Downregulation of IL-22 can be considered as a risk factor for onset of type 2 diabetes: ASADIKARAM et al.

Abstract

There is some controversy as for the roles played by tumor growth factor‐β (TGF‐β), interleukin‐1β (IL‐1β), and IL‐22 in the onset process of type 2 diabetes (T2D). The main aim of this project was to examine serum levels of TGF‐β, IL‐1β, and IL‐22 in the new cases and long period T2D patients as well as healthy controls. In this study, 115 new T2D patient cases (group 1), 434 T2D patients who have suffered from the disease more than 2 years (group 2), and 104 healthy controls have been selected from 6240 (3619 females) patients who were under study population from Kerman Coronary Artery Disease Risk Factor Study. Serum levels of TGF‐β, IL‐1β, and IL‐22 have been evaluated using commercial kits. Serum levels of TGF‐β and IL‐1β significantly increased, while IL‐22 decreased in 2 groups in comparison to healthy controls. Serum levels of IL‐22, but not TGF‐β and IL‐1β, were significantly decreased in group 1 in comparison to healthy controls. There were no significant differences between groups 1 and 2 as for the cytokine levels. Serum levels of IL‐22 increased in the females in group 2 when compared to females in group 1. It appears that TGF‐β and IL‐1β participate in the induction of inflammation after establishment of T2D, while decrease in IL‐22 may be considered as a key factor for onset of the disease. Gender can also be considered as the main risk factor for variation in cytokine levels.

Full text

Received: 12 March 2018
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Accepted: 24 May 2018
DOI: 10.1002/jcb.27194
RESEARCH ARTICLE
Downregulation of IL‐22 can be considered as a risk factor
for onset of type 2 diabetes
Gholamreza Asadikaram
1,2
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Hamed Akbari
2,3
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Zohreh Safi
4
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Mitra Shadkam
4
|
Mohammad Khaksari
4,5
|
Nader Shahrokhi
4,5
|
Hamid Najafipour
4,5
|
Mojgan Sanjari
1
|
Mohammad Kazemi Arababadi
6,7
1
Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences,
Kerman, Iran
2
Department of Biochemistry, Afzalipur Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
3
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
4
Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
5
Department of Physiology, Afzalipur Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
6
Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
7
Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
Correspondence
Gholamreza Asadikaram, Endocrinology
and Metabolism Research Center,
Institute of Basic and Clinical Physiology
Sciences, Kerman University of Medical
Sciences, Kerman 7616914115, Iran.
Email: gh_asadi@kmu.ac.ir;
Mohammad Kazemi Arababadi,
Immunology of Infectious Diseases
Research Center, Rafsanjan University of
Medical Sciences, Rafsanjan 7719617996,
Iran.
Email: dr.kazemi@rums.ac.ir
Funding information
Kerman University of Medical Sciences
Abstract
There is some controversy as for the roles played by tumor growth factor‐β
(TGF‐β), interleukin‐1β(IL‐1β), and IL‐22 in the onset process of type 2 diabetes
(T2D). The main aim of this project was to examine serum levels of TGF‐β,
IL‐1β, and IL‐22 in the new cases and long period T2D patients as well as
healthy controls. In this study, 115 new T2D patient cases (group 1), 434 T2D
patients who have suffered from the disease more than 2 years (group 2), and
104 healthy controls have been selected from 6240 (3619 females) patients who
were under study population from Kerman Coronary Artery Disease Risk
Factor Study. Serum levels of TGF‐β,IL‐1β, and IL‐22 have been evaluated
using commercial kits. Serum levels of TGF‐βand IL‐1βsignificantly increased,
while IL‐22 decreased in 2 groups in comparison to healthy controls. Serum
levels of IL‐22, but not TGF‐βand IL‐1β, were significantly decreased in group 1
in comparison to healthy controls. There were no significant differences
between groups 1 and 2 as for the cytokine levels. Serum levels of IL‐22
increased in the females in group 2 when compared to females in group 1. It
appears that TGF‐βand IL‐1βparticipate in the induction of inflammation after
establishment of T2D, while decrease in IL‐22 may be considered as a key factor
for onset of the disease. Gender can also be considered as the main risk factor
for variation in cytokine levels.
KEYWORDS
IL‐1β,IL‐22, TGF‐β, type 2 diabetes
J Cell Biochem. 2018;1‐7. wileyonlinelibrary.com/journal/jcb © 2018 Wiley Periodicals, Inc.
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1

1
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INTRODUCTION
It has been hypothesized that cytokines play crucial roles in
the onset, inhibition and pathogenesis of type 2 diabetes
(T2D).
1
The pro‐inflammatory and anti‐inflammatory cyto-
kines are the immune system–related molecules which may
participate in the pathogenesis of T2D.
2
However, cytokines
can interfere with several intracellular signaling pathways
and also organelles such as mitochondria which play
important roles during T2D.
3
Recently, it has been reported
that interleukin‐22 (IL‐22), IL‐1β, and tumor growth factor‐β
(TGF‐β) can play controversial roles in the pathogenesis of
T2D.
4-9
Accordingly, Kolumam et al
10
reported that IL‐22
plays key roles in the improvement of mucosal immunity
and its chronic inflammation. IL‐22 also increases insulin
sensitivity and lipid metabolisms in the fat mice.
10
Interest-
ingly, it has been documented that IL‐22 administration to
the diabetic animal models leads to decrease in endoplasmic
reticulum and oxidative stresses, which are the main
pancreas damage inducers and finally decrease blood
glucose.
11
Intraperitoneum administration of IL‐22 can also
decrease glucose resistance in animal models.
12
In contrast
to the aforementioned investigations, Guo et al
13
demon-
strated that serum levels and numbers of IL‐22 and its
corresponded lymphocytes (Th22), respectively, are in-
creased in the new incidence cases of T2D patients. Based
on the aforementioned investigations it has been hypothe-
sized that IL‐22 may play key roles in protection from T2D
and the increase in its expressionatthestartofthedisease
may be a normal immune response to avoid T2D incidence.
But its roles in the developed T2D have yet to be clarified.
Additionally, there are controversial reports as for the
roles of IL‐1βand TGF‐βin the pathogenesis of T2D. It
has been reported that TGF‐βis a cytokine with anti‐and
proinflammatory characteristic.
14
TGF‐βalone and in
association with IL‐6 participates in the development of
IL‐17A and T regulatory lymphocytes, respectively.
14
Both protective and inducer roles of IL‐1βand TGF‐βin
the pathogenesis of T2D have been demonstrated
previously.
4,6,15-17
Thus, some controversies exist as for the roles played
by IL‐22, IL‐1β, and TGF‐βin the pathogenesis of T2D.
Accordingly, the main aim of this study was to determine
the serum levels of IL‐22, IL‐1β, and TGF‐βin the healthy
controls, new T2D patients and T2D patients who suffer
from the disease more than 2 years.
2
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MATERIALS AND METHODS
2.1
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Subjects
In the current study concentrations of TGF‐β,IL‐1β, and
IL‐22 were determined in 115 of the new T2D patient
cases with less than 1‐year diabetes history (group 1), 434
of T2D patients who suffered from the disease more than
2 years (group 2), and 104 healthy control individuals.
Fasting blood sugar (FBS) more than 126 mg/dL was
considered as diabetic, cholesterol, and triglycerides (TG)
values more than 200 mg/dL were considered as over
normal values.
This convenience sampling study was carried out on a
subpopulation of a larger study which focused on the risk
factors of coronary artery diseases (CAD; i.e., Kerman
Coronary Artery Disease Risk Factor Study [KERCADRS]),
that was performed on 5895 (3238 female) subjects ranging
between 15 and 75 years of age in 2010‐2011 and in the
second phase on 6240 (3619 females) people ranging
between 15 and 80 years of age in 2015‐2016 on urban
population in Kerman. Kerman is the largest city in the
southeast of Iran with a population of about 750 000. More
details about the city conditions and sampling and data
collection methods have been previously published at
IJPH.
18
The study was approved by the Ethics Committee
of the Kerman University of Medical Sciences (ethic code IR.
KMU.REC.1394.147). All participants signed a written
informed consent document prior to entering the project.
Briefly, 1 stage cluster sampling method was used for
subject selection. 12 773 subjects (6205 individuals in phase 1
and 6568 individuals in phase 2 of the study) were invited to
participate in the project, of which about 95% responded to
the invitation. They were referred to the clinical study site
located in the downtown area of the city where they went
through several steps of face to face interviews to disclose
their demographic characteristics and past medical history.
After 12 to 14 hours fasting, 10 mL of intravenous blood was
collected both in tubes containing EDTA (1 mg/mL blood)
and in tubes without anticoagulant and centrifuged at
2500 rpm for 5 minutes. Plasma and serum were separated
and aliquoted, and some parts were sent to the clinical
laboratory and the rest were immediately stored at −70°C for
further investigations.
Additionally, to determine the effects of treatment with
chemical drugs on the serum levels of TGF‐β,IL‐1β,and
IL‐22, the patients in each group were categorized to patients
who were administrated with antidiabetic, antidiabetic/
hypertension, antidiabetic/hypertension/dyslipidemia, anti-
diabetic/hypertension/dislipidemia/cardiovascular disease
(CVD), antidiabetic/hypertension/CVD, antidiabetic/CVD,
antidiabetic/dislipedmia, and anti‐CVD/hypertension/dislipi-
demia drugs as well as the patients without treatment with
the medications.
2.2
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Measurement of biochemical factors
Some biochemical factors such as FBS, cholesterol,
TG, low‐density lipoprotein (LDL), high‐density
2
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ASADIKARAM ET AL.

lipoprotein (HDL), and HbA1c were measured using
commercial kits (Kimia Kits, Kimia Co, Tehran, Iran),
by an autoanalyzer ( Hitachi 902, Roche, Basel,
Switzerland) in a standard laboratory setting.
2.3
|
Blood pressure measurement
Blood pressure was measured with standard manometer
(Rishter mercury manometer, RishterCo, Berlin, Germany)
in sitting position after at least 10 minutes at rest, if
abnormal it was measured once again about 1 hour after
the first time. Hypertension was defined as having systolic
blood pressure more than 140 mm Hg and diastolic blood
pressure more than 90 mm Hg or participants who
consumed any kind of antihypertensive drugs.
19
2.4
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Cytokine assay
Serum levels of TGF‐β,IL‐1β, and IL‐22 were evaluated
using commercial kits from R&D System Company
(R&D, Minneapolis, MN).
2.5
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Statistical analysis
The differences among groups as for serum levels of TGF‐β,
IL‐1β,IL‐22,FBS,TG,cholesterol,LDL,andHDLwere
calculated using one‐way analysis of variance followed by
Tukey multiple comparisons test. Differences of HbA1c as
well as serum levels of the variables between male and
female patients have been analyzed using independent
Student ttest. Correlations between the variables have been
ASADIKARAM ET AL.
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3
FIGURE 1 Serum levels of TGF‐β,IL‐1β, and IL‐22 in the patients suffering from type 2 diabetes lower than 1 year (group 1) and higher
than 2 years (group 2) and healthy controls. The results showed that serum levels of TGF‐βand IL‐1βsignificantly increased in the group 2
when compared to the group 1 and healthy controls. Serum levels of TGF‐βwere not different between group 1 and healthy controls,
while serum levels of IL‐1βsignificantly increased in groups 1 and 2 in comparison to controls without differences between groups 1 and 2.
IL‐22 significantly decreased in groups 1 and 2 in comparison to healthy controls. The serum levels of IL‐22 were not different between 2
diabetic groups

evaluated using Pearson correlation of coefficient (r). Data
are presented as mean ± standard error of mean.
3
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RESULTS
Serum levels of FBS (P< .001), TG (P< .001), and HbA1c
(P= .008) were significantly different among groups.
Accordingly, serum levels of FBS were 152.39 ± 2.97,
125.74 ± 4.43, and 91.00 ± 1.01 pg/mL in group 2, group 1,
and healthy controls, respectively. Serum levels of TG also
increased in group 1 (178.35 ± 9.08) and group 2
(172.72 ± 4.19) in comparison to healthy controls
(120.76 ± 5.05). Also, HbA1c increased in group 2 (7.54 ±
0.23) when compared to group 1 (8.28 ± 0.11). Serum levels
of cholesterol (P= .848), HDL (P= .543), and LDL
(P= .065) as well as age (P= .127) did not differ among
groups.
The results revealed that serum levels of TGF‐β
(P< .001), IL‐1β(P< .001), and IL‐22 (P= .001) were
significantly different among groups.
As it is illustrated in Figure 1, serum levels of TGF‐β
significantly increased in group 2 (688.01 ± 4.28) when
compared to group 1 (668.89 ± 5.71; P= .040) and healthy
4
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ASADIKARAM ET AL.
FIGURE 2 Serum levels of TGF‐β,IL‐1β, and IL‐22 in the male and female of the patients suffering from type 2 diabetes lower than
1 year (group 1) and higher than 2 years (group 2). The results showed that serum levels of TGF‐βsignificantly increased in male
patients when compared to female patients within group 1, while serum levels of IL‐1βand IL‐22 were not differ between male and female
patients within group 1. Serum levels of TGF‐β,IL‐1β, and IL‐22 were also not different between male and female patients in group 2.
Serum levels of TGF‐βand IL‐22, but not IL‐1β, significantly increased in female within group 1 when compared to female within group 2.
Serum levels of TGF‐β,IL‐1β, and IL‐22 were also not different between female patients in group 1 in comparison to group 2

controls (659.24 ± 4.59; P< .001). Serum levels of TGF‐β
were not different between group 1 and healthy controls
(P= .414).
Serum levels of IL‐1βsignificantly increased in group 1
(20.11 ± 0.43; P= .020) and group 2 (21.31 ± 0.24; P< .001)
in comparison to controls (18.74 ± 0.31). The differences
between groups 1 and 2 were not significant (P= .056).
Serum levels of IL‐22 significantly decreased in group 1
(172.00 ± 2.04; P< .001) and group 2 (176.49 ± 0.96;
P= .016) in comparison to healthy controls (182.69 ±
1.98). The serum levels of IL‐22 did not differ between
2diabeticgroups(P=.92).
The results also revealed that serum levels of TGF‐β
(P= .938), IL‐1β(P= .604), and IL‐22 (P= .496) were not
significantly different among the patients treated with
antidiabetic, antihypertension, anti‐CVD, and antidysli-
pidemia as well as the treated patients within group 1.
Serum levels of TGF‐β(P= .378), IL‐1β(P= .216), and
IL‐22 (P= .795) were also not different among the
patients treated with antidiabetic, antihypertension,
anti‐CVD, and antidislipidemia as well as the treated
patients within group 2.
By evaluation of group 1 and as for the roles of
gender on expression of TGF‐β,IL‐1β,andIL‐22, it was
revealed that serum levels of TGF‐βsignificantly
increased in male patients (685.87 ± 6.98) when com-
pared to female (660.49 ± 7.69) patients (P= .019).
Serum levels of IL‐1β(P= .854) and IL‐22 (P= .727)
did not differ between male and female patients in
group 1 (Figure 2).
Serum levels of TGF‐β(P= .524), IL‐1β(P= .705), and
IL‐22 (P= .786) were also not different between male and
female patients in group 2 (Figure 2).
Serum levels of TGF‐β(P= .602), IL‐1β(P= .181), and
IL‐22 (P= .470) in males in group 1 were not different
when compared to male in group 2.
However, serum levels of TGF‐β(P= .008) and IL‐22
(P= .040), but not IL‐1β(P= .076), in female in group 2
were significantly increased when compared to female in
group 1 (Figure 2).
Statistical analysis also demonstrated that there were
no correlations among serum levels of TGF‐β,IL‐1β,
IL‐22, age, FBS, TG, cholesterol, LDL, HDL, and HbA1c
within group 1 (Table 1) and group 2 (Table 2).
ASADIKARAM ET AL.
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5
TABLE 1 Correlation among serum levels of cytokines, age, and biochemical variables within group 1
IL‐22 IL‐1βTGF‐βAge FBS Cholesterol TG HDL LDL HA1C
IL‐22
Pearson correlation 1 .185 .117 −.054 −.035 −.101 .054 .032 −.136 −.136
Pvalue .218 .439 .569 .712 .285 .566 .738 .154 .240
IL‐1β
Pearson correlation .185 1 .061 .097 .010 .150 .067 −.143 .167 −.055
Pvalue .218 .688 .527 .947 .326 .663 .350 .283 .727
TGF‐β
Pearson correlation .117 .2061 1 .047 −.151 −.133 .012 −.187 −.105 −.070
Pvalue .439 .688 .760 .322 .385 .938 .218 .505 .660
The table illustrates that there are no correlation among serum levels of cytokines, age, and biochemical variables within group 1.
FBS, fasting blood sugar; HDL, high density lipoprotein; IL‐22, interleukin‐22; LDL, low density lipoprotein; TG, triglycerides; TGF‐β, tumor growth factor‐β.
TABLE 2 Correlation among serum levels of cytokines, age, and biochemical variables within group 2
IL‐22 IL‐1βTGF‐βAge FBS Cholesterol TG HDL LDL HA1C
IL‐22
Pearson correlation 1 .149 .018 .005 −.035 .044 −.076 −.014 .083 −.033
Pvalue .166 .864 .923 .473 .363 .114 .769 .088 .504
IL‐1β
Pearson correlation .149 1 −.030 .097 .054 .034 .015 −.045 .044 −.003
Pvalue .166 .782 .368 .619 .757 .892 .677 .683 .982
TGF‐β
Pearson correlation .018 −.030 1 −.045 .122 −.097 −.054 .017 −.087 .081
Pvalue .864 .782 .678 .256 .366 .616 .873 .420 .461
The table illustrates that there are no correlation among serum levels of cytokines, age, and biochemical variables within group 2.
FBS, fasting blood sugar; HDL, high density lipoprotein; IL‐22, interleukin‐22; LDL, low density lipoprotein; TG, triglycerides; TGF‐β, tumor growth factor‐β.

4
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DISCUSSION
The results showed that serum levels of FBS and TG as
well as HbA1c, significantly increased in group 2 in
comparison to group 1 and in group 1 when compared to
healthy controls. The results not only approved the
diabetes in the patients, but also revealed that the
duration of diabetes results in deterioration of diabetes.
No differences as for age demonstrated that age, as an
interfere factor, was unable to affect serum levels of
TGF‐β,IL‐1β, and IL‐22, as the main evaluated factors.
The results showed that serum levels of TGF‐βand
IL‐1βincreased significantly in group 2 in comparison to
group 1 and healthy controls, while there were not
significant differences between group 1 and healthy
controls. Increased serum levels of TGF‐βand IL‐1βin
the patients who suffered from T2D more than 2 years,
but not in the new cases’patients, demonstrated that
stable diabetes is a main factor which leads to upregula-
tion of the cytokines. TGF‐βplays dual functions from
anti‐inflammatory/tissue repairing to inflammatory prop-
erties.
14
In anti‐inflammatory feature, TGF‐βleads to
development of T regulatory lymphocytes which are the
main cells to inhibit inflammation and suppress inflam-
matory based diseases.
20
However, TGF‐βin association
with IL‐6, an innate immunity inflammatory cytokine, is
a main factor for development of Th17 lymphocytes that
play important roles in the pathogenesis of proinflam-
matory based diseases.
21,22
IL‐1βalso is another proin-
flammatory cytokine which is activated and released
from immune cells following inflammasomes activa-
tions.
23
Inflammasomes are the main inflammatory
molecules whose upregulation during T2D has been
reported previously.
1,24
Based on the fact that T2D is a
proinflammatory based disease and according to the
results, it may be concluded that increased duration of
diabetes leads to upregulation of TGF‐βand IL‐1βand
consequently increased inflammation in the T2D pa-
tients. Interestingly, previous investigations approved the
hypothesis and reported that IL‐17A, the main product of
Th17 cells, is upregulated in the T2D patients.
25,26
Although increased serum levels of TGF‐βand IL‐1β
have been reported previously,
7,27
the current study
demonstrated that new T2D patients did not show
increased serum levels of the cytokines. Thus, it appears
that TGF‐βand IL‐1βare not the inducers of T2D and are
produced secondary in response to stable high FBS.
In contrast to TGF‐βand IL‐1β, results showed that
serum levels of IL‐22 decreased in both T2D groups when
compared to healthy controls, while there were no
differences between 2 T2D groups. Although IL‐22 is a
proinflammatory cytokine, based on the results it seems
that it acts as an antidiabetic cytokine. In contrast to
TGF‐βand IL‐1β, decreased serum levels of IL‐22 in both
new cases and the patients with more than 2 years T2D,
demonstrated that decreased serum levels of IL‐22 may
be considered as a reason for induction of T2D. Previous
investigations revealed that IL‐22 plays key roles in the
improvement of mucosal immunity and its chronic
inflammation,
10
increasing in insulin sensitivity and lipid
metabolisms,
10
decreasing in endoplasmic reticulum and
oxidative stresses and decreasing glucose resistance.
12
Based on our results, it seems that downregulation of
IL‐22 in both new cases and long period patients with
T2D, may be a main reason for induction of inflamma-
tion, decreasing in insulin sensitivity and lipid metabo-
lisms, and increasing in endoplasmic reticulum and
oxidative stresses in the patients suffering from T2D.
Although an investigation reported that either number of
Th22, the main source of IL‐22, or serum levels of IL‐22
increased in the new cases T2D patients,
13
our study was
performed on a large size sample with lowest variation in
the results. Additionally, the ethnicity of our participants
differs when compared to the previous investigations.
Furthermore, our results demonstrated that serum levels
of TGF‐β,IL‐1β, and IL‐22 were not different between
T2D patients in each group with various drug adminis-
trations and age. Thus, it seems that T2D and its duration
are the sole factors which affect expression of the
cytokines in our patients. However, serum levels of
IL‐22 in females in group 2 were significantly increased
when compared to females in group 1. It appears that
gender needs to be considered as an important factor
because the results approved the effects of gender on
expression of TGF‐βtoo.
Collectively, based on the results, it may be hypothe-
sized that TGF‐βand IL‐1βpositively and IL‐22
negatively participates in the onset of T2D and its
complications. However, it seems that more investiga-
tions as for the crucial roles played by the cytokines in
the pathogenesis of T2D, especially the roles of gender,
need to be performed to clarify the main mechanisms
responsible for leading to T2D.
ACKNOWLEDGMENTS
Authors wish to express their sincere thanks to all
patients and controls who helped us to perform the
project. This study was supported by grants from Kerman
University of Medical Sciences. The authors thankfully
acknowledge for support of the dissertation grant.
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
6
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ASADIKARAM ET AL.

AUTHORS’CONTRIBUTIONS
GA, MK, NS, HN, MS, and MKA are responsible for the
conception and design of the study. HA, ZS, and MS,
collected data. GA and MKA contributed to statistical
analysis, interpreted data, and manuscript writing. All
authors approved the final version of the manuscript. GA
takes responsibility for the integrity of the data and the
accuracy of the data analysis.
ORCID
Mohammad Kazemi Arababadi http://orcid.org/0000-
0002-4315-8153
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How to cite this article: Asadikaram G, Akbari
H, Safi Z, et al. Downregulation of IL‐22 can be
considered as a risk factor for onset of type 2
diabetes. J Cell Biochem. 2018;1–7.
https://doi.org/10.1002/jcb.27194
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