SHOCK, Vol. 47, No. 3, pp.

276–287, 2017

Review Article
DIABETES MELLITUS AND SEPSIS: A CHALLENGING ASSOCIATION

Silvia C. Trevelin, * † Daniela Carlos, ‡ Matteo Beretta, * João S. da Silva, ‡

and Fernando Q. Cunha †
*Cardiovascular Division, British Heart Foundation Centre, King’s College London, London, UK;
†
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto,
Brazil; and ‡ Department of Biochemistry and Immunology, Ribeirao Preto Medical School,
University of Sao Paulo, Ribeirão Preto, Brazil

Received 27 Jul 2016; first review completed 15 Aug 2016; accepted in final form 13 Oct 2016

ABSTRACT—Sepsis is a life-threatening organ dysfunction caused by a deregulated host response to infection. This
inappropriate response to micro-organism invasion is characterized by an overwhelmed systemic inflammatory response
and cardiovascular collapse that culminate in high mortality and morbidity in critical care units. The occurrence of sepsis in
diabetes mellitus (DM) patients has become more frequent, as the prevalence of DM has increased dramatically worldwide.
These two important diseases represent a global public health concern and highlight the importance of increasing our
knowledge of the key elements of the immune response related to both conditions. In this context, it is well established that
the cells taking part in the innate and adaptive immune responses in diabetic patients have compromised function. These
altered responses favor micro-organism growth, a process that contributes to sepsis progression. The present review
provides an update on the characteristics of the immune system in diabetic and septic subjects. We also explore the
beneficial effects of insulin on the immune response in a glycemic control-dependent and independent manner.
KEYWORDS—Diabetes mellitus, histamine, hyperglycemia, immune response, mast cells, neutrophils, sepsis

ABBREVIATIONS—AGE—advanced glycation end-products; ALX—alloxan; CLP—cecal ligation and puncture;

DM—diabetes mellitus; HbA1c—glycated hemoglobin; IL—interleukin; KO—knockout mice; LPS—lipopolysaccharide;
NO—nitric oxide; PPAR-g—peroxisome proliferator-activated receptor gamma; ROS—reactive oxygen species; STZ—
streptozotocin; T1D—type 1 diabetes mellitus; T2D—type 2 diabetes mellitus; TNF-a—tumor necrosis factor-alpha;
WT—wild-type mice

INTRODUCTION million deaths annually (2). Together, these findings underscore

the need for the rapid diagnosis of patients with sepsis and the
According to The Third International Consensus Definitions
determination of prognosis to prescribe aggressive treatment
for Sepsis and Septic Shock, ‘‘sepsis is a life-threatening organ
within the initial minutes of arrival at the hospital (1).
dysfunction secondary to a deregulated host response to an
Frequently, septic patients present with chronic diseases such
infection’’ (1). Despite recent improvements in its diagnosis
as diabetes mellitus (DM). In fact, a recent study that evaluated
and treatment, sepsis remains a common, costly, and lethal
1,104 patients with sepsis found that 241 (21.8%) had a medical
condition in hospitals worldwide. A meta-analysis study, in
history of DM (3). According to the authors, patients with DM
which the authors searched 15 international citation databases
were older, had a higher body mass index (BMI), a higher
from 1979 to 2015, revealed that the mortality rates due to
modified Charlson Comorbidity Index (calculated without the
sepsis and severe sepsis are 17% and 26%, respectively (2).
contribution of DM) and were admitted with more chronic
Additionally, a tentative extrapolation from high-income
comorbidities, such as cardiovascular dysfunction, hyperten-
country data suggests global estimates of 31.5 million sepsis
sion, and renal insufficiency. One of the reasons for this
and 19.4 million severe sepsis cases, with potentially 5.3
significant percentage of diabetic and septic patients could
be increases in the global incidence and prevalence of DM.
Address reprint requests to Professor Dr Fernando Q. Cunha, PhD, Department of The number of people with DM has doubled over the past three
Pharmacology, Ribeirao Preto Medical School, Bandeirantes Avenue, 3900, 14049-
900 Ribeirão Preto, SP, Brazil. E-mail: fdqcunha@fmrp.usp.br decades (4, 5). In 2014, the prevalence of DM was 5% for men
This work was supported by grants from the Sao Paulo Research Foundation and 7.9% for women (6). Additionally, this number is predicted
(FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior to be 439 million by 2030, which represents 7.7% of the
(CAPES), and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico
(CNPq). total adult population of the world aged between 20 and 79 years
This work was also supported by grants from the European Union Seventh (4–6).
Framework Programme [FP7-2007-2013] under grant agreement no. HEALTH-F4- There are two forms of DM: type 1 (T1D) and type 2 (T2D).
2011-281608 (TIMER), from FAPESP under grant agreements no. 2009/54764-6
(Projeto Temático), 2011/19670-0 (Projeto Temático), 2013/08216-2 (Center for T1D is described as an autoimmune response triggered against
Research in Inflammatory Disease), 2011/03293-3 (S.C.T fellowship), and from the the insulin-producing pancreatic b cells that leads to progress-
University of Sao Paulo NAP-DIN under grant agreement no. 11.1.21625.01. ive islet damage and insulin production insufficiency. The
The authors report no conflicts of interest.
DOI: 10.1097/SHK.0000000000000778 initiation of T1D does not involve one single factor, but it
Copyright ß 2016 by the Shock Society has been associated with several genetic and environmental
276
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
SHOCK MARCH 2017
features (7). On contrast to T1D, which is a deficiency in insulin
production, T2D is characterized by insulin resistance in the
peripheral tissues and has previously been associated with
obesity, genetic susceptibility, and fetal undernutrition (6, 8).
In both T1D and T2D, there are enhanced glucose levels in the
blood and glycemia-dependent and glycemia-independent
immune response alterations that could influence the patho-
genesis of life-threating conditions such as sepsis.
In this review, we discuss the alterations in the innate and the
adaptive immune responses that occur during DM and their
implications for sepsis outcome. Regarding innate immunity,
the mechanisms underlying the impairment of neutrophil func-
tion are explored. Further, Th17 and Treg cells are discussed in
the context of sepsis and DM. We also evaluate the benefits of
insulin treatment on the immunological system, which include
effects dependent and independent of glycemia control. More-
over, we refer to some studies completed in humans with DM
and sepsis and discuss how they can be better interpreted in
comparison to studies completed in mice.
T1D and T2D compromise sepsis outcome
Several studies performed in animals showed that DM could
impair sepsis outcome (9–14). Goto-Kakizaki rats, which
develop T2D spontaneously, showed higher IL-6 mRNA levels
in the liver and higher lactate levels in the plasma (a marker of
tissue lesion) than control Wistar-Kyoto rats after polymicro-
bial sepsis induced by cecal ligation and puncture (CLP) (9).
Akita mice, which contain a mutation in the insulin gene and a
progressive loss of pancreatic b-cell function and are a model
for T1D, showed a 75% increase in mortality rates after CLP
compared with wild-type (WT) mice (10). Nonobese diabetic
(NOD) mice, which spontaneously developed the autoimmune
T1D, exhibited approximately 30% higher mortality after CLP
compared with control normoglycemic mice (11). Rats and
mice, after treatment with alloxan (ALX, 2,4,5,6-pyrimidine-
tetrone) or streptozotocin (STZ) to induce T1D, showed higher
mortality when they were subjected to sepsis or endotoxemia in
comparison to controls animals treated with vehicle (11–14).
Notably, unfavorable sepsis outcomes in diabetic animals have
been extensively associated with a compromised innate
immune system and disturbances in the adaptive immune
response.
Impaired neutrophil function during T1D reduces sepsis
survival
Neutrophils are considered to be the first line of innate
immune defense against an infection. The phagocytosis of
microorganisms and the concomitant release of reactive oxygen
and nitrogen-derived species (ROS and RNS) and proteases
into the phagosomes are key events that contribute to host
defense against pathogens (15). The ROS and RNS generated
by neutrophils have destructive potential. Therefore, the
recruitment of these leukocytes into the tissue compartments
is a tightly regulated multistep process (16, 17).
The migration of neutrophils is initiated by the sensing of
inflammatory mediators that are released by resident macro-
phages, fibroblasts, and endothelial cells (ECs) after body
invasion. These mediators diffuse throughout the affected organ
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
DIABETES MELLITUS AND SEPSIS ASSOCIATION 277
and its blood vessels, inducing neutrophil rolling, firm
adhesion, transmigration, and chemotaxis toward the focus
of infection. All these steps require precise communication
between the leukocytes and ECs (17). Tumor necrosis factor
[TNF]-a, interleukin [IL]-1b, IL-17, chemokines, and eicosa-
noids are some of the inflammatory mediators released
during sepsis. The synthesis of these mediators depends
on the intracellular signaling initiated by the recognition of
damaged-associated molecules (HMGB1, DNA, RNA) and
pathogen-associated molecular patterns (lipopolysaccharide
[LPS], lipoteichoic acid, oligodeoxynucleotides containing
non-methylated CpG sequences [ODN CpG]). In turn, the
inflammatory molecules induce the activation of ECs that
express E-selectin and stimulate the fusion of the Weibel–
Palade bodies containing P-selectin with the membrane. This
favors their transient interaction with leukocytes that express
P-selectin glycoprotein ligand-1 and E-selectin ligand-1. Acti-
vated ECs also generate nitric oxide (NO), which results in
vasodilatation and, consequently, marginalization of leuko-
cytes. Furthermore, the CD11bCD18 integrin on activated
neutrophils interacts with intercellular (ICAM-1) and vascular
adhesion molecules expressed on ECs, leading to the firm
adhesion, crawling, and transmigration of leukocytes. Outside
the blood vessel, neutrophils are guided to the infection site via
several chemoattractants, including chemokines (CXCL8 and
CCL2 in humans; CXCL1, CXCL2, CCL2, and CXCL5 in
mice), cytokines (IL-17A), lipid mediators (leukotriene B4
[LTB4]), and bacterial products (N-formylmethionine-leucyl-
phenylalanine [fMLP]) (17–20). Altogether, the migration
process during sepsis must be a highly controlled process,
since the migration of an insufficient number of neutrophils
into the infection site could result in the failure to control
infection, whereas misguided neutrophil accumulation could
lead to tissue injury (17, 18).
Neutrophils from diabetic patients have reduced chemotactic
and phagocytic abilities and lower antimicrobial activity com-
pared with those obtained from healthy controls (20). In 1971,
the first study showing impaired chemotaxis in blood neutro-
phils purified from 31 diabetic patients relative to that in 31
healthy matched controls was published (21). The impaired
chemotaxis was initially attributed to decreased neutrophil
membrane fluidity (22); however, subsequent studies (11,
12, 23) described other mechanisms involved in the failure
of neutrophil migration in diabetic subjects with sepsis, and we
will discuss this topic in more detail in the following section.
Neutrophils purified from patients with T1D showed reduced
synthesis and release of LTB4 compared with healthy controls
(24). Moreover, it was shown that the in vitro chemotaxis of
neutrophils purified from patients with T1D toward fMLP or
platelet-activating factor (PAF) was inversely correlated with
the main indices of glycemic control (fasting plasma glucose
and glycated-hemoglobin levels). PAF and fMLP also induced
significantly lower lysosomal enzyme secretion and LTB4
production in neutrophils from diabetic patients compared with
those from healthy controls. Interestingly, these authors
observed that neutrophils from the same diabetic patients
responded normally after stimulation with A23187 (a calcium
ionophore), serum-opsonized zymosan, or phorbol myristate
278 SHOCK VOL. 47, No. 3
acetate (PMA) (23). Therefore, T1D was proven to be associ-
ated with sustained abnormalities in neutrophil activation and
function, but only in response to agonists that initiate a response
via G protein-coupled receptors.
CXCR2 is a G protein-coupled receptor expressed on the
surface of neutrophils that recognizes the chemokines CXCL1,
CXCL2, and CXCL5 (25). It is regulated by specific kinases,
such as GRK2 (26). GRK2 phosphorylates serine/threonine
residues on CXCR2, leading to receptor internalization and
intracellular sorting, which results in either recycling or degra-
dation (27–29). Our group has previously demonstrated that
mice treated with ALX to induce T1D have a worse prognosis
in CLP-induced sepsis (11). This was associated with a
reduction in the rolling, adhesion, and migration of neutrophils
to the infection site (Fig. 1). After sepsis induction, CXCR2 was
strongly down-regulated in neutrophils from diabetic mice
compared with those from non-diabetic mice. This phenom-
enon was attributed to increased expression of GRK2 (12). In
this study, treatment with insulin restored neutrophil migration,
increased CXCR2 expression on the cell membrane, and
prevented GRK2 induction. In a later study, we observed that
diabetic mice exhibit mast cell accumulation in the peritoneal
cavity and higher plasma levels of histamine than non-diabetic
mice after septic stimuli. The activation of histamine receptor 2
(H2R) was associated with an increase in the intracellular
expression of GRK2 and the internalization of CXCR2 in
neutrophils from diabetic mice (Fig. 1) (11). Corroborating
our data, another research group showed that intratracheal
instillation of LPS in rats treated with STZ to induce T1D
resulted in reduced neutrophil migration to the bronchoalveolar
space compared with non-diabetic rats (30). Additionally, the
study showed that rats with T1D exhibited deficient leukocyte
adhesion and migration and lower expression of ICAM-1 in the
internal spermatic fascia after stimulation with TNF-a (30).
This result is in line with the evidence indicating that CXCR2
activation on leukocytes is essential for the induction of ICAM-
1 expression on ECs (31).
The impaired neutrophil migration in T1D mice after non-
severe CLP led to a higher bacterial load in the peritoneal
cavity, bacteremia, a systemic inflammatory response, multi-
organ failure and death. Indeed, non-severe CLP diabetic mice
showed 100% mortality after 7 days, while non-diabetic mice
showed 20% mortality. Moreover, sepsis aggravation in dia-
betic mice subjected to non-severe CLP (27G needle perfor-
ation of the cecum) could be compared with that observed in
non-diabetic mice after severe sepsis (18G needle perforation
of the cecum). This last condition is characterized by a sig-
nificant failure in neutrophil migration to the focus of infection,
a higher number of neutrophils trapped in the lungs, enhanced
bacteremia, and increased plasma levels of systemic pro-
inflammatory cytokines (TNF-a and CXCL2) as well as
enhanced levels of serum markers of organ damage or dys-
function (aspartate aminotransferase and alanine aminotrans-
ferase [liver damage], urea [renal dysfunction], and creatine
kinase-MB [heart damage]) (11, 12).
In addition to impaired chemotaxis, neutrophils from dia-
betic patients also showed altered phagocytosis and lower
intracellular killing ability than those purified from healthy
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
TREVELIN ET AL.
individuals. These parameters were not correlated with the
blood glucose levels of the patients enrolled in the study, which
included 21 subjects without infection and 10 with recurrent
infections (32). However, another study investigating these
parameters in 10 diabetic patients verified that circulating
blood neutrophils had partially recovered the ability to phag-
ocytose and kill Staphylococcus aureus within 36 h of insulin
treatment (33).
All these studies concluded that DM, particularly T1D,
significantly impairs neutrophil function, suggesting therefore
an association between DM and the failure to control the
growth of microorganisms during an infection, resulting in a
worsened sepsis outcome. Although neutrophil function can be
improved by insulin treatment, it seems to also be independent
of blood glucose levels, as is discussed in more detail in the
following sections.
Neutrophil dysfunctions related to hyper-glycemia
Some of the neutrophil dysfunctions in T1D diabetic mice
were shown to be restored by normalization of glycemia
through insulin administration (12, 24). Since neutrophil func-
tions require energy, metabolic changes (i.e., activation of
glycolytic and glutaminolytic pathways) may be possibly
responsible for the reduction in neutrophil function observed
in DM. Indeed, several metabolic routes linking hyperglycemia
to neutrophil dysfunction have been described: advanced
protein glycosylation reactions, the polyol pathway, ROS for-
mation by mitochondrial complexes I and III, the nitric oxide-
cyclic guanosine-30 -50 -monophosphate pathway, and the gly-
colytic and glutaminolytic pathways (reviewed in (34)).
For instance, it is well established that hyper-glycemia can
induce nonenzymatic glycation of the free amino acid groups of
proteins (more specifically, lysine residues), leading to struc-
tural and functional alterations (35). Protein glycation starts
with the formation of a Schiff base and is followed by inter-
molecular rearrangement and conversion to Amadori products,
such as glycated hemoglobin (HbA1c). HbA1c is the most
widely used marker of long-term glycoregulation, as it reflects
glucose levels during the 120 days prior to measurement. It has
been shown that plasma levels of HbA1c were higher in patients
who developed blood infections (36). Moreover, a study involv-
ing 286 patients with T2D concluded that HbA1c might be
considered an independent predictive factor (r ¼ 0.29;
P <0.001) for hospital mortality of diabetic patients with
sepsis (37).
The impairment of neutrophil function in diabetic patients
does not seem to be directly related to Amadori products such
as HbA1c but rather to the products of their oxidative cleavage,
which results in advanced glycation end-products (AGEs) (38,
39). AGEs derived from albumin bind to the membrane of
neutrophils with high affinity, and this has been associated with
impaired transendothelial migration (40). In addition, AGEs are
able to stimulate the expression of inducible nitric oxide
synthase (iNOS) and heme-oxygenase (HO-1) in neutrophils
(41). Our group has previously demonstrated that NO produced
by iNOS reduces neutrophil migration to the site of infection.
The failure of neutrophil migration was associated with the
down-regulation of CXCR2 on the surface of neutrophils and
SHOCK MARCH 2017 DIABETES MELLITUS AND SEPSIS ASSOCIATION 279

FIG. 1. H2R activation in diabetes mellitus (DM) aggravates sepsis by impairing neutrophil migration. DM causes an increase in the number of mast
cells that degranulate after sepsis stimuli. Histamine release into the site of infection increases the level of blood histamine, which targets H2R on circulating
neutrophils. H2R activation induces GRK2 expression and CXCR2 internalization. In addition to chemotactic deficiency, CXCR2 desensitization decreases
neutrophil adhesion by impairing ICAM-1 expression and activation on endothelial cells. The failure of neutrophil migration can result in deficient control of
bacterial growth in the site of infection, culminating with higher bacteremia, systemic inflammation, and death. H2R indicates histamine receptor 2; ICAM-1,
intracellular molecule adhesion 1.

reduced ICAM-1 expression on ECs (27, 42, 43). Additionally,
HO-1 products were linked to impaired neutrophil rolling and
adhesion in mesentery venules and to the internalization of
CXCR2 (44).
Neutrophil dysfunction independent of hyper-glycemia
Another factor associated with DM that could modulate
neutrophil migration during sepsis is a1-acid glycoprotein
(AGP). After CLP, T1D mice displayed a significant increase
in AGP mRNA expression in the liver and elevated serum
protein levels, which have been negatively correlated with
neutrophil migration to the infection site (11).
AGP participates in glycocalyx formation and is able to
directly bind to the membrane of ECs, particularly to caveolae,
as determined by immunodetection for electron microscopy
(45). The glycocalyx is a glycoprotein-polysaccharide complex
that surrounds EC membranes. Disruption of the glycocalyx in
sepsis has been associated with increased interaction of EC
adhesion molecules (mainly ICAM-1) with neutrophils
(CD11b), resulting in an increase in firm adhesion, and con-
sequently in their recruitment to the site of infection (46).
Therefore, it is logical to hypothesize that the higher levels of
AGP in non-surviving septic mice with DM might result in the
thickening of the glycocalyx layer, which could contribute to
the lack of neutrophil recruitment to the infection site. How-
ever, even if quite plausible, this hypothesis should be further
investigated in future studies.
Interestingly, the treatment of rats with aminoguanidine (a
non-selective inhibitor of nitric oxide synthase enzymes) pre-
vented the AGP-induced failure of neutrophil migration to the
peritoneal cavity in a model of peritonitis induced by carra-
geenan. Accordingly, iNOS-deficient mice, which received
AGP and were subjected to peritoneal inflammation, exhibited
increased neutrophil migration to the inflammation site relative
to WT mice under the same treatment (47). However, the
molecular mechanisms through which iNOS inhibition rescued
the AGP-mediated failure of neutrophil migration are still
unknown.
The increased number of mast cells migrating into the
peritoneal cavity of diabetic mice is another characteristic that
seems to be independent of glycemia. These cells can degra-
nulate after septic stimulus, resulting in a higher plasma
concentration of histamine. We verified that the compound
48/80, a drug that depletes histamine from mast cell granules,
restores neutrophil migration to the focus of infection in
diabetic mice with sepsis, although it does not reduce blood
glucose levels (11).
Insulin improves sepsis outcome: effects dependent and
independent of glycemia control
Insulin is a pivotal regulator of glucose metabolism and
performs an important anabolic function throughout the body.
Insulin promotes glucose uptake by cells and might control the
processes that require energy, such as mitogenesis and gene

Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
280 SHOCK VOL. 47, No. 3
transcription (48). Adequate concentrations of insulin are
essential for normal EC and neutrophil function throughout
the course of an inflammatory response (49–51). Our group has
shown that daily insulin treatment starting on the fifth day after
ALX injection increased the survival rates of diabetic mice
subjected to sepsis (12). Importantly, insulin treatment before
CLP significantly increased the rolling and adhesion of neu-
trophils on mesenteric venules and in vitro chemotaxis toward
CXCL2. Furthermore, insulin administration before CLP
reduced the serum levels of pro-inflammatory cytokines and
chemokines such as CXCL1, CXCL2, and IL-6 (12). Other
groups have shown similar results concerning the beneficial
effects of insulin treatment in diabetic animals and humans
under infection (52–55). Although insulin treatment reduced
overall glycemia after 10 days of T1D induction with ALX in
our study, we did not measure blood glucose levels hourly
during the early phases of sepsis. Therefore, it is plausible that
the improved neutrophil function could be primarily due to
the increased levels of insulin rather than to the reduction of
hyper-glycemia (51). Indeed, we already mentioned that the
neutrophil dysfunctions during T1D might occur independently
of hyperglycemia (13, 14).
The beneficial effects of insulin treatment during sepsis
might be correlated to direct control of the transcription of
inflammatory mediators. Indeed, LPS-treated diabetic mice
exhibited altered phosphorylation of extracellular signal-
regulated kinase, protein-38 mitogen-activated protein kinase,
protein kinase (PKC)-a, and PKC-d, and this altered expression
was completely or partially restored by insulin treatment (56).
In addition, insulin has been shown to regulate the expression of
inducible enzymes such as iNOS and COX-2, therefore affect-
ing the levels of NO, PGE-2, and IL-6 during the early phases of
allergic lung inflammation in diabetic rats. These results
suggest that insulin is required for the optimal transduction
of the intracellular signals that drive the inflammatory response
(57). Furthermore, insulin significantly decreased the release of
TNF-a and IL-1b by macrophages after LPS stimulation and
improved neutrophil killing. Indeed, insulin has been shown to
exert anti-apoptotic and anti-inflammatory effects at the cel-
lular and molecular levels in vitro and in vivo (33, 58).
Importantly, insulin affects cells from healthy individuals.
Specifically, insulin significantly increased the chemotaxis of
neutrophils purified from healthy donors toward fMLP (59).
This finding reinforces the idea of the overall beneficial effects
of insulin, which also occur independently of the control of
blood glucose levels.
An infusion of insulin (4.5–6.1 mmol/L) to maintain glucose
levels between 80 and 110 mg/dL dramatically reduced
mortality and morbidity in critically ill patients. Other meta-
bolic effects of insulin include the inhibition of lipolysis and the
normalization of dyslipidemia, and other immunologic effects
include the suppression of excessive inflammation and the
improvement of macrophage function (60). In agreement with
these beneficial effects, patients with severe trauma or SIRS
who received intensive insulin therapy exhibited a significant
decrease in the levels of the pro-inflammatory mediators TNF-
a, IL-6, and C-reactive protein compared with controls (61).
Rats that received thermal injury and were treated with insulin
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
TREVELIN ET AL.
exhibited a lower hepatic inflammatory response. Insulin treat-
ment also increased the hepatic expression of the cytokine
IL-10 at the mRNA and protein levels compared with control
animals treated with saline. Furthermore, insulin increased Bcl-
2-mediated hepatocyte proliferation and decreased hepatocyte
apoptosis (lower caspase-3 and -9 expression) along with
improving liver morphology (62). Another study on severely
burned rats showed that insulin improved mitochondrial state-3
respiration, resulting in reduced hepatic apoptosis (63).
Insulin treatment for septic patients
The initial metabolic response to sepsis is closely related
to endocrine changes. Previous studies have suggested that
both the concentration and secretion pattern of hormones are
deregulated during sepsis (49, 50).
During the early hyper-glycemic phase of sepsis, there is an
intensive release of cortisol, epinephrine, and glucagon (50,
64). In rats undergoing CLP, after 2 h of hyper-glycemia, there
is increased uptake of glucose by the skeletal and heart muscles,
which was due to increased insulin release. Six and 24 h after
CLP, there was sustained glucose uptake by the liver, lung, and
spleen. Glucose uptake by the kidneys and adipose tissue
decreased only 6 and 24 h after CLP, respectively (65). There-
fore, the uptake of glucose by different tissues is an attempt to
keep glycemia under control, mainly during the initial phases
of sepsis.
The use of glucometers has become common in hospitals due
to their ease of use, availability, and ability to provide rapid
results. However, this is a limited test, and many devices are not
accurate enough to be applied to critically ill patients. Con-
tinuous glucose sensors have been developed to measure
glucose concentrations; however, intravascular devices remain
in preclinical and limited clinical testing. The measurement of
blood glucose levels using a precise arterial blood gas instru-
ment is recommended before starting intensive insulin therapy.
It is important to mention that lower hematocrit values gener-
ally result in overestimation of blood glucose levels, potentially
masking hypo-glycemia. In this regard, clinicians should use
caution with the interpretation of hyper- or hypo-glycemia
in septic patients who have recently received intensive fluid
therapy (66, 67).
According to published protocols, intervention should be
taken if blood glucose levels are below 70 mg/dL (3.9 mmol/L,
hypo-glycemia) or above 180 mg/dL (10 mmol/L, hypergly-
cemia). In case of hypoglycemia, an intravenous dose of 15 g to
20 g dextrose has been recommended by the American Diabetes
Association, with instructions to measure the blood glucose
level in 5 to 15 min and repeat as needed. In hyper-glycemic
patients, insulin treatment should be initiated with 0.5 to
1 U/mL diluted in Ringer or 0.9% sodium chloride solution.
Intravenous insulin infusion is preferred for patients with T1D
who are hemodynamically unstable, patients with hypergly-
cemia, and patients in whom long-acting basal insulin should
not be initiated due to a change in clinical status (hypothermia,
edema, frequent interruption of dextrose intake, etc.). Subcu-
taneous insulin regimens with basal and rapid-acting insulin are
frequently initiated after the stabilization of blood glucose
levels with intravenous insulin (68, 69).
SHOCK MARCH 2017
In addition to the control of hyperglycemia, insulin admin-
istration during the early phases of sepsis allows better control
of the serum levels of other counter-regulatory hormones
(cortisol, glucagon, growth hormone, and catecholamines).
When taken in advance, insulin also prevents a condition of
insulin resistance, the main characteristic of T2D (70). Indeed,
patients with sepsis and hyperglycemia who were not diag-
nosed with DM before or during hospitalization should be
considered a population at increased risk of developing T2D.
A recent study evaluating 276 septic patients showed that 15%
of them developed T2D, with a relative risk of 1.89 for patients
with normal glycemia and 4.89 for hyperglycemic patients
when they were in septic state (71).
Disturbances in the adaptive immune response during
DM and sepsis
Unlike the impaired neutrophil function described above for
T1D, which implies an impaired innate immune response, there
are studies that also demonstrate enhanced lymphocyte acti-
vation and overwhelmed adaptive immune response during
both T1D and T2D (72, 73).
Soluble cytotoxic T lymphocyte-associated protein 4
(sCTLA-4) can act as a competitor of CD28, which binds to
the costimulatory molecules CD80 or CD86. However, sCTLA-
4 blocks T-lymphocyte activation, which is the opposite effect
of that obtained with sCD28 or membrane-bound CD28. The
plasma concentration of sCTLA-4 was significantly lower,
whereas the sCD28 level was significantly higher in patients
with T2D compared with control subjects, which could explain
the increased T-cell activation observed in T2D subjects (73).
Diabetic patients or mice have higher plasma concentrations
of inflammatory cytokines and enhanced activation of tran-
scription factors associated with different subtypes of T helper
(Th) lymphocytes (72). The adaptive immune response during
DM is directed by at least four different types of effector CD4þ
T helper (Th) cells, named Th1, Th2, Th17, and regulatory T
cells (Treg). Each phenotype orchestrates a particular response
through the production of a distinct array of cytokines and
inflammatory mediators (Fig. 2).
Th1 cells produce interferon (IFN)-g and IL-12, which
induces iNOS expression and stimulates the generation of
NO by M1 macrophages. Subsequently, NO can react with
superoxide (produced by NADPH oxidase 2), generating per-
oxynitrite (ONOO), which might result in nitrosative damage
of pancreatic cells. Th2 cells produce IL-4, IL-5, and IL-13,
which have anti-inflammatory properties, probably by media-
ting the conversion of M1 macrophages to the M2 phenotype.
This latter type of macrophages expresses lower levels of iNOS
and increased levels of arginase, which produces urea from L-
arginine, preventing NO synthesis, and possibly pancreatic b-
cell injury. Th17 cells release IL-17A and IL-17F, which recruit
neutrophils into pancreatic tissue. This neutrophil infiltration is
followed by the significant generation of ROS and RNS,
contributing, therefore, to cellular damage. Treg cells produce
soluble suppressive mediators, such as IL-10, and control the
activation and proliferation of other subtypes of CD4þ T cells
by direct contact. In addition, Treg cells also stimulate fibro-
blast proliferation, leading to the deposition of extracellular
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
DIABETES MELLITUS AND SEPSIS ASSOCIATION 281
matrix and type I collagen into the pancreas, which results in
aggravated insulin deficiency in the late phases of DM (72).
Although cytokines derived from all subtypes of CD4þ T
cells can be detected in the serum of diabetic patients (72), there
seems to be a sequential pattern of response during the course of
DM pathogenesis. During the initial phase of T1D, there are an
increased number of Th17 cells in the spleen and in the
pancreatic draining lymph nodes (PLNs). IL-17A is essential
for the induction of DM: animals that do not express the IL-17
receptor (IL17RA/) have blunted T1D progression, with
reduced peri-insulitis and better preservation of insulin-pro-
ducing b-cells compared with WT mice. On the other hand, at a
later phase of T1D development, there is an increase in the
absolute number of Treg IL-10þ cells in the PLNs, which was
associated with increased control of the inflammatory process
(74–76).
Recently, our group showed the role of mast cells in the
modulation of the adaptive immune response in mice with T1D.
Mast cell-deficient mice developed severe insulitis and showed
accelerated hyperglycemia compared with controls; these
changes were associated with a decreased number of Treg
cells and a significant increase in the number of Th17 cells
in PLNs (77).
We also studied the role of the nucleotide-binding oligome-
rization domain-containing protein 2 (NOD2) in governing the
CD4þ T cell-mediated adaptive immune response in the patho-
genesis of T1D. NOD2-, but not NOD1-, deficient mice exhibit
lower susceptibility to STZ-induced T1D, which was attributed
to a lower number of Th1 and Th17 cells in the PLNs compared
with WT mice. Furthermore, it was shown that WT mice
depleted of the gut microbiota have a response to T1D induc-
tion that is similar to that of NOD2-deficient mice, and this was
abolished by treatment with the NOD2 agonist muramyl dipep-
tide (MDP). Therefore, bacterial products from the bowel were
associated with NOD2 activation, favoring T1D development
via an increase in the number of Th1 and Th17 cells in the PLNs
(76).
In addition to taking part in the pathogenesis of DM, Th17
and Tregs also participate in sepsis. Peripheral blood mono-
nuclear cells purified from the blood of septic patients and
stimulated with PMA showed greater differentiation to Th17
cells than cells from healthy volunteers (78). Our laboratory
showed that IL-17 is essential for controlling infection during
sepsis. Indeed, IL17RA/ mice subjected to non-severe CLP
showed impaired neutrophil recruitment to the site of infection,
a higher bacterial load in the blood, increased systemic inflam-
matory responses and a higher rate of multi-organ failure
compared with WT mice (79). Regarding the role of Tregs
in sepsis, our group and others have showed an increased
number of Treg cells in the spleen, lymph nodes and thymus
until 15 days after CLP; this effect was associated with a
reduction in the proliferation of CD4þ T effector cells. We
showed that these Tregs could have an essential role in the
induction of immunodeficiency post-sepsis. Indeed, mice sur-
viving CLP died after non-lethal Legionella pneumophila
infection, which was not observed in sham mice (80).
The enhanced levels of IL-17 in the serum during the early
phases of DM should be carefully evaluated with regard to its
282 SHOCK VOL. 47, No. 3 TREVELIN ET AL.

FIG. 2. Adaptive immune response profile during diabetes mellitus. CD4þ T cells that produce interferon (IFN)-g and interleukin (IL)-12 are classified as
Th1 cells. This phenotype is mainly characterized by the induction of the nitric oxide synthase enzyme (iNOS) and the generation of nitric oxide (NO) by M1
macrophages. Th2 cells produce IL-4, IL-5, and IL-13, which have anti-inflammatory properties, by mediating the conversion of M1 macrophages to the M2
phenotype. Th17 cells produce IL-17A and IL17-F, leading to the recruitment of neutrophils into the pancreas. Regulatory T (Treg) cells produce IL-10, which
controls the proliferation of other subtypes of CD4þ T cells. Treg cells also favor fibroblast proliferation, which results in the deposition of extracellular matrix and
type I collagen into pancreatic tissue, aggravating insulin-producing b-cell dysfunction.

relationship with sepsis outcome. Since IL-17 can attract
neutrophils by working as a chemotactic agent and can enhance
neutrophil activation, higher IL-17 concentrations at the focus
of infection would be beneficial during sepsis. However, high
systemic levels of IL-17, which occurs during DM, do not
improve sepsis outcome. In fact, our studies in T1D mice
subjected to CLP clearly showed that T1D impairs neutrophil
recruitment to the infection site and not the opposite. Moreover,
IL-17A should not be considered as an isolated mediator
because there are many factors involved in the failure of
neutrophil migration during sepsis associated with DM, such
as an increased number of mast cells in the peritoneal cavity,
H2R activation on blood circulating neutrophils and increased
levels of AGP in the serum (11, 12). With regard to Tregs, their
higher numbers in the later phases of DM might contribute to
post-sepsis immunodeficiency. However, more experimental
evidence is required to shed light on this matter.
IL-6 signaling in T2D and sepsis
Several studies have shown that the occurrence of chronic
low-grade inflammation in obese subjects contributes to
insulin resistance and, consequently, to T2D onset (81–83).
Patients with T2D exhibit the infiltration of inflammatory cells
such as macrophages, T cells, B cells, and neutrophils into
adipose tissue (81). Adipose tissue in obese subjects is also
characterized by increased infiltration of M1 macrophages
(pro-inflammatory phenotype) rather than M2 macrophage
(anti-inflammatory phenotype) (83).
A recent study has demonstrated that expression of the
receptor for IL-6 on myeloid cells (neutrophils and macro-
phages) prevents obesity-induced insulin resistance. According
to the authors, IL-6 augmented the response of macrophages to
IL-4, favoring the switch to M2 type. In mice with conditional
inactivation of the Il6ra gene in myeloid cells, there is a higher
propensity to develop obesity-induced inflammation and
glucose intolerance (84). Interestingly, T2D rats showed a
2.68-fold increase in IL-6 plasma levels relative to non-diabetic
controls 20 h after CLP (9). Perhaps the increased synthesis of
IL-6 during sepsis in T2D mice is a compensatory response to
insulin resistance and increased M1 macrophage infiltration
into the adipose tissue.
Serum IL-6 levels also play a role in sepsis pathogenesis/
outcome, as this cytokine determines the phenotypic switch in
macrophages. Indeed, endotoxemic mice that received IL-6,

Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
SHOCK MARCH 2017
had lower iNOS, TNF-a, and IL-12 expression compared with
WT controls after LPS injection (84). It is well established that
M2 macrophages are more prone to synthesize urea from
arginine instead of NO. Furthermore, reduced NO release could
result in lower nitrosative stress in the heart. A previous study
from our group has demonstrated significant myocytolysis and
tumefaction of cardiac myocells as well as reduced myosin and
actin density after severe CLP-induced sepsis. These changes
were associated with the increased presence of 4-(hydroxyl-2-
nonenal)-modified protein, a marker of ONOO production, in
the myocardium of septic mice compared with sham mice (85).
However, the association among IL-6, M2 macrophages, lower
NO levels, and improvement in sepsis survival should be taken
carefully. Our laboratory has reported that NO has a dual role in
sepsis: it impairs neutrophil migration to the focus of infection
and is also essential to control the growth of microorganisms
when released inside phagosomes (42, 43, 86). Benjamin and
colleagues observed that low doses of iNOS inhibitors improve
sepsis outcome by increasing neutrophil recruitment to the site
of infection. In contrast, mice treated with high doses of the
same drugs or those deficient in iNOS presented higher
mortality rates associated with impaired killing ability and
higher bacterial load in the blood (86).
Altogether, we can conclude that T2D has a particular
phenotype with respect to IL-6 release during sepsis. However,
more studies using animal models are necessary to confirm if
T2D favors or impairs sepsis outcome.
Clinical studies involving diabetic patients with sepsis
Some studies evaluating sepsis in humans and correlating its
outcome with the occurrence of T1D or T2D have demonstrated
interesting results. In a retrospective study, Kuperman et al.
(87) evaluated 845 patients and observed that those surviving
sepsis had a higher average body mass index (BMI) than non-
survivors (27.6 vs. 26.3 kg/m2, P ¼ 0.03). The authors also
showed that T2D-affected patients had a higher BMI and
decreased mortality due to sepsis (odds ratio of 0.53).
Esper et al. (88), who evaluated 12.5 million hospitalizations
due to sepsis (data collected from the National Center for
Health Statistics of the United States from 1979 to 2003),
showed that 17% of these patients had DM. These patients were
less likely to develop acute respiratory failure (9% vs. 14%,
P <0.05) and hematological dysfunction (1.6% vs. 3.1%,
P <0.05) than non-diabetic septic patients. Although Esper
et al. did not discriminate between patients with T1D and
patients with T2D, they considered leptin, a hormone highly
elevated in obese humans with T2D, as one possible mediator
involved in protection during sepsis. Indeed, leptin knockout
mice exposed to a septic stimulus showed increased serum
levels of TNF-a and increased mortality rates compared with
WT controls (89, 90). Additionally, a recent study demon-
strated that leptin deficiency triggers a cascade of neuroendo-
crine events that involve the hypothalamic-pituitary-adrenal
axis and result in hyper-glycemia and ketoacidosis, which
could aggravate sepsis (91).
Drugs such as antidiabetic agents may also contribute to the
higher sepsis survival rates in patients with T2D. In a preclin-
ical study, rosiglitazone, a potent agonist of peroxisome
Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
DIABETES MELLITUS AND SEPSIS ASSOCIATION 283
proliferator-activated receptor-gamma (PPARg) used to treat
patients with T2D, was found to exert both in vitro and in vivo
anti-inflammatory effects that reduced endotoxin-induced
acute lung injury in rats (92). A study from our laboratory
showed that treatment with the PPARg agonist pioglitazone
resulted in lower STAT1-dependent MyD88 expression and
increased IL-10 levels in the serum, which reduced systemic
inflammation after CLP. The PPARg agonist also increased
neutrophil recruitment to the infection foci, resulting in lower
bacterial loads in the blood (93). Additionally, PPARg has also
been associated with induction of fibroblast growth factor 21
(FGF21). FGF21 is a key regulator of glucose and lipid
metabolism, and its plasma levels have been shown to be
increased in humans with a variety of conditions, such as
T2D, obesity, and nonalcoholic fatty liver disease (94).
FGF21 levels were significantly higher in plasma obtained
from patients with sepsis than healthy controls. According to
this study, FGF21 could be used as a serum marker to identify
septic patients, but its implication in human sepsis outcome
should be better investigated (95). Feingold et al. (96) showed
that mice treated with FGF21 after CLP showed a 10% to 20%
higher survival rate than mice treated with vehicle.
The quality of food in the diet can also determine the sepsis
outcome in patients with DM. Diabetic patients including
prebiotics in their diet may have reduced sepsis-related inflam-
mation, endotoxemia, and cytokine levels in the serum com-
pared with normoglycemic subjects. The administration of
prebiotics such as fermentable dietary fibers promotes the
expression of glucagon-like peptide 1 and peptide YY (ano-
rexigenic) and decreases the expression of ghrelin (orexigenic).
In four prospective 21-day intervention studies on patients with
T2D carried out in Cuba (n ¼ 65), Italy (n ¼ 24), Ghana
(n ¼ 23), and China (n ¼ 16), the effect of the macrobiotic
compound Ma-Pi 2 (conceived by Mario Pianesi) in the diet
was investigated. All four studies suggested that prebiotic
treatment caused a significant improvement in fasting blood
glucose levels, plasma lipid fractions, and plasma insulin levels
and helped in maintaining body homeostasis (97–101).
Actually, the influence of diet was previously linked to both
T2D and T1D. Studies reviewed by Piya et al. (102) showed
that diet affects the development of gut microbiota, and this is a
determinant in the pathogenesis of inflammatory-induced
obesity and T2D. In addition, we have shown that the depletion
of gut flora with antibiotics reduced susceptibility to STZ-
induced T1D (76).
Confirming that changes in diet could affect inflammation,
mice fed a high-fat diet (HFD) and genetically obese mice have
increased mortality as a result of S aureus-induced sepsis com-
pared with low-fat diet (LFD)-fed controls. The lower survival
rates were associated with a higher bacterial load and systemic
inflammation in HFD-fed mice (103). On the other hand, mice
fed a HFD rich in omega-3, and omega-6 fatty acids had higher
survival rates and a lower bacterial load than LFD-fed controls
after S aureus-induced sepsis (104, 105). Therefore, not only the
ingestion of fat but also the quality of the lipids in the diet can
determine sepsis outcome in patients with DM.
In contrast to Kuperman et al. (87) and to Esper et al. (88),
Chang et al. (106) suggested that diabetic patients have neither
284 SHOCK VOL. 47, No. 3 TREVELIN ET AL.

FIG. 3. Scheme depicting the immune response of patients with diabetes mellitus during sepsis. During early sepsis, patients with T1D have defective
neutrophil functions (chemotaxis, phagocytosis, and killing), resulting in impaired bacterial control at the site of infection, bacteremia and a poor sepsis outcome.
The synthesis hepatic of a-1 glycoprotein acid (AGP) and its deposition on endothelial cells increases the glycocalyx layer over ICAM-1 adhesion molecules, which
contributes to lower neutrophil recruitment to infection foci during sepsis (1). The failure in neutrophil migration to the site of infection was also attributed to an
increased number of mast cells and histamine activation of H2R, which leads to CXCR2 internalization through GRK2 (2). On the other hand, patients with T2D
seem to have a better sepsis prognosis due to several reasons: diets rich in unsaturated fat (3), the use of prebiotics, higher levels of leptin (4), and the use of
PPARg agonists (5). Diets rich in polyunsaturated fatty acids and/or prebiotics enhance sepsis survival, while the intake of saturated fatty acids aggravates the
systemic inflammatory response and bacteremia (3). Leptin seems to be beneficial during sepsis by preventing acute lung injury (4). The T2D insulin-resistance
treatment that targets PPARg activation results in greater levels of fibroblast growth factor (FGF)-21 and higher neutrophil migration ability (5). In late sepsis, there
are greater numbers of regulatory T cells in DM patients, which could favor immunosuppression after sepsis. Additionally, the lack of control of glycemia in early
sepsis is associated with insulin resistance and T2D development in late sepsis. DM indicates diabetes mellitus; H2R, histamine receptor 2; ICAM-1, intracellular
molecule adhesion 1; PPARg, peroxisome proliferator-activated receptor gamma; T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus.

a greater risk nor a lesser risk of complications than non-
diabetic patients. This study evaluated 16,497 subjects with
severe sepsis who had been enrolled in the Taiwan National
Health Insurance program from 1995 to 2008 without classi-
fication according to the type of DM. Despite better lung
function, diabetic patients experiencing sepsis had a higher
risk of developing acute kidney injury and were more likely to
be undergoing hemodialysis in the intensive care units (15.55%
vs. 7.24%; DM patients [n ¼ 4,573] versus non-diabetic sub-
jects with sepsis [n ¼ 11,924]).
The discrepancies in clinical studies of patients with DM
noted here could be due to the lack of stratification of patients
into T1D and T2D or different sepsis etiology (e.g., pneumonia,
bloodstream infection, urinary infection), as well as the distinct
glycemic levels of patients and drug administration regimens
used to control blood glucose levels. Additionally, considering
the septic condition, we should be aware of gravity scores when
evaluating if diabetes increases or has no effect on mortality
rates. Indeed, more studies evaluating different responses to
sepsis in patients with T1D and T2D are required to better
design treatment regimens in intensive care units. Considering
the septic condition, we should exercise caution when using the
gravity scores to evaluate if DM increases or decreases
mortality rates. The APACHE II score could overestimate
the diabetes/sepsis correlation because it already includes
hyperglycemia and chronic diseases (in the case of T1D or
T2D) in its grade. The SOFA score, which assesses the severity
of organ failure, would be more appropriate (107).
CONCLUDING REMARKS
DM is a common comorbidity in septic patients. Several
studies have shown that T1D in humans and experimental
animal models is associated with many deficiencies in the
innate immune response, making these patients prone to infec-
tions and sepsis. Impairments in the innate immune response

Copyright © 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
SHOCK MARCH 2017
occur both dependently and independently of glycemic control.
These changes in innate immunity occur mainly in neutrophils,
which can exhibit impaired migration, phagocytosis, and ROS
production during the course of T1D. Additionally, patients
with T1D have increased numbers of Th17 and Treg cells, and
the roles of these cells in sepsis associated with DM should be
better explored in the future. In contrast to the well-character-
ized response exhibited by patients with T1D during sepsis, we
still require better understanding of the association between
T2D and sepsis. T2D is correlated with increased levels of
leptin, which favors the control of inflammation. The treatment
utilized in patients with T2D also favors a better sepsis prog-
nosis. PPARg agonists increase neutrophil migration, enhance
transcription of FGF21, and, as a consequence, improve sepsis
outcome (Fig. 3). Because the sepsis mortality rates are still
high and this illness is frequent in diabetic patients, the devel-
opment of new treatments specifically for this population is
required. Understanding sepsis pathophysiology in T1D or T2D
is crucial for addressing this last issue, and animal models have
revealed some targets, such as H2R and AGP, for T1D. These
potential targets should be better explored in clinical studies to
determine their potential benefits to humans.
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