It death.(Reaven 1988) (Zavaroni et al. 1989)
showed that these levels are high in diabetes (Kaplan NM 1989). Nowadays diabetes and
than normal. As a token of support, insulin atherosclerosis have been closely related
treatment also reverses the protein level and considered as a chronic inflammatory
(Żurawska-Płaksej et al. 2015). In human disease (Menu et al. 2012). All types of
CXCR1 and CXCR2 are homologous white blood cells including granulocytes
proteins bind to ELR+ chemokine play a lymphocytes and monocytes are associated
crucial role of functional activities like with insulin resistance but in beta cell
migration and ROS production in destruction only granulocytes and
neutrophils. A non-obese diabetes mouse lymphocytes have a role (Lee et al. 2014).
(NOD) is a model for T1D.they found a 2.1 Monocytes:
decrease in CXCR1 mRNA level and its THP-1 is the human myeloid cell
CXCR1 promoter activity in neutrophils line is the best model system for mimic
from NOD mice. So there is a chance for its monocyte and macrophage for metabolic
contribution in T1D complications. syndrome studies like diabetes. (Naderi et
(Haurogné et al. 2015). al. 2014) Isolated peripheral blood
From the above data, it was clearly monocytes are sensitive to insulin (The
evident that hyperglycaemia alters many of wissen et al. 2014). Insulin internalization
the normal functions and cytokine study on human circulating monocytes by
secretions of neutrophils. In many of the 125I revealed that the process is energy and
results they just show the correlation with temperature dependent. The type II diabetic
hyperglycaemia. So in future, we have to patient monocytes have decreased insulin
identify the pathways and its downstream internalization ability when compared to
targets for a better therapeutic approach normal. It may have a role in insulin
towards complications in diabetes. resistance to cells in Type II diabetic
patients (Trischitta et al. 1986).
2. Insulin and Immune Cells i. Proliferation:-
Insulin is a therapeutically important Insulin stimulates proliferation of
hormone for treatment and regulation of THP-1 cell line up on 24h treatment. But the
glucose in diabetes. (Verhagen et al. 2011) effect of stimulation reduced in longer time
It is essentially required to maintain exposure. It affects morphology and
metabolic homeostasis. Initially, insulin adherence and has a pro-inflammatory
bind to its receptor present on the immune effect on monocyte proliferation (Naderi et
cell surface to exhibit its action i.e. al. 2014). When human monocytic cells
Monocytes, macrophages, and neutrophils treated with high insulin leads to increased
Insulin mainly activates PI3K-AKT/PKB expression levels of resistin and
pathway and ras/MAPK pathway extends its proinflammatory cytokines like TNF- α, IL-
effects like decrease glucose levels (Xiu et 6 and Il-1 β might have a role in insulin
al. 2014) (Defronzo et al. 1978).(Xiu et al. sensitivity related complications (Tsiotra et
2014). al. 2013).
Insulin resistance arise studies so far ii. Insulin resistance:-
conducted on the insulin resistance In females when monocytes are
concluded that it may be due to low-level isolated after the intense to moderate
inflammation in innate immunity mediated exercise. The M1 marker expression is
by pattern recognition receptors suppressed and the M2 marker MCP-1

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 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

expression levels are enhanced. Similarly increases The release of growth factors and
the serum PPAR-γ target gene CD36 and its chemotactic proteins of vascular smooth
activity increases. So exercise has a positive muscle and endothelial cells .i.e. Heparin-
effect in control the inflammatory binding epidermal growth factors, (VCAM-
complication and reduces insulin resistance 1) vesicular cell adhesion molecules and
somehow through PPAR-γ in diabetes metalloproteinase involve in adhesion and
specially T2D (Ruffino et al. 2016). Human migration have a crucial role in
PBMC are used to evaluate the receptor atherosclerotic progression.(Iida et al.
expression levels in correlation with C- 2001).
reactive protein (CRP) and inflammatory ii. Insulin resistance:-
cytokines involved in insulin resistance. The adipocyte-derived factor called
Surprising the IL-6 and TNF – α levels is pigment epithelium- derived factor (PEDF)
more and also enhanced P2X7 receptor activates macrophages, through the
expression along with high CRP in T2D production of TNF mediates insulin
monocytes than health (Hong Wu et al. resistance in NOD mice pancreas.
2015, 7). Interestingly PEDF inhibitor emetine
Monocytes migration is the main (emetic) inhibits macrophage activation by
reason for inflammation in atherosclerosis. PEDF, show attenuation in pancreatic TNF
Out of glucose, insulin, and insulin-like level, insulitis and hyperglycaemia in
growth factor only insulin has an effect on C57B16 mice, so hopefully as it will show
THP-1 monocytic and bone marrow derived positive results as target in T1D diabetes
monocytic cells migration (BDMC). (Hudson et al. 2016).
Pathways studies using pathway inhibitors 2.3 Neutrophils:
and surface expression inhibitors concluded These are the nonspecific immune
that insulin increase surface expression of cells recruited as the first line of host
macrophage-1 antigen (mac-1).which defense. These are the cells that respond to
mediates via the Akt pathway for monocyte inflammation as early as possible and then it
migration through endothelium, these data communicates with other immune cells.
suggest the insulin role in atherosclerosis in Neutrophils produce proteases among this
T2D(S. Y. Jin et al. 2014) neutrophil elastase is one to promote the
2.2 Macrophages: inflammatory response. When hepatocytes
i. Atherosclerosis:- treated with neutrophil elastases it leads to
Hyperinsulinemia effects on inflammation and insulin resistance. After
macrophages make more prone to heart removal of elastase from high-fat diet
coronary diseases like atherosclerosis. But it induced obese mice has less tissue
was a mystery how insulin involves in the inflammation along with low adipose tissue
development of atherosclerosis. (Iida et al. neutrophil and macrophage content.
2001) Macrophages interact with acetylated Implying that it might affect glucose
low-density lipoproteins (LDL) through tolerance and insulin resistance specifically
scavenger receptors or acetyl- LDL in type 2 diabetes (Talukdar et al. 2012).The
receptor, degrade them and transform into neutrophil function requires ATP-dependent
foam cells involve in atherosclerotic initial energy produced by glucose metabolism
stages. These macrophage foam cells are (Borregaard and Herlin 1982). It was
found in atherosclerotic (Steinberg 1997). reported that 50% reduction in glycolysis
The effect of insulin (10-7M) and glucose use in diabetic patients (Munroe
increase the expression level of TNF- α and Shipp 1965). As the glycolysis is
gene and protein release from the monocyte- impaired in diabetes neutrophils due to loss
derived macrophage THP-1 cell. It of synthase phosphatase activity it affects
communicates its activation effect through neutrophil functional properties (V 1983).
ERK pathway in MAPK family.. TNF- α

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 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

Activin A is a transforming growth intramolecular rearrangements. It forms

factor beta family cytokine has a role in Amador product such as glycated
inflammation caused insulin resistance. So hemoglobin which is elevated in diabetes.
this activin A release by TNF-α in insulin Further modification by irreversible
deficiency was checked in murine bone chemical changes forms AGE. (Michael
marrow derived precursor neutrophils From Brownlee 2001) (Alba- Loureiro et al.
8 to 10 weeks old C57BL6/J male mice 2007). AGE interaction with receptors
(Wang et al. 2014). It was concluded that changes its properties leads to micro and
TNF- α stimulated activin A release from macro vasculature complications as the
the neutrophils. It has to be under control by result of its accumulation, mainly under a
insulin or it may create inflammatory hyperglycemic condition as in diabetes.
complications in T2D (Hui Wu et al. Monocytes are activated by the soluble
2013).Diabetes was associated with greater AGEs and monocyte migration is inhibited
blood neutrophil count found in non- by the AGE interaction with basement
Hispanic white HFE C282Y homozygote’s membrane and their receptor for advanced
(Barton et al. 2016).T2D is associated with glycation end products (RAGE). As a result
insulin resistance (IR) which is due to of RAGE activation, there is a
inflammation. As the Neutrophil transcription factor nuclear factor-B and
lymphocyte ratio (NLR) is the indicator for its target genes upregulation. AGE
inflammation. It was proved that there is an +RAGE interaction in endothelium
increase in the insulin resistance along with increases its permeability, block nitric oxide
the NLR ratio increase. So it provides us a production and also increases ROS
way to make it a marker for insulin generation. It has also been proved to have
resistance (Lou et al. 2015). an inducing effect on the two oxidized LDL
receptors on macrophages i.e.CD36 and
3. AGES FORMATION AND EFFECT macrophages scavenger receptor class A. It
ON IMMUNE CELLS makes macrophages to uptake more
In diabetes due to metabolic and oxidized LDL and then they transform into
functional impairment leads to accumulation foam cells. Which are present more in
of glucose and it’s analog. Its fusion with atherosclerotic lesions ((Goldin et al. 2006)
proteins and lipids catalyzed by non- (Alba-Loureiro et al. 2007).
enzymatic reaction leads to a formation of i. AGE on monocytes:-
advanced glycation end product (AGE). Earlier studies proved that AGE bind
AGE play a crucial role in long-term with RAGE generate ROS which triggers
complications by altered receptor function, cytokine secretion contributes to
enzymatic activity and disrupt molecular proliferation and inflammation in cells. Nam
conformation of proteins lipids and et al determine the effect of AGE on the
sometimes nucleic acid (Singh et al. 2014). HUVEC and THP-1 co-culture with VSMC
AGE quantitatively and qualitatively results showed that proliferation was
modifies the extracellular components like induced by the AGE in VSMC along with
laminin, collagen, and vitronectin. It also significant elevation in the cytokine
has an effect on adhesion, matrix expression like IL-6 and MCP-1(Nam et al.
accumulation, growth. AGE-modified 2011). The AGE didn’t have any effect on
proteins interact with receptors on the cell viability but enhance the expression of
macrophages and endothelial cells to alters VCAM-1 and MCP-1 in HUVEC. Whereas
their normal functions (M. Brownlee 1992) AGE with PKC- β inhibitor decreases their
3.1 Age Formation and Interaction: expression. So this pathway could be a
AGE is formed by glycosylation and therapeutic target for AGE-induced
glycoxidation, at first; it gives rise to Atherosclerotic complication in diabetes.
reversible Schiff's base later on due to (Rempel et al. 2015)

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 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

When examining the effect of AGE RAGE/NF-kB pathway and mediate serious
or RAGE on (ATP-Binding Cassette complications like thrombosis and
Transporter) ABCA1 expression using atherosclerosis through tissue factors in
RAGE ligand S100B along with some other DM.
genes like ABCA1, ABCG1, ABCG8 and Heparanase (HPA) devoid of its
LXR target genes LXR- α and LXR-beta on enzymatic activity it can also
THP-1 monocyte cells. The results revealed phosphorylated some signaling pathways
that ABCA1 protein and mRNA levels are like AKT in macrophages migration
significantly reduced in S100B ligand pathways in the presence of AGE. In-vitro
treatment. This reduction was prevented study using ana-1 macrophages, the HPA
using anti-RAGE antibody on THP-1 cells. protein and mRNA level are significantly
As a support of these results the peripheral high in the presence of AGE. Anti HPA
blood monocytes (PBMC) from diabetes antibody which identified only non-
also showed a reduction in ABCA1 enzymatic terminal pretreatment results in
expression. Liver X receptor (LXR) ligand termination of AKT phosphorylation and
treatment reverses the effects of S100B. So macrophage migration. LY294002
It was concluded that the RAGE can reduce (PI3k/AKT inhibitor) also prevents
the cholesterol transport mediated by migration of macrophages. The anti-RAGE
ABCA1 in monocytes which have a role in antibody also attenuates AGE-induced HPA
atherosclerotic complications in diabetes. expression, AKT phosphorylation and
(P. Kumar et al. 2013) macrophage migration. So these results
It was concluded that AGE effect on proved that AKT phosphorylation is one of
monocytes induces proliferation and it also the pathways for macrophage migration
decrease cholesterol efflux through which was mediated by HPA (Qin et al.
ABCA1.future research has to focus on this 2013).
to find more interesting facts. Albumin isolated from T1D patients
ii. AGE on macrophage:- are used to treat J774 macrophages. While
On incubation with AGE –albumin isolating albumin they found glycated
human macrophage U937 cell line, which modified and carboxyl-methyl-lysine
has RAGE shown dose- dependent (CML) modified albumins are higher in
expression of tissue factors (TF). As well as T1D than control. Also observed the
PBMC from normal and diabetic patients alterations in APOA-1/HDL mediated
treated with AGE –albumin also results in cholesterol efflux in diabetic albumin
increased expression of tissue factors in treated in comparison with controlled
diabetes as normal control. Tissue factor albumin and correlates with a reduction in
expression is thought to be by the ABCA-1 protein content. Elevations of
involvement of oxidant stress. (Ichikawa et intracellular lipids level are observed even
al. 1998) When evaluating the action of in cholesterol acceptor presence. It was
AGE on macrophage polarization. It induces correlated with enhanced stearoyl-CoA
the expression of IL-6 and TNF- α in desaturase-1 expression and reduced
macrophages and also up regulates the M1 expressions of Janus kinase-2 were induced
markers like iNOS, CD11c, and CD86 by albumin from T1D patients. This
whereas M2 markers arg1 and CD206 are albumin-mediated lipid accumulation and
not affected or unchanged. It also increases ABCA1 alteration possibly have a role in
the RAGE expression and NF-kB activation. atherosclerotic complications (Machado-
These results caused by AGE are attenuated Lima et al. 2013).In glyceraldehydes
by using an anti-RAGE antibody or NF-kB (inducer of AGE formation) treatment
inhibitor PDTC (X. Jin et al. 2015). So as a macrophages there is decrease in the efflux
conclusion the AGE can positively regulate of HDL-mediated cholesterol and 7-keto
M1 phenotype differentiation via cholesterol in correlation with decreased

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 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

expression of ABCA-1 and ABCG-1(Ibarra diabetes. The greatest challenge for future
et al. 2011). scientists to study diabetes is that ―a different
In conclusion AGE on macrophages stage of diabetes has a different effect on
induce migration, reduce cholesterol efflux, immune cells ―. Hope future scientists will
alters pathway, and induces M1 polarization decode the cause for complications in diabetes
and provide the best treatment and improve the
and insulin resistance. lifespan of a diabetic patient.
iii. AGE on neutrophils:-
When PMN treated with AGE-HAS ACKNOWLEDGEMENT
the results showed the dose and time- First and Foremost I would like to thank
dependent rise in ROS and reactive nitrogen my guide Dr. Piruthivi Sukumar for his valuable
intermediates (RNI) production. It might be suggestions and guidance without him I can't
via NADPH oxidase and inducible nitric imagine the start of my scientific career. Last
oxide synthase (iNOS). When using but not least I would like to say heartful thanks
inhibitor for both enzymes to scientific journal for their support, without
diphenyleneiodonium, a flavoprotein and you I can't pay my debt towards the research
also anti-RAGE prevent the rise in ROS and field.
I am dedicating this review article to my
RNI. So the AGE –RAGE interaction via
parents (R.chinnayya & R.jaya), brother
NADPH and iNOS is one cause for (R.vijaykumar), and brother in law and sister
oxidative stress and diabetic complications. (L.Rajaravikumar & L.krishnaveni) for their
(Bansal et al. 2012).While accessing the unconditional love and support.
plasma levels of AGEs and their effect on
the proteolytic enzymes like cysteine, ABBREVIATIONS
cathepsin B in plasma and neutrophils in DM-diabetes Mellitus
T2D patients. There is a significant rise in TID-type 1 diabetes
AGE formation in diabetic than normal. T2D-type 2 diabetes
Also found that AGEs reduces the activity ERK-extracellular signal-regulated protein
of cathepsin. These AGE related cathepsin kinase
activities possibly play a role in diabetic MAPK-mitogen-activated protein kinase
MPK-1-mitogen-activated protein phosphatase-
complications. (Grzebyk, Knapik-Kordecka,
1
and Piwowar 2013) PKC-protein kinase C
In conclusion, AGE has an effect on PBMC-peripheral blood mononuclear cells
neutrophils functional properties. But till LPS-lipopolysaccharide
now limited data is available regarding the NET-neutrophil extracellular trap
effect of AGE on neutrophils. Hope the PMN-polymorph nuclear neutrophils
ongoing research will provide more data in HUVEC-human umbilical vein endothelial cells
near feature. ROS-reactive oxygen species
PEM-peripheral exudates macrophages
SUMMARY SPM-splenic macrophages
The immune system is important for AGE-advanced glycation endproduct
protection. In diabetes, hyperglycemia and
hyperinsulinemia condition alters the normal REFERENCES
functioning properties of the innate immune  Alba-Loureiro, T. C., C. D. Munhoz, et al.
system but not or very less effect on the 2007. ―Neutrophil Function and Metabolism
adaptive immune system. There is a lot of in Individuals with Diabetes Mellitus.‖
alteration in immune cellular functions in Brazilian Journal of Medical and Biological
diabetes mellitus and some of the controversial Research = Revista Brasileira De Pesquisas
results might be due to the differences in the Médicas E Biológicas / Sociedade Brasileira
experimental procedures, experimental De Biofísica ... [et Al.] 40 (8): 1037–44.
conditions and maintenance time. Still, there is a  Bansal, Savita, Manushi Siddarth, et al.
need for better experimental procedures to get a 2012. ―Advanced Glycation End Products
better understanding how immune cells act in Enhance Reactive Oxygen and Nitrogen

International Journal of Health Sciences & Research (www.ijhsr.org) 268

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

Species Generation in Neutrophils in Vitro.‖ Journal of Clinical Endocrinology &

Molecular and Cellular Biochemistry 361 Metabolism 86 (3): 1301–5.
(1-2): 289–96. doi:10.1007/s11010-011- doi:10.1210/jcem.86.3.7308.
1114-9.  Chang, Yu-Cheng, Wayne H.-H. Sheu, et al.
 Barton, James C., J. Clayborn Barton, Paul 2013. ―Hyperglycaemia Accelerates ATP-
C. Adams, and Ronald T. Acton. 2016. Binding Cassette Transporter A1
―Risk Factors for Insulin Resistance, Degradation via an ERK-Dependent
Metabolic Syndrome, and Diabetes in 248 Pathway in Macrophages.‖ Journal of
HFE C282Y Homozygotes Identified by Cellular Biochemistry 114 (6): 1364–73.
Population Screening in the HEIRS Study.‖ doi:10.1002/jcb.24478.
Metabolic Syndrome and Related Disorders  Cheng, Cheng-I., Po-Han Chen, Yu-Chun
14 (2): 94–101. doi:10.1089/met.2015.0123. Lin, and Ying-Hsien Kao. 2015. ―High
 Bernal-Lopez, M. R., V. Llorente-Cortes, et Glucose Activates Raw264.7 Macrophages
al. 2013. ―Effect of Different Degrees of through RhoA Kinase-Mediated Signaling
Impaired Glucose Metabolism on the Pathway.‖ Cellular Signalling 27 (2): 283–
Expression of Inflammatory Markers in 92. doi:10.1016/j.cellsig.2014.11.012.
Monocytes of Patients with  Daoud, A. K., M. A. Tayyar, I. M. Fouda,
Atherosclerosis.‖ Acta Diabetologica 50 (4): and N. Abu Harfeil. 2009. ―Effects of
553–62. doi:10.1007/s00592-011-0337-2. Diabetes Mellitus vs. in Vitro
 Bogomolski-Yahalom, V., and Y. Matzner. Hyperglycaemia on Select Immune Cell
1995. ―Disorders of Neutrophil Function.‖ Functions.‖ Journal of Immunotoxicology 6
Blood Reviews 9 (3): 183–90. (1): 36–41.
doi:10.1016/0268-960X(95)90024-1. doi:10.1080/15476910802604564.
 Borregaard, Niels, and Troels Herlin. 1982.  Defronzo, Ralph A., Vijay Soman, Robert
―Energy Metabolism of Human Neutrophils S. Sherwin, Rosa Hendler, and Philip Felig.
during Phagocytosis.‖ Journal of Clinical 1978. ―Insulin Binding to Monocytes and
Investigation 70 (3): 550–57. Insulin Action in Human Obesity,
 Boyanova, Lyudmila, and Ivan Mitov. 2013. Starvation, and Refeeding.‖ Journal of
―Antibiotic Resistance Rates in Causative Clinical Investigation 62 (1): 204–13.
Agents of Infections in Diabetic Patients:  de Souza Ferreira, Cláudia, Tomaz
Rising Concerns.‖ Expert Review of Anti- Henrique Araújo, et al.2012a. ―Neutrophil
Infective Therapy 11 (4): 411–20. Dysfunction Induced by Hyperglycaemia:
doi:10.1586/eri.13.19. Modulation of Myeloperoxidase Activity.‖
 Brinkmann, V., U. Reichard, C. Goosmann, Cell Biochemistry and Function 30 (7):
et al. 2004. ―Neutrophil Extracellular Traps 604–10. doi:10.1002/cbf.2840.
Kill Bacteria.‖ Science 303 (5663): 1532–  ———. 2012b. ―Neutrophil Dysfunction
35. doi:10.1126/science.1092385. Induced by Hyperglycaemia: Modulation of
 Brownlee, M. 1992. ―Glycation Products Myeloperoxidase Activity.‖ Cell
and the Pathogenesis of Diabetic Biochemistry and Function 30 (7): 604–10.
Complications.‖ Diabetes Care 15 (12): doi:10.1002/cbf.2840.
1835–43.  de Vries, Marijke A., Arash Alipour, et al.
 Brownlee, Michael. 2001. ―Biochemistry 2015. ―Glucose-Dependent Leukocyte
and Molecular Cell Biology of Diabetic Activation in Patients with Type 2 Diabetes
Complications.‖ Nature 414 (6865): 813– Mellitus, Familial Combined
20. doi:10.1038/414813a. Hyperlipidemia and Healthy Controls.‖
 Caron, Emmanuelle, and Alan Hall. 1998. Metabolism: Clinical and Experimental 64
―Identification of Two Distinct Mechanisms (2): 213–17.
of Phagocytosis Controlled by Different doi:10.1016/j.metabol.2014.10.011.
Rho GTPases.‖ Science 282 (5394): 1717–  Duffield, Jeremy S. 2003. ―The
21. Inflammatory Macrophage: A Story of
 Ceolotto, Giulio, Alessandra Gallo, et al. Jekyll and Hyde.‖ Clinical Science
2001. ―Hyperglycaemia Acutely Increases (London, England: 1979) 104 (1): 27–38.
Monocyte Extracellular Signal-Regulated doi:10.1042/.
Kinase Activity in Vivo in Humans.‖ The

International Journal of Health Sciences & Research (www.ijhsr.org) 269

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

 Espinoza-Jim&#xe9, Arlett Nez, Pe&#xf3, 605.

Alberto N. N, Luis I. Terrazas, Espinoza- doi:10.1161/CIRCULATIONAHA.106.621
Jim&#xe9, Arlett Nez, Pe&#xf3, Alberto N. 854.
N, and Luis I. Terrazas. 2012.  Gonzalez, Y., M.T. Herrera, G. Soldevila, et
―Alternatively Activated Macrophages in al. 2012. ―High Glucose Concentrations
Types 1 and 2 Diabetes, Alternatively Induce TNF-α Production through the
Activated Macrophages in Types 1 and 2 down-Regulation of CD33 in Primary
Diabetes.‖ Mediators of Inflammation, Human Monocytes.‖ BMC Immunology 13.
Mediators of Inflammation 2012, 2012 doi:10.1186/1471-2172-13-19.
(December): e815953.  Grzebyk, Ewa, Maria Knapik-Kordecka,
doi:10.1155/2012/815953, and Agnieszka Piwowar. 2013. ―Advanced
10.1155/2012/815953. Glycation End-Products and Cathepsin
 Esposito, Katherine, Francesco Nappo, et al. Cysteine Protease in Type 2 Diabetic
2002. ―Inflammatory Cytokine Patients.‖ Polskie Archiwum Medycyny
Concentrations Are Acutely Increased by Wewnętrznej 123 (7-8): 364–70.
Hyperglycaemia in Humans Role of  Gyurko, Robert, Camille C. Siqueira, et al.
Oxidative Stress.‖ Circulation 106 (16): 2006. ―Chronic Hyperglycaemia
2067–72. Predisposes to Exaggerated Inflammatory
doi:10.1161/01.CIR.0000034509.14906.AE. Response and Leukocyte Dysfunction in
 Fuchs, T.A., U. Abed et al. 2007. ―Novel Akita Mice.‖ Journal of Immunology
Cell Death Program Leads to Neutrophil (Baltimore, Md.: 1950) 177 (10): 7250–56.
Extracellular Traps.‖ Journal of Cell  Haurogné, Karine, Marija Pavlovic, Hélène
Biology 176 (2): 231–41. Rogniaux, Jean-Marie Bach, and Blandine
doi:10.1083/jcb.200606027. Lieubeau. 2015. ―Type 1 Diabetes Prone
 Fujimoto, Hirokazu, Tetsuaki Hirase, et al. NOD Mice Have Diminished Cxcr1 mRNA
2011. ―IL-27 Inhibits Hyperglycaemia and Expression in Polymorphonuclear
Pancreatic Islet Inflammation Induced by Neutrophils and CD4+ T Lymphocytes.‖
Streptozotocin in Mice.‖ The American PloS One 10 (7): e0134365.
Journal of Pathology 179 (5): 2327–36. doi:10.1371/journal.pone.0134365.
doi:10.1016/j.ajpath.2011.08.001.  Henderson, Robert B., Josie A. R. Hobbs,
 Gao, Yun, Jun Zhang, et al. 2015. Meg Mathies, and Nancy Hogg. 2003.
―Protection of Vascular Endothelial Cells ―Rapid Recruitment of Inflammatory
from High Glucose-Induced Cytotoxicity by Monocytes Is Independent of Neutrophil
Emodin.‖ Biochemical Pharmacology 94 Migration.‖ Blood 102 (1): 328–35.
(1): 39–45. doi:10.1016/j.bcp.2015.01.006. doi:10.1182/blood-2002-10-3228.
 Geerlings, Suzanne E., and Andy I. M.  Hua, Kuo-Feng, Szu-Hsuan Wang, et al.
Hoepelman. 1999. ―Immune Dysfunction in 2012. ―High Glucose Increases Nitric Oxide
Patients with Diabetes Mellitus (DM).‖ Generation in Lipopolysaccharide-Activated
FEMS Immunology & Medical Macrophages by Enhancing Activity of
Microbiology 26 (3-4): 259–65. Protein Kinase C-α/δ and NF-κB.‖
doi:10.1111/j.1574-695X.1999.tb01397.x. Inflammation Research: Official Journal of
 Ghoshal, Kakali, Sangita Das, et al. 2016. the European Histamine Research Society ...
―A Novel Sensor to Estimate the Prevalence [et Al.] 61 (10): 1107–16.
of Hypochlorous (HOCl) Toxicity in doi:10.1007/s00011-012-0503-1.
Individuals with Type 2 Diabetes and  Hudson, LaQueta K., Meghan E. Dancho, et
Dyslipidemia.‖ Clinica Chimica Acta; al. 2016. ―Emetine Di-HCl Attenuates Type
International Journal of Clinical Chemistry 1 Diabetes Mellitus in Mice.‖ Molecular
458 (July): 144–53. Medicine (Cambridge, Mass.) 22 (June).
doi:10.1016/j.cca.2016.05.006. doi:10.2119/molmed.2016.00082.
 Goldin, Alison, Joshua A. Beckman, Ann  Iborra, Rodrigo T., Adriana Machado-Lima,
Marie Schmidt, and Mark A. Creager. 2006. et al. 2011. ―Advanced Glycation in
―Advanced Glycation End Products Macrophages Induces Intracellular
Sparking the Development of Diabetic Accumulation of 7-Ketocholesterol and
Vascular Injury.‖ Circulation 114 (6): 597– Total Sterols by Decreasing the Expression

International Journal of Health Sciences & Research (www.ijhsr.org) 270

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

of ABCA-1 and ABCG-1.‖ Lipids in Health Proceedings of the National Academy of

and Disease 10: 172. doi:10.1186/1476- Sciences 109 (12): E715–24.
511X-10-172. doi:10.1073/pnas.1111600109.
 Ichikawa, Koujiro, Mototaka Yoshinari, et  Kaplan NM. 1989. ―The Deadly Quartet:
al. 1998. ―Advanced Glycosylation End Upper-Body Obesity, Glucose Intolerance,
Products Induced Tissue Factor Expression Hypertriglyceridemia, and Hypertension.‖
in Human Monocyte-like U937 Cells and Archives of Internal Medicine 149 (7):
Increased Tissue Factor Expression in 1514–20.
Monocytes from Diabetic Patients.‖ doi:10.1001/archinte.1989.00390070054005
Atherosclerosis 136 (2): 281–87. .
doi:10.1016/S0021-9150(97)00221-9.  Kappala, Shanti S., Javier Espino, et al.
 Iida, Kaoruko Tada, Hitoshi Shimano, et al. 2014. ―FMLP-, Thapsigargin-, and H₂O₂-
2001. ―Insulin Up-Regulates Tumor Evoked Changes in Intracellular Free
Necrosis Factor-α Production in Calcium Concentration in Lymphocytes and
Macrophages through an Extracellular- Neutrophils of Type 2 Diabetic Patients.‖
Regulated Kinase-Dependent Pathway.‖ Molecular and Cellular Biochemistry 387
Journal of Biological Chemistry 276 (35): (1-2): 251–60. doi:10.1007/s11010-013-
32531–37. doi:10.1074/jbc.M009894200. 1890-5.
 Jialal, Ishwarlal, Beverley Adams-Huet, and  Kolb-Bachofen, V., and H. Kolb. 1989. ―A
Roma Pahwa. 2016. ―Selective Increase in Role for Macrophages in the Pathogenesis
Monocyte p38 Mitogen-Activated Protein of Type 1 Diabetes.‖ Autoimmunity 3 (2):
Kinase Activity in Metabolic Syndrome.‖ 145–55. doi:10.3109/08916938909019963.
Diabetes & Vascular Disease Research 13  Koley, Hemanta, Poushali Ghosh, et al.
(1): 93–96. 2016. ―Streptozotocin-Induced
doi:10.1177/1479164115607829. Hyperglycaemic Mice Are Susceptible to
 Jin, Seo Yeon, Eun Kyoung Kim, et al. Invasive Enteric Bacterial Infection.‖
2014. ―Insulin Regulates Monocyte Trans- Japanese Journal of Infectious Diseases,
Endothelial Migration through Surface May. doi:10.7883/yoken.JJID.2015.418.
Expression of Macrophage-1 Antigen.‖  Kumar, Prabhakaran, Somasundaram
Biochimica Et Biophysica Acta 1842 (9): Raghavan, Gobinath Shanmugam, and
1539–48. doi:10.1016/j.bbadis.2014.06.003. Narkunaraja Shanmugam. 2013. ―Ligation
 Jin, Xian, Tongqing Yao, et al. 2015. of RAGE with Ligand S100B Attenuates
―Advanced Glycation End Products ABCA1 Expression in Monocytes.‖
Enhance Macrophages Polarization into M1 Metabolism: Clinical and Experimental 62
Phenotype through Activating RAGE/NF- (8): 1149–58.
κB Pathway.‖ BioMed Research doi:10.1016/j.metabol.2013.02.006.
International 2015: 732450.  Kumar, V., and A. Sharma. 2010.
doi:10.1155/2015/732450. ―Neutrophils: Cinderella of Innate Immune
 Joshi, Manjunath B., Apurva Lad, et al. System.‖ International
2013. ―High Glucose Modulates IL-6 Immunopharmacology 10 (11): 1325–34.
Mediated Immune Homeostasis through doi:10.1016/j.intimp.2010.08.012.
Impeding Neutrophil Extracellular Trap  Kzhyshkowska, Julia, Alexandru Gudima,
Formation.‖ FEBS Letters 587 (14): 2241– Kondaiah Moganti, Alexei Gratchev, and
46. doi:10.1016/j.febslet.2013.05.053. Alexander Orekhov. 2016. ―Perspectives for
 Kang, Xia, Along Hou, et al. 2016. Monocyte/Macrophage-Based Diagnostics
―Macrophage TCF-4 Co-Activates p65 to of Chronic Inflammation.‖ Transfusion
Potentiate Chronic Inflammation and Insulin Medicine and Hemotherapy: Offizielles
Resistance in Mice.‖ Clinical Science Organ Der Deutschen Gesellschaft Fur̈
(London, England: 1979) 130 (14): 1257– Transfusionsmedizin Und
68. doi:10.1042/CS20160192. Immunham̈atologie 43 (2): 66–77.
 Kanter, Jenny E., Farah Kramer, et al. 2012. doi:10.1159/000444943.
―Diabetes Promotes an Inflammatory  Lamharzi, Najib, Catherine B. Renard, et al.
Macrophage Phenotype and Atherosclerosis 2004. ―Hyperlipidemia in Concert With
through Acyl-CoA Synthetase 1.‖ Hyperglycaemia Stimulates the Proliferation

International Journal of Health Sciences & Research (www.ijhsr.org) 271

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

of Macrophages in Atherosclerotic Lesions Controlled Type 1 Diabetes Mellitus

Potential Role of Glucose-Oxidized LDL.‖ Patients Alters Macrophage Gene
Diabetes 53 (12): 3217–25. Expression Impairing ABCA-1-Mediated
doi:10.2337/diabetes.53.12.3217. Reverse Cholesterol Transport.‖
 Laskin, Debra L., Vasanthi R. Sunil, Carol Diabetes/Metabolism Research and Reviews
R. Gardner, and Jeffrey D. Laskin. 2011. 29 (1): 66–76. doi:10.1002/dmrr.2362.
―Macrophages and Tissue Injury: Agents of  Manna, Prasenjit, and Sushil K. Jain. 2014.
Defense or Destruction?‖ Annual Review of ―Effect of PIP3 on Adhesion Molecules and
Pharmacology and Toxicology 51: 267–88. Adhesion of THP-1 Monocytes to HUVEC
doi:10.1146/annurev.pharmtox.010909.1058 Treated with High Glucose.‖ Cellular
12. Physiology and Biochemistry: International
 Lee, Chee-Tin Christine, Stewart B. Harris, Journal of Experimental Cellular
et al. 2014. ―White Blood Cell Subtypes, Physiology, Biochemistry, and
Insulin Resistance and β-Cell Dysfunction Pharmacology 33 (4): 1197–1204.
in High-Risk Individuals--the PROMISE doi:10.1159/000358688.
Cohort.‖ Clinical Endocrinology 81 (4):  Menegazzo, Lisa, Stefano Ciciliot, et al.
536–41. doi:10.1111/cen.12390. 2015. ―NETosis Is Induced by High
 Li, Mei-Fang, Rong Zhang, et al.2016. Glucose and Associated with Type 2
―High Glucose Increases the Expression of Diabetes.‖ Acta Diabetologica 52 (3): 497–
Inflammatory Cytokine Genes in 503. doi:10.1007/s00592-014-0676-x.
Macrophages Through H3K9  Menu, P., A. Mayor, R. Zhou, et al. 2012.
Methyltransferase Mechanism.‖ Journal of ―ER Stress Activates the NLRP3
Interferon & Cytokine Research: The Inflammasome via an UPR-Independent
Official Journal of the International Society Pathway.‖ Cell Death & Disease 3 (1):
for Interferon and Cytokine Research 36 (1): e261. doi:10.1038/cddis.2011.132.
48–61. doi:10.1089/jir.2014.0172.  Metzler, K.D., T.A. Fuchs, et al. 2011.
 Lim, M.B.H., J.W.P. Kuiper, A. Katchky, ―Myeloperoxidase Is Required for
H. Goldberg, and M. Glogauer. 2011. ―Rac2 Neutrophil Extracellular Trap Formation:
Is Required for the Formation of Neutrophil Implications for Innate Immunity.‖ Blood
Extracellular Traps.‖ Journal of Leukocyte 117 (3): 953–59. doi:10.1182/blood-2010-
Biology 90 (4): 771–76. 06-290171.
doi:10.1189/jlb.1010549.  Munroe, John F., and Joseph C. Shipp.
 Liu, Guangwei, Xue-Pei Xia, Shou-Liang 1965. ―Glucose Metabolism in Leucocytes
Gong, and Yong Zhao. 2006. ―The from Patients with Diabetes Mellitus, with
Macrophage Heterogeneity: Difference and without Hypercholesteremia.‖ Diabetes
between Mouse Peritoneal Exudate and 14 (9): 584–90. doi:10.2337/diab.14.9.584.
Splenic F4/80+ Macrophages.‖ Journal of  Naderi, Jamal, Astrid Feuerherm, Thanh
Cellular Physiology 209 (2): 341–52. Nguyen, and Berit Johansen. 2014.
doi:10.1002/jcp.20732. ―Cellular Effect of Insulin on Proliferation
 Liu, Yue J., Abha Saini, David J. Cohen, of Monocytes (1011.4).‖ The FASEB
and Boon S. Ooi. 1995. ―Modulation of Journal 28 (1 Supplement): 1011.4.
Macrophage Proliferation by  Nagareddy, Prabhakara R., Andrew J.
Hyperglycaemia.‖ Molecular and Cellular Murphy, et al. 2013. ―Hyperglycaemia
Endocrinology 114 (1–2): 187–92. Promotes Myelopoiesis and Impairs the
doi:10.1016/0303-7207(95)96799-N. Resolution of Atherosclerosis.‖ Cell
 Lou, Meiqin, Peng Luo, et al. 2015. Metabolism 17 (5): 695–708.
―Relationship between Neutrophil- doi:10.1016/j.cmet.2013.04.001.
Lymphocyte Ratio and Insulin Resistance in  Nam, Mi-Hyun, Hyun-Sun Lee, Young
Newly Diagnosed Type 2 Diabetes Mellitus Seomun, Yanhouy Lee, and Kwang-Won
Patients.‖ BMC Endocrine Disorders 15: 9. Lee. 2011. ―Monocyte-Endothelium-
doi:10.1186/s12902-015-0002-9. Smooth Muscle Cell Interaction in Co-
 Machado-Lima, Adriana, Rodrigo T. Iborra, Culture: Proliferation and Cytokine
Raphael S. Pinto, et al. 2013. ―Advanced Productions in Response to Advanced
Glycated Albumin Isolated from Poorly Glycation End Products.‖ Biochimica Et

International Journal of Health Sciences & Research (www.ijhsr.org) 272

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

Biophysica Acta 1810 (9): 907–12. Journal of Applied Physiology, June.

doi:10.1016/j.bbagen.2011.06.005. doi:10.1007/s00421-016-3414-y.
 Nishikawa, Takeshi, Diane Edelstein, et al.  Saini, Abha, Yue J. Liu, David J. Cohen,
2000. ―Normalizing Mitochondrial and Boon S. Ooi. 1996. ―Hyperglycaemia
Superoxide Production Blocks Three Augments Macrophage Growth Responses
Pathways of Hyperglycaemic Damage.‖ to Colony-Stimulating Factor-1.‖
Nature 404 (6779): 787–90. Metabolism 45 (9): 1125–29.
doi:10.1038/35008121. doi:10.1016/S0026-0495(96)90012-8.
 Petrofsky, M., and L. E. Bermudez. 1999.  Saito, Yuriko, Ippei Takahashi, et al. 2013.
―Neutrophils from Mycobacterium Avium- ―The Influence of Blood Glucose on
Infected Mice Produce TNF-Alpha, IL-12, Neutrophil Function in Individuals without
and IL-1 Beta and Have a Putative Role in Diabetes.‖ Luminescence: The Journal of
Early Host Response.‖ Clinical Biological and Chemical Luminescence 28
Immunology (Orlando, Fla.) 91 (3): 354–58. (4): 569–73. doi:10.1002/bio.2495.
doi:10.1006/clim.1999.4709.  Shanmugam, Narkunaraja, Marpadga A.
 Qin, Qiaojing, Jianying Niu, et al. 2013. Reddy, Mausumee Guha, and Rama
―Heparanase Induced by Advanced Natarajan. 2003. ―High Glucose-Induced
Glycation End Products (AGEs) Promotes Expression of Proinflammatory Cytokine
Macrophage Migration Involving RAGE and Chemokine Genes in Monocytic Cells.‖
and PI3K/AKT Pathway.‖ Cardiovascular Diabetes 52 (5): 1256–64.
Diabetology 12: 37. doi:10.1186/1475-  Shiny, Abhijit, Bhaskaran Regin, et al.
2840-12-37. 2013. ―Convergence of Innate Immunity
 Rao, Xiaoquan, Jixin Zhong, and Qinghua and Insulin Resistance as Evidenced by
Sun. 2014. ―The Heterogenic Properties of Increased Nucleotide Oligomerization
Monocytes/macrophages and Neutrophils in Domain (NOD) Expression and Signaling in
Inflammatory Response in Diabetes.‖ Life Monocytes from Patients with Type 2
Sciences 116 (2): 59–66. Diabetes.‖ Cytokine 64 (2): 564–70.
doi:10.1016/j.lfs.2014.09.015. doi:10.1016/j.cyto.2013.08.003.
 Reaven, Gerald M. 1988. ―Role of Insulin  Singh, Varun Parkash, Anjana Bali, Nirmal
Resistance in Human Disease.‖ Diabetes 37 Singh, and Amteshwar Singh Jaggi. 2014.
(12): 1595–1607. ―Advanced Glycation End Products and
doi:10.2337/diab.37.12.1595. Diabetic Complications.‖ The Korean
 Rempel, Lisienny C. T., Alessandra B. Journal of Physiology & Pharmacology :
Finco, et al. 2015. ―Effect of PKC-β Official Journal of the Korean Physiological
Signaling Pathway on Expression of MCP-1 Society and the Korean Society of
and VCAM-1 in Different Cell Models in Pharmacology 18 (1): 1–14.
Response to Advanced Glycation End doi:10.4196/kjpp.2014.18.1.1.
Products (AGEs).‖ Toxins 7 (5): 1722–37.  Spartano, N. L., S. Lamon-Fava, et al. 2014.
doi:10.3390/toxins7051722. ―Regulation of ATP-Binding Cassette
 Rosenberger, Carrie M., and B. Brett Finlay. Transporters and Cholesterol Efflux by
2003. ―Phagocyte Sabotage: Disruption of Glucose in Primary Human Monocytes and
Macrophage Signalling by Bacterial Murine Bone Marrow-Derived
Pathogens.‖ Nature Reviews Molecular Cell Macrophages.‖ Experimental and Clinical
Biology 4 (5): 385–96. Endocrinology & Diabetes: Official Journal,
doi:10.1038/nrm1104. German Society of Endocrinology [and]
 Ross, R. 1993. ―The Pathogenesis of German Diabetes Association 122 (8): 463–
Atherosclerosis: A Perspective for the 68. doi:10.1055/s-0034-1374600.
1990s.‖ Nature 362 (6423): 801–9.  Spindler, Matthew P., Alvin M. Ho, et al.
 Ruffino, J. S., N. A. Davies, et al. 2016. 2016. ―Acute Hyperglycaemia Impairs IL-6
―Moderate-Intensity Exercise Alters Expression in Humans.‖ Immunity,
Markers of Alternative Activation in Inflammation and Disease 4 (1): 91–97.
Circulating Monocytes in Females: A doi:10.1002/iid3.97.
Putative Role for PPARγ.‖ European  Steinberg, Daniel. 1997. ―Low Density
Lipoprotein Oxidation and Its

International Journal of Health Sciences & Research (www.ijhsr.org) 273

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

Pathobiological Significance.‖ Journal of Resistin and Inflammatory Cytokine

Biological Chemistry 272 (34): 20963–66. Production from Human Mononuclear
doi:10.1074/jbc.272.34.20963. Cells.‖ BioMed Research International
 Sun, Chenming, Lina Sun, et al. 2012. ―The 2013: 487081. doi:10.1155/2013/487081.
Phenotype and Functional Alterations of  Vaquer, Guillaume, Richard Magous, et al.
Macrophages in Mice with Hyperglycaemia 2013. ―Short-Term Intravenous Insulin
for Long Term.‖ Journal of Cellular Infusion Is Associated with Reduced
Physiology 227 (4): 1670–79. Expression of NADPH Oxidase p47(phox)
doi:10.1002/jcp.22891. Subunit in Monocytes from Type 2 Diabetes
 Sunderkötter, Cord, Tatjana Nikolic, et al. Patients.‖ Fundamental & Clinical
2004. ―Subpopulations of Mouse Blood Pharmacology 27 (6): 669–71.
Monocytes Differ in Maturation Stage and doi:10.1111/j.1472-8206.2012.01057.x.
Inflammatory Response.‖ Journal of  Verhagen, Sandra N., Annemarie MJ
Immunology (Baltimore, Md.: 1950) 172 Wassink, Yolanda van der Graaf, Petra M.
(7): 4410–17. Gorter, and Frank LJ Visseren. 2011.
 Talukdar, S., D.Y. Oh, G. Bandyopadhyay, ―Insulin Resistance Increases the
et al. 2012. ―Neutrophils Mediate Insulin Occurrence of New Cardiovascular Events
Resistance in Mice Fed a High-Fat Diet in Patients with Manifest Arterial Disease
through Secreted Elastase.‖ Nature without Known Diabetes. The SMART
Medicine 18 (9): 1407–12. Study.‖ Cardiovascular Diabetology 10:
doi:10.1038/nm.2885. 100. doi:10.1186/1475-2840-10-100.
 Terasawa, Tomoko, Yoshimasa Aso, et al.  V, Esmann. 1983. ―The Polymorphonuclear
2015. ―Bezafibrate, a Peroxisome Leukocyte in Diabetes Mellitus.‖ Journal of
Proliferator-Activated Receptor α Agonist, Clinical Chemistry and Clinical
Decreases Circulating CD14(+)CD16(+) Biochemistry. Zeitschrift Fur Klinische
Monocytes in Patients with Type 2 Chemie Und Klinische Biochemie 21 (9):
Diabetes.‖ Translational Research: The 561–67.
Journal of Laboratory and Clinical Medicine  Volkman, A., and J. L. Gowans. 1965. ―The
165 (2): 336–45. Origin of Macrophages from Bone Marrow
doi:10.1016/j.trsl.2014.07.008. in the Rat.‖ British Journal of Experimental
 Thewissen, M. M., J. van de Gaar, et al. Pathology 46 (1): 62–70.
2014. ―Monocytes, but Not T Cells,  Walrand, Stéphane, Christelle Guillet, Yves
Respond to Insulin with Akt(S473) Boirie, and Marie-Paule Vasson. 2006.
Phosphorylation Independent of the Donor ―Insulin Differentially Regulates Monocyte
Glucometabolic State.‖ and Polymorphonuclear Neutrophil
Diabetes/Metabolism Research and Reviews Functions in Healthy Young and Elderly
30 (4): 323–32. doi:10.1002/dmrr.2498. Humans.‖ The Journal of Clinical
 Torres-Castro, Israel, Úrsula D. Arroyo- Endocrinology & Metabolism 91 (7): 2738–
Camarena, et al. 2016. ―Human Monocytes 48. doi:10.1210/jc.2005-1619.
and Macrophages Undergo M1-Type  Wang, Yudong, Yang Xiao, et al. 2014.
Inflammatory Polarization in Response to ―Increased Neutrophil Elastase and
High Levels of Glucose.‖ Immunology Proteinase 3 and Augmented NETosis Are
Letters 176 (June): 81–89. Closely Associated with β-Cell
doi:10.1016/j.imlet.2016.06.001. Autoimmunity in Patients with Type 1
 Trischitta, V., D. Gullo, S. Squatrito, V. Diabetes.‖ Diabetes 63 (12): 4239–48.
Pezzino, I. D. Goldfine, and R. Vigneri. doi:10.2337/db14-0480.
1986. ―Insulin Internalization into  Wehrwein, Gabriele, Markus Neumeier, et
Monocytes Is Decreased in Patients with al. 2006. ―Lipopolysaccharide Regulated
Type II Diabetes Mellitus.‖ The Journal of Protein Expression Is Only Partly Impaired
Clinical Endocrinology and Metabolism 62 in Monocytes from Patients with Type I
(3): 522–28. doi:10.1210/jcem-62-3-522. Diabetes.‖ Cardiovascular Diabetology 5
 Tsiotra, Panayoula C., Eleni Boutati, (March): 5. doi:10.1186/1475-2840-5-5.
George Dimitriadis, and Sotirios A. Raptis.  Wen, Yeshao, Jiali Gu, et al. 2006.
2013. ―High Insulin and Leptin Increase ―Elevated Glucose and Diabetes Promote

International Journal of Health Sciences & Research (www.ijhsr.org) 274

Vol.7; Issue: 12; December 2017
 Vinod Kumar Rajana. Immune Dysfunction in Diabetes Mellitus (DM)

Interleukin-12 Cytokine Gene Expression in Journal of Medical Sciences 10 (6): 758–65.

Mouse Macrophages.‖ Endocrinology 147 doi:10.7150/ijms.6155.
(5): 2518–25. doi:10.1210/en.2005-0519.  Yano, Hidekazu, Manabu Kinoshita, Keiichi
 Wiernsperger, N. F. 2003. ―Oxidative Stress Fujino, et al. 2012. ―Insulin Treatment
as a Therapeutic Target in Diabetes: Directly Restores Neutrophil Phagocytosis
Revisiting the Controversy.‖ Diabetes & and Bactericidal Activity in Diabetic Mice
Metabolism 29 (6): 579–85. and Thereby Improves Surgical Site
 Wu, Hong, Yijun Nie, et al. 2015. ―P2X7 Staphylococcus Aureus Infection.‖ Infection
Receptor Expression in Peripheral Blood and Immunity 80 (12): 4409–16.
Monocytes Is Correlated With Plasma C- doi:10.1128/IAI.00787-12.
Reactive Protein and Cytokine Levels in  Yates, Christopher, Kerry May, et al. 2009.
Patients With Type 2 Diabetes Mellitus: A ―Wound Chronicity, Inpatient Care, and
Preliminary Report.‖ Inflammation 38 (6): Chronic Kidney Disease Predispose to
2076–81. doi:10.1007/s10753-015-0189-y. MRSA Infection in Diabetic Foot Ulcers.‖
 Wu, Hui, Yi Chen, Wendy R. Winnall, Diabetes Care 32 (10): 1907–9.
David J. Phillips, and Mark P. Hedger. doi:10.2337/dc09-0295.
2013. ―Regulation of Activin A Release  Zavaroni, Ivana, Enzo Bonora, Massimo
from Murine Bone Marrow-Derived Pagliara, et al. 1989. ―Risk Factors for
Neutrophil Precursors by Tumour Necrosis Coronary Artery Disease in Healthy Persons
Factor-α and Insulin.‖ Cytokine 61 (1): with Hyperinsulinemia and Normal Glucose
199–204. doi:10.1016/j.cyto.2012.09.018. Tolerance.‖ New England Journal of
 Xiu, Fangming, Mile Stanojcic, et al. 2014. Medicine 320 (11): 702–6.
―Stress Hyperglycaemia, Insulin Treatment, doi:10.1056/NEJM198903163201105.
and Innate Immune Cells, Stress  Żurawska-Płaksej, Ewa, Agnieszka
Hyperglycaemia, Insulin Treatment, and Ługowska, Katarzyna Hetmańczyk, Maria
Innate Immune Cells.‖ International Journal Knapik-Kordecka, and Agnieszka Piwowar.
of Endocrinology, International Journal of 2015. ―Neutrophils as a Source of
Endocrinology 2014, 2014 (May): e486403. Chitinases and Chitinase-Like Proteins in
doi:10.1155/2014/486403, Type 2 Diabetes.‖ PloS One 10 (10):
10.1155/2014/486403. e0141730.doi:10.1371/journal.pone.014173
 Xu, Wei, Hai-feng Wu, Shao-gang Ma, et 0.
al. 2013. ―Correlation between Peripheral
White Blood Cell Counts and
Hyperglycemic Emergencies.‖ International

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