Hindawi Publishing Corporation

International Journal of Endocrinology

Volume 2014, Article ID 486403, 9 pages
http://dx.doi.org/10.1155/2014/486403

Review Article
Stress Hyperglycemia, Insulin Treatment, and
Innate Immune Cells

Fangming Xiu,1 Mile Stanojcic,1,2 Li Diao,1,2 and Marc G. Jeschke1,2,3

1
Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue,
Room D704, Toronto, ON, Canada
2
Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada M4N 3M5
3
Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Toronto, ON, Canada

Correspondence should be addressed to Marc G. Jeschke; [email protected]

Received 28 January 2014; Revised 6 April 2014; Accepted 8 April 2014; Published 8 May 2014

Academic Editor: Kristin Eckardt

Copyright © 2014 Fangming Xiu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from
the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed
a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive
review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This
review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater
insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs
glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function
of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated
with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality
observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However,
there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine
the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment
regimen for these patients.

1. Stress Hyperglycemia in Critical Illness responses result in persistent hyperglycemia and insulin
resistance, which can be potentially deleterious in the long
The effects of severe trauma, infection, and surgery result in run [2]. In combination with inadequate systemic insulin
remarkable metabolic stress on the human body. Stress asso- levels and insulin resistance due to the increased secretion
ciated with critical illness is characterized by the activation of counter-regulatory hormones, the negative manifestations
of inflammatory cellular mediators and the hypothalamic- inflicted by hyperglycemia lead to life-threatening conditions
pituitary-adrenal (HPA) axis. The release of cortisol, cate- in these patients [3].
cholamines, glucagon, and growth hormone is an essential Incidences of stress-induced hyperglycemia, defined as
component of the general adaptation to illness and stress. The plasma glucose levels exceeding 200 mg/mL in patients, have
acute response to critical illness (energy conservation toward been documented for more than 100 years in patients experi-
vital organs, modulation of the immune system, and a delay in encing severe trauma or injury [4]. Although hyperglycemia
anabolism) is generally considered to be an appropriate and is believed to be an adaptive stress response, long-term stress-
adaptive response that occurs in the first few days after insult. induced hyperglycemia is linked to poor clinical outcomes
Mild-to-moderate stress hyperglycemia is protective because and increased risk of mortality [5]. The underlying causes
it provides a source of fuel for the immune system and brain of hyperglycemia during critical illness are attributed to the
at a time of stress [1]. However, many of the chronic endocrine increased hepatic glucose production and impaired glucose
2 International Journal of Endocrinology

consumption by peripheral tissues as well as insufficient since blockade of TLR2 and/or TLR4 inhibited IP-10 release
pancreatic insulin production. In addition, the production [11]. Other studies further demonstrated that HG-induced
and accumulation of counter regulatory hormones, such as TLR-2 and -4 expressions are via protein kinase C (PKC)
glucagon, cortisol, catecholamines, and growth hormone, activation and by the stimulation of NADPH oxidase [16].
will increase lipolysis, protein breakdown, and impair glu- However, other studies showed that cytokine secretion
cose usage by peripheral tissues [4]. At the cellular level, was inhibited in the presence of higher concentration of
increased blood glucose levels result in mitochondrial injury glucose or C-peptide using in vitro culture of U937 cell
and endothelial dysfunction by generating reactive oxygen line or ex vivo culture of freshly isolated leukocytes from
species and inhibiting nitric oxide production, respectively. healthy volunteers. Inhibited cytokines include IL-6, IL-8,
Recently, it has been found that the endoplasmic reticulum macrophage inflammatory protein- (MIP-) 1𝛼, MIP-1𝛽 [17],
(ER) stress response and its subsequent unfolded protein TNF-𝛼, and reactive oxygen species [18].
response are activated in various tissues under conditions Furthermore, HG influences monocyte HLA-DR expres-
related burn and severe trauma. ER stress has been identified sion. Monocytes from healthy volunteers that were exposed
as one of the central intracellular signaling pathways that link for 24 hours to high concentrations of glucose (400 mg/dL)
insulin resistance, hyperglycemia, and inflammation [6]. presented a decreased HLA-DR [19]. It indicates that HG
In this paper, we intend to review recent advances on may impair the antigen presenting activity of monocytes.
the regulating effects of hyperglycemia and insulin on innate Hyperglycemia has also shown to regulate other functions of
immunity, with a particular emphasis on severe burns. In monocytes, such as adhesion, migration, and transmigration.
addition, we will explore the history of insulin treatment Nandy et al. observed that high concentration of glucose
on stress-induced hyperglycemia during critical illness and augmented monocyte adhesion to human umbilical vein
update the present understanding in regard to the ongoing endothelial cell monolayer and increased migration [20]. In
moderate versus intensive insulin treatment debate. Although contrast, another study showed that adhesion of monocytes
cytokine products and reactive oxygen species produced by to human aortic endothelial cells was diminished in the
innate immune cells may have profound effects on glucose presence of 30 mM/L glucose and C-peptide [17]. The phago-
disposal and utilization in the periphery as well as on insulin cytic ability of innate immune system has been found to be
production by the pancreas, we only focus on the effects of marginally enhanced by hyperglycemia [18].
hyperglycemia and insulin on innate immune cells. Taken together, numerous studies have investigated the
effects of hyperglycemia on monocyte functions including
2. Hyperglycemia and Innate Immune Cells cytokine secretion and migration. As a result of the inconsis-
tent findings, there is a lack of consensus on the relationship
2.1. Monocytes. Monocytes, macrophages, and dendritic cells between monocytes and high glucose conditions and further
are antigen-presenting cells that possess phagocytic capabil- investigation is required. The discrepancies may be resulted
ities that play a crucial role in maintaining immune home- from the different model system and exposure time among
ostasis and mounting an immune response against infection. investigators. We would like to emphasize that the effects of
In severely burned and septic patients, monocyte phenotype hyperglycemia on monocytes are not necessarily equivalent
and function are disrupted, resulting in a lowered expression to the status of monocytes in severely injured patients,
of HLA-DR on circulating monocytes as early as 2-3 days such as burned and septic patients. There are many other
after injury. This effect of decreased HLA-DR expression and factors that contribute to monocyte phenotype in addition to
cytokine production has shown to persist for 28 days in burn hyperglycemia.
and septic patients [7].
The adverse effects of hyperglycemia on innate immu- 2.2. Macrophages. Macrophages are an essential component
nity manifest through the regulation of monocyte cytokine of the immune system, with three fundamental homeostatic
secretion. This notion is well supported by previous studies activities: host defense, wound healing, and immune regula-
using THP-1 monocyte cell line and human peripheral tion. Due to the large number of macrophages in the tissues
blood monocytes, which when cultured under high glucose and its role as a major source of cytokines during injury,
conditions caused elevated expression of MCP-1, TNF-𝛼, IL- hyperactive macrophages are the leading contributors of sys-
1𝛽 [8, 9], COX2 [10], IP-10 [11], and IL-6 [12]. A study using temic inflammatory response syndrome (SIRS). Interestingly,
primary human monocytes shows that HG-induced TNF-𝛼 recent research has shown that macrophages are heavily
production is through the downregulation of CD33 [13]. involved not only in proinflammatory signaling cascades but
Importantly, hyperglycemia-induced abnormal cytokine are also pivotal in the phases of anti-inflammatory, wound
production in patients with severe sepsis exacerbates the healing, and sepsis in critical illness.
clinical outcomes of these patients experiencing stress hyper- To examine the effects of high glucose on macrophage
glycemia [14]. Accumulating evidence indicates that IL-6 proliferation, Liu et al. cultured monocyte/macrophage cell
is involved in glucose metabolism and insulin action. The line WEHI-3 and splenic macrophages in hyperglycemic
proinflammatory cytokine IL-6 is normally released upon media with various concentrations (5.6–30 mM) of glucose.
infection; however, it induces insulin resistance during con- They found that macrophage proliferation increased with
ditions of hyperglycemia [15]. Devaraj and Jialal found that the greater concentrations of glucose [21]. The enhanced
increased secretion of IP-10 from monocytes cultured with macrophage proliferation may result from increased CSF-1
high concentration glucose was via TLR2 and TLR4 pathway, receptor (CSF-1R) under these conditions [22]. In addition,
International Journal of Endocrinology 3

hyperlipidemia has combined effect with hyperglycemia to function of neutrophils. Hyperglycemia also reduces neu-
stimulate the proliferation of macrophages since hyperme- trophil degranulation and exaggerates coagulation in healthy
tabolisms including hyperglycemia and hyperlipidemia are humans that accepted glucose infusion and injection with
very common in critical illness [23]. In addition, hyper- endotoxin [30]. Since glucose and glutamine play a key role
glycemia also enhances the immunological responses, as is in neutrophil function, changes in metabolism of neutrophils
shown in that hyperglycemia augmented increased cytokine under the condition of hyperglycemia may play an important
production and phagocytosis in response to LPS [24]. This role in the impaired neutrophil function observed in diabetes
effect may be associated with elevated TLR expression [16]. [31]. Sustained decreases in neutrophil function associated
Extending the in vitro experiments using cell lines and with hyperglycemia are associated with the extent of hyper-
isolated splenic macrophages, there has been an ex vivo glycemia [32].
study examining the effects of hyperglycemia on alveolar
macrophage function [25]. In contrast to studies using cell 2.4. 𝛾𝛿 T Cells. 𝛾𝛿 T cells, a T-cell subset expressing 𝛾𝛿 TCR,
lines, hyperglycemia significantly decreased the respiratory account for approximately 3–5% of all lymphoid cells found
burst of alveolar macrophages and impaired proinflamma- in the secondary lymphoid tissues and the blood. They are
tory cytokine secretion, such as TNF-𝛼 and IL-6. It also relatively abundant in the skin epithelia, intestine, uterus, and
demonstrated a reduced response to multiple TLR ligands tongue where they can account for up to 50% of the total
in alveolar macrophages. The impaired reactivity of alveolar intraepithelial lymphocyte population.
macrophage to TLR ligands might result from HG-induced Resident intraepithelial 𝛾𝛿 T cells are responsible for
alteration of intracellular signaling and is unlikely due to the maintaining epithelial integrity, regulating homeostasis and
modulation of TLR expression itself [25]. Hyperglycemia also providing a first line of defense against pathogens and injury
promotes the inflammatory response by activating the NF- in mice and humans. Schwacha and collaborators found that
𝜅B pathway. Using a rat model of hyperglycemia and burn 𝛾𝛿 T cells play a role in neutrophil-mediated remote organ
injury, Kulp et al. investigated the effects of hyperglycemia on (i.e., lung, small intestine) injury early after burn injury by
inflammatory responses in the liver. Streptozotocin-induced increasing chemokine levels in both the plasma and tissues
hyperglycemia in severely burned rats rapidly activated NF- [33]. Another study from the same group showed a 6-fold
𝜅B pathways in the liver and markedly increased liver reduction in cellular infiltrate in burn wound and a marked
acute-phase proteins and proinflammatory cytokines. On decrease of levels of MCP-1, IL-6, and TNF-𝛼 in the wound in
the contrary, long-term exposure to hyperglycemia leads to 𝛾𝛿 T cells receptor-deficient mice [34]. More recently, a study
alternative activation of macrophage. F4/80(+) peritoneal showed that hyperglycemia negatively impacts homeostasis
exudate macrophages (PEMs) from mice with diabetes for and functionality of skin 𝛾𝛿 T cells. Hyperglycemia results
4 months displayed significantly reduced proinflammatory in impaired skin 𝛾𝛿 T cell proliferation, ultimately resulting
cytokines TNF-𝛼 and IL-6 production but enhanced nitric in half the normal amount residing in the epidermis. These
oxide (NO) secretion when treated with IFN-𝛾 and LPS, 𝛾𝛿 T cells expressed decreased levels of NR4A1 and NR4A3,
while the activity of arginase in PEMs from diabetic mice was two orphan nuclear receptors that have been shown to
significantly higher than control mice when stimulating with sensitize muscle to insulin, suggesting their decreased insulin
IL-4 [26]. sensitivity. The dysfunctional 𝛾𝛿 T cells can also result from
In summary, hyperglycemia has established itself as the effects of chronic inflammatory mediators, such as TNF-
a regulator of macrophage proliferation and activity. The 𝛼, in the local environment [35].
detrimental effects of hyperglycemia on thermal injury out- Overall, skin 𝛾𝛿 T cells recognize epithelial damage and
come may be mediated in part by augmenting macrophage release cytokines and growth factors that facilitate wound
inflammation via the activation of hepatic NF-𝜅B pathway repair. Their activities are compromised by hyperglycemia,
[27]. rendering host defense mechanisms vulnerable to further
injury and infection in patients with critical illness.
2.3. Neutrophil. Neutrophils are typically the first leukocytes
to be recruited to the inflammatory site and are capable 3. Insulin and Innate Immune Cells
of eliminating pathogens by multiple mechanisms. Follow-
ing infection, the localization of neutrophils to the site Insulin exerts its effects on immune cells by binding to
of inflammation is crucial for the clearance of pathogens. the insulin receptor (IR), that is, extensively expressed on
When considering burn shock, the inflammatory response- immune cells, such as neutrophils and monocytes/macro-
related hyperactivation of neutrophil contributes to oxidative phages. Upon insulin’s binding to the IR, insulin rapidly
cell/tissue damage and potentially initiates organ-system increases tyrosine phosphorylation of its own receptor fol-
dysfunction and failure. Severe burn and sepsis result in an lowed by the phosphorylation of the insulin receptor sub-
inhibition of neutrophil function including migration [28] strate proteins (IRS). The IRS is linked to the activation of
and neutrophil paralysis leads to increased rate of infec- two main signaling pathways: the phosphatidylinositol 3-
tious complications in short-term hyperglycemic critically ill kinase (PI3K)—AKT/protein kinase B (PKB) pathway and
patients [29]. the Ras/mitogen-activated protein kinase (MAPK) pathway.
Hyperglycemia induces neutrophil dysfunction by modu- It has been shown that mice deficient in insulin have an
lating one of the neutrophil biochemical pathways, myeloper- exaggerated cytokine response to peritoneal inflammation
oxidase (MPO). MPO plays an important role in the killing compared to controls, indicating that insulin treatment not
4 International Journal of Endocrinology

Table 1: Effects of hyperglycemia and insulin on innate immune cells.

Hyperglycemia Insulin
(1) Enhances pathogen clearance [34, 35]
(2) Promotes IL-8/CXCL8 secretion [38]
(1) Generally enhances cytokine production [7–10, 13–15] (3) Increases superoxide production [40]
Monocyte (2) Regulates adhesion, migration, and transmigration (4) Promotes TNF-𝛼 and IL-6 secretion in the presence of
[13, 14, 17] palmitate [37]
(5) Regulates monocyte metabolism by increasing the
phagocytosis of oxidized low-density lipoprotein [36, 37]
(1) Promotes proliferation [18, 19]
(1) Inhibits TNF-𝛼, IL-1, and IL-8 secretion [42, 44]
(2) Enhances cytokine production and phagocytosis in
(2) Reduces macrophage accumulation in tissue [43]
Macrophage response to LPS in vitro [16, 20]
(3) Promotes human macrophage foam cell formation
(3) Impairs proinflammatory cytokine secretion, such as
[47, 48]
TNF-𝛼 and IL-6 ex vivo [21]
(1) Increases the total number of PMN and their surface
(1) Inhibits neutrophil function such as degranulation [25–27] expression of CD11b, CD115, CD62L, and CD89 [50]
Neutrophil
(2) Downregulates production of myeloperoxidase (MPO) [25] (2) Increases PMN function including chemotaxis,
phagocytosis, and bactericidal capacities [50, 51]
(1) Impairs skin T cell proliferation [30]
𝛾𝛿 T cells N/A
(2) Inhibits neutrophil tissue infiltration [28, 29]

only decreases glucose levels but also inhibits the inflam- IL-6 and TNF-𝛼, compared to monocytes incubated with
mations [36]. Recent studies indicate that insulin levels vary palmitate alone. However, incubation of monocytes with
in patients but that higher insulin levels may be associ- insulin alone did not affect the production of IL-6 or TNF-𝛼
ated with increased mortality, perhaps suggesting insulin [45]. Hyperinsulinemia also influences monocytic HLA-DR
resistance [37, 38]. In the following section, we will review expression. Monocytes from healthy volunteers were treated
insulin’s effects on immune function and metabolism of with insulin (concentration from 10 𝜇U to 200 𝜇U) for 24
innate immune cells (summarized in Table 1). For more hours in vitro and monocytic HLA-DR was significantly
detailed insulin signaling pathway, please refer to a decent decreased in a dose-dependent manner [19].
review paper [39]. Lastly, insulin also regulates other activities of monocytes
including superoxide production and the expression of tissue
factor (TF) and MMP-9. It stimulates superoxide (O2 − )
3.1. Monocytes. Insulin is considered to be a regulator of
production in monocytes and macrophages [46], which is
monocyte function, which includes chemotaxis, phagocyto-
dependent on NADPH oxidases. NADPH oxidase plays a
sis, and oxidative burst capacity. In a rabbit model of burn
pivotal role in insulin-induced activation of monocytes [46].
injury, researchers found that insulin improved the capacity
Insulin may influence the hypercoagulability in patients by
for phagocytosis and oxidative burst within 3 days after
inhibiting tissue factor expression in monocyte, the principal
burn, with no effect on chemotaxis [40]. A similar effect
initiator of the extrinsic coagulation pathway [47].
was observed in trauma patients receiving intensive insulin
therapy, which showed enhanced monocyte phagocytosis
[41]. 3.2. Macrophages. Generally speaking, insulin attenuates the
Another role that insulin has is influencing the metabo- immune response of macrophages. It inhibits TNF-𝛼 and IL-
lism of monocyte. Insulin increased oxidized low-density 8 secretion by macrophage in response to LPS. This effect is
lipoprotein phagocytosis of monocytes isolated from healthy via the release of activin A and the signaling by cytoplasmic
obese participants [42]. The effects of insulin on the rates SH2-containing inositol 5󸀠 -phosphatase (SHIP) [48]. It also
of glucose transport in monocytes were measured with modulates tissue inflammation by reducing macrophage
the NBDG fluorescent d-glucose analog. Insulin caused an accumulation in visceral adipose tissue in mice [49]. Another
increase in the uptake of glucose and the expression of study also showed that insulin inhibits cytokine secretion
glucose transporter (GLUT) isoforms GLUT3 and GLUT4 in (TNF-𝛼 and IL-1𝛼) by macrophage and improves its survival
the plasma membrane [43]. [50]. Pretreatment of cells with specific covalent inhibitor
Insulin also regulates chemokine and cytokine secretion of phosphoinositide 3-kinases significantly inhibited insulin-
of monocytes. The addition of insulin to human monocyte mediated cell survival and BclXL expression. In addition,
cell culture promotes IL-8/CXCL8 secretion. IL-8/CXCL8 is the enhancing effect of insulin on BclXL expression is dose-
a potent chemoattractant for neutrophils and causes degran- dependent [51]. Furthermore, macrophages from mice with
ulation of neutrophil-specific granules and azurophilic gran- streptozotocin- (STZ-) induced diabetes display a dysfunc-
ules. These results suggest that insulin may regulate the tional phenotype, reduced CD86 expression, and proinflam-
recruitment and activity of neutrophils by inducing IL- matory cytokines such as TNF-𝛼 and IL-6 production but
8/CXCL8 secretion from monocytes [44]. THP-1 monocytes enhanced nitric oxide (NO) secretion [26]. These functional
incubated with insulin and palmitate together produced more changes of macrophages could be efficiently reversed by
International Journal of Endocrinology 5

insulin treatment and this effect is dependent on the activities injured patients have shown improved wound healing by
of AKT and ERK [26]. 6.9% in the early stages in comparison to burn controls
Insulin also regulates macrophage metabolism. Recent [60]. Severely burned pediatric patients had reduced urinary
study shows that insulin promotes human macrophage foam tract infections and sepsis in the IIT group with a positive
cell formation by increasing type II scavenger receptor CD36 association with survival [61]. Early control of hyperglycemia
and decreasing the expression of the ATP-binding cassette is essential since a lack of early glycemic control (mean daily
transporter ABCA1. As a result, it leads to 2-3-folds more blood glucose < 150 mg/dL in at least two consecutive days
cholesterol accumulation within a short period by increasing by postburn day 3) was associated with higher mortality
oxidized LDL uptake and decreasing cholesterol efflux to [62].
apolipoprotein A1 (apoA1) [52]. Insulin also promotes foam Despite the vast benefits of tight glycemic control with
cell formation by accelerating endocytic uptake of advanced IIT, it is accompanied by a mandate for critically monitoring
glycation end products (AGE) proteins [53]. In addition, and awareness of sudden fluctuations in blood glucose. There
insulin specifically promotes the protein degradation of LRP1 was no overall impact on hospital or ICU length of stay in
and therefore decreases LRP1 expression on macrophages. severely burned paediatric patients who received IIT [60].
The decreased expression of LRP1 impairs the cellular inter- In addition, there was a significant concern regarding the
nalization of alpha-2-macroglobulin, which may modulate use of IIT in managing elevated blood glucose in traumatic
cytokine secretion by macrophage [54]. brain injury patients. IIT did not result in reduced cerebral
metabolic rate, but it did increase markers of neural metabolic
distress and showed no improvement in mortality [63].
3.3. Neutrophils. In vitro study indicated that insulin reg-
More recently, IIT in both critically ill neurological and
ulated isolated neutrophil cytokine secretion. Activin A, a
stroke patients showed more episodes of hypoglycemia and
transforming growth factor-𝛽 family cytokine, plays a crucial
little to worsening effect of patient outcomes compared to
role in regulating the onset and severity of many inflamma-
nonaggressive approaches [64].
tory conditions. Bone marrow-derived neutrophil precursors
There has been an ongoing debate regarding the effec-
contained 7-fold higher concentrations of activin A than bone
tiveness of IIT versus modest insulin treatment [65]. In
marrow mononuclear cells. These isolated neutrophils could
fact, hyperglycemia can be safely avoided using a moderate
release activin A in response to TNF-𝛼. However, production
glycemic control protocol without inducing hypoglycemia
of activin A would be blocked upon pretreatment with insulin
[66]. Using a retrospective approach, Kutcher and colleagues
[55].
concluded that the two treatments had no significant impact
The in vivo effects of insulin on neutrophils were con-
on multiorgan failure and mortality. However, the moder-
ducted in healthy subjects under strict euglycemia and
ate regime had scarce hyperglycemia episodes, low glucose
physiological insulinemia. They found that insulin increased
variability, and intermediate blood glucose ranges of hypo-
the total number of neutrophils and the number of these
glycemia [66].
expressing CD11b, CD15, CD62L, and CD89, whereas the
Along with the numerous investigations of insulin ther-
density of these molecules was downregulated. In addi-
apy to manage stress hyperglycemia, there are numerous
tion, insulin increased PMN function including chemotaxis,
other treatment options that have been studied. The use
phagocytosis, and bactericidal capacities [56]. Interestingly,
of metformin in treating hyperglycemia decreases endoge-
although insulin stimulated phagocytosis and bactericidal
nous glucose production and increases glucose clearance
activity in young-adult subjects, these effects were compro-
and oxidation [67]. The use of other agents in combina-
mised in the elderly subjects [57]. Studies of patients who
tion with insulin, such as glucagon-like peptide-1 (GLP-
underwent major surgery showed that insulin treatment not
1) analogue exenatide, has shown to reduce the amount
only significantly decreased the level of blood glucose, but it
of insulin required to achieve euglycemia [4]. Lastly, the
also increased the number of neutrophils in the circulation as
lipolysis agonist Fenofibrate treatment can reduce insulin
well as their ability to ingest foreign particles [58].
resistance [68] and, when used in combination with insulin,
reduces hypoglycemic episodes with clear improvements in
4. Intensive versus Moderate skeletal muscle insulin signaling, glucose oxidation, and
Insulin Treatment mitochondrial function [69].
There is compelling evidence for the multifaceted
Stress hyperglycemia leads to an increased incidence of effect of hyperglycemia treatment and the respective out-
infection and higher morbidity and mortality in severely comes in critically injured and burn patients. Patients
traumatic patients [59]. To manage hyperglycemia in patients will benefit most from the use of moderate insulin treat-
with severe trauma and illness, van den Berghe and col- ment regimens with rigorous attention being given in the
leagues conducted the first clinical study of IIT over 10 first few days of injury to obtain blood glucose levels
years ago [2]. The study showed that maintaining blood within the well-established target ranges (summarized in
glucose at or below 110 mg/dL by IIT reduces morbidity Table 2). Future prospective randomized trials need to
and mortality among critically ill patients in the surgical place emphasis on the frequency of hypoglycemic and
intensive care unit. With a total of 1548 patients enrolled, hyperglycemic episodes and the extreme changes in glu-
IIT reduced mortality rate from 8% with conventional treat- cose variability to determine the detrimental impact on
ment to 4.6% [2]. Intensive insulin protocols in thermally survival.
6 International Journal of Endocrinology

Table 2: Comparison of intensive and moderate insulin treatment.

Intensive Moderate
Target Blood glucose: 110 mg/dL [1] Blood glucose: 120–150 mg/dL [33, 59]
(1) Improves wound healing in burned patients [54]
(1) Does not induce hypoglycemia [60]
Advantages (2) Reduces urinary tract infections and sepsis in burned
(2) Scarce hyperglycemia episodes [60]
pediatric patients [55]
(3) Low glucose variability [60]
(3) Reduces morbidity and mortality [1]
(1) Requires continual and critical monitoring [54]
Disadvantages (2) No overall impact on hospital or ICU length of stay [54] No significant impact on mortality and multiorgan
failure [60]
(3) More episodes of hypoglycemia [58]

Stress

Cortisol Catecholamines Glucagon Growth hormones

↓ Peripheral usage ↑ Glucose production

Insulin Hyperglycemia

↓ Inflammatory mediators Tissue

↑ Cellular function

↑ Inflammatory mediators

↓ Cellular function
↓ Morbidity/mortality ↓

↑ Morbidity/mortality ↑

Cytokines
Neutrophils
Monocytes

Figure 1: Schematic summary of hyperglycemia and insulin treatment regulation of innate immune cells. Overwhelming stress resulted from
critical illness, such as severe burn, major surgery, or sepsis stimulates the release of cortisol, catecholamines, glucagon, and growth hormone,
which increase hepatic glucose production and impair glucose consumption by peripheral tissues. Long-term stress-induced hyperglycemia
induces hyperproinflammatory responses and depressed cell functions, which is linked to increased risk of mortality and morbidity. Insulin
plays a different role in regulating innate immune cells including monocytes, macrophages, and neutrophils. It generally improves their
cellular activities and attenuates their inflammatory responses.
International Journal of Endocrinology 7

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insulin in the regulation of innate immunity will guarantee [11] S. Devaraj and I. Jialal, “Increased secretion of IP-10 from
a more rational and an effective insulin treatment for these monocytes under hyperglycemia is via the TLR2 and TLR4
patients. pathway,” Cytokine, vol. 47, no. 1, pp. 6–10, 2009.
[12] S. Devaraj, S. K. Venugopal, U. Singh, and I. Jialal, “Hyper-
Disclosure glycemia induces monocytic release of interleukin-6 via induc-
tion of protein kinase C-𝛼 and -𝛽,” Diabetes, vol. 54, no. 1, pp.
No competing financial interests exist. There are no disclo- 85–91, 2005.
sures for Fangming Xiu, Mile Stanojcic, Li Diao, and Marc G. [13] Y. Gonzalez, M. T. Herrera, G. Soldevila et al., “High glu-
Jeschke. cose concentrations induce TNF-alpha production through the
down-regulation of CD33 in primary human monocytes,” BMC
Immunology, vol. 13, article 19, 2012.
Conflict of Interests [14] L. Leonidou, A. Mouzaki, M. Michalaki et al., “Cytokine pro-
No conflict of interests is declared by the authors. duction and hospital mortality in patients with sepsis-induced
stress hyperglycemia,” Journal of Infection, vol. 55, no. 4, pp.
340–346, 2007.
Acknowledgments [15] Y. Wei, K. Chen, A. T. Whaley-Connell, C. S. Stump, J. A.
Ibdah, and J. R. Sowers, “Skeletal muscle insulin resistance:
The authors thank Dr. Peter Chen for his critical review role of inflammatory cytokines and reactive oxygen species,”
of the paper. This work is supported by Grants from the The American Journal of Physiology—Regulatory Integrative and
National Institutes of Health (R01 GM087285-01); CIHR Comparative Physiology, vol. 294, no. 3, pp. R673–R680, 2008.
Funds (123336), CFI Leader’s Opportunity Fund (Project no. [16] M. R. Dasu, S. Devaraj, L. Zhao, D. H. Hwang, and I. Jialal,
25407); Physician’s Services Incorporated Foundation: Health “High glucose induces toll-like receptor expression in human
Research Grant Program. monocytes Mechanism of activation,” Diabetes, vol. 57, no. 11,
pp. 3090–3098, 2008.
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