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Aim
Elevated
inflammatory cytokines play an emerging role in the diabetogenesis with
metabolic syndrome (Met-S). The production of interleukin-6 (IL-6),
interleukin-17 (IL-17), interleukin-23 (IL-23) seem to be strong association in
patients with type 2 diabetes and Met-S. These components may form a target for
novel treatment approaches.
Methods
This case-control
study investigated 45 patients with metabolic syndrome and onset of type 2
diabetes (male aged 36.92 ± 2.40 years), comprising 45 healthy control (male
aged 37.28 ± 2.05 years). We compared the circulating levels of the serum IL-6,
IL-17, IL-23 and adipokines levels were measured using the ELISA in metabolic
syndrome with onset of Type 2 diabetes mellitus with all clinical settings.
Results
Serum levels of
IL-6, IL-17 and IL-23 were found to be significant difference between serum
levels of IL-6, IL-17 and IL-23 in metabolic syndrome with type 2 diabetic
patients than in healthy subjects (IL-6; 27.53 ± 2.61 vs. 6.07 ± 1.76 pg/ml 𝑃<0.001);
(IL-17; 9.21 ± 0.55 vs. 2.05 ± 0.78 pg/ml 𝑃<
0.001); (IL-23; 3.64 ± 0.34 vs. 1.18 ± 0.02 pg/ml 𝑃<
0.001). Further, serum levels of adiponectin were found significant decreased
and serum level of leptin were found significantly higher in patients with
metabolic syndrome and type 2 diabetes than in healthy subjects (𝑃<
0.001).
Conclusions
Patients with Met-S
had significantly greater serum IL-6, IL-17 and IL-23 levels than the controls,
supporting the evidence that inflammation plays an important role in the
immunopathogenesis of the disease. Additionally, this study clearly
demonstrates that the circulating serum levels of pro-inflammatory cytokines
and adipokines defiantly have strong association in primary mediators of
inflammation in in Met-s patients with type 2 diabetes.
Keywords: IL-6, IL-17, IL-23, Adipokines, Metabolic
syndrome, Onset T2DM
Abbreviations: Met-S: Metabolic syndrome; BMI: Body mass index;
WC: Waist circumference; FBS: Fasting blood sugar; HbA1c: Glycosylated
hemoglobin; CVD: Cardiovascular disease; TC: Total cholesterol; TG:
Triglyceride; LDL: Low density lipoprotein cholesterol; HDL: High density
lipoprotein-cholesterol; VLDL: Very low density lipoprotein; hs-CRP: High
sensitivity C-reactive protein; T2DM: Type 2 diabetes mellitus; NEFA:
Non-esterified fatty acids; IL: Interleukin
INTRODUCTION
Countries [1] in the past two decades, the world has seen a sustained increase in obesity and the levels of overweight and obese persons worldwide have reached epidemic proportions [2]. Metabolic syndrome (Met-S) is a disorder related with an increase in various risk factors [2]. That predisposes an individual to include abdominal obesity, atherogenic dyslipidemia, hypertension, pro-inflammatory, insulin resistance, glucose intolerance and/or type 2 diabetes mellitus, cardiovascular disease and pro-thrombotic state. It has been established that the frequency diabetes mellitus is increasing globally and type 2 diabetes is the most prevalent type of diabetes mellitus [3].
Inflammation is
defined as the local physiological response to tissue injury and regulated by
pro-inflammatory cytokines [4]. Recently, chronic inflammation has received
considerable attention as a very important pathophysiological mechanism in type
2 diabetes mellitus. Inflammatory cytokines have been postulated to be
important pathogenic factors in the development of type 2 DM [4].
Circulating
IL-6 serum levels have been reported to be increased in obese people and in
people with type 2 diabetes mellitus and to correlate with indirect
measurements of adiposity and insulin resistance, such as body mass index,
waist-to-hip ratio and fasting insulin concentrations [5]. However, to our
knowledge, no study has examined the relationship between circulating IL-6
levels and direct measures of adiposity, insulin action and insulin secretion.
Thus, it is unclear whether the association between insulin resistance and
markers of inflammation is independent of metabolic syndrome.
Interleukin-6
is a pleiotropic cytokine with several functions in different tissues.
Initially, interleukin-6 was described as an important factor of the immune
system. However, it has been shown that this cytokine also plays a vital role
in glucose homeostasis, especially on metabolic regulation [6].
Interleukin-17
is a newly identified inflammatory cytokine produced by activated and memory T
lymphocytes. It has pleiotropic activities including the induction of diverse
inflammatory cytokines (e.g. TNF-α and IL-6) and chemokines (e.g. CCL2/MCP- 1,
CXCL1/KC and CXCL2/MIP-2) from a large variety of cells [7]. Interleukin-17
acts as highly potent inflammatory cytokine that initiates tissue inflammation
and induces the infiltration of other inflammatory cells into the target organs
[8].
Increasing
evidence suggests that interleukin-17 plays a crucial role in various
inflammatory responses and autoimmune diseases [9]. Recent studies have shown
that serum elevated Interleukin-17 levels were analyzed in STZ-induced diabetic
animal models and non-obese diabetic mice from insulitis to diabetes [10,11].
However, to date, there are little published data evaluating the role of IL-17
in type 2 DM.
OBJECTIVES
The aim of the
study was to clarify whether serum levels of Ienterleukin-17demonstrate a change
in metabolic syndrome
patients with type 2 diabetes, we compared its concentration in the serum IL-17 in 25 patients with
type 2 diabetes and age-matched healthy controls. Serum concentrations of Ienterleukin-6 and Ienterleukin-23 were also measured
in the same group because development and maintenance of Th17 cells,
as the main source of
Ienterleukin-17, require these two cytokines.
Meanwhile, we evaluate the correlation between serum levels of IL-6, IL-17 and
IL-23 with adipokines and anthropometric measurements involved in metabolic syndrome patients with onset of
type 2diabetes. Our results suggest that IL-17 might be involved in the
pathogenesis of type 2 diabetes as an inflammation cytokine.
RESEARCH
DESIGN AND METHODS
Selection of Met-S patients and controls
A total of 90
subjects, including 45 healthy controls from the Medicine Department at S.P. Medical College
and associated group of P.B.M. Hospitals and 45 in metabolic
syndrome patients with type 2diabetes, were enrolled in the study. The clinical
history and disease status of each participant were taken by a General
Medicine. Metabolic syndrome was diagnosed based on the International Diabetes Federation (IDF) definition [12]. 45 patients with Met-S and onset
of newly confirmed type 2 diabetes age between 25 to 40 years (mean age 36.92 ±
2.40) and exclusively HbA1c (%) level (Mean ± S.D.; 8.12 ± 0.96) were included
in the study. The 45 healthy control subjects aged-matched individuals (45
males with mean age=37.28 ± 2.05 years) were selected as controls healthy based
on lack of prior medical history, lack of prescribed medication use, normal
test results, also not suffering from any chronic illness and signed informed
consent was procured by all the individuals before their inclusion in the
study.
Ethics statement
This study involving humans was approved
by the Developmental Research Committee (DRC) at the Rajasthan University of
Health Sciences, Jaipur, India. The patients involved in this study had signed
an informed consent prior to the start of this study.
Anthropometric measurement
At the time of presentation demographic
details were noted down and complete history was obtained regarding the patients
with metabolic syndrome, type 2 diabetes, hypertension, any inflammatory
disease, joint pains, infections, hyperlipidemias, endocrine disorders and
smoking habits. Drug history was also obtained. The details were noted on a
questionnaire and the patient’s consent was also taken before initialization of
the study.
Measurements of adiposity
Body Mass Index
was calculated according to the formula as the ratio of weight (kg) to the
square of height (m) (kg/m2).Waist circumference was measured at the
slimmest point using a flexible tape with average of two measurements taken
after subject inspiration and after expiration (mean between the two
measurements @1.5cm) at the midpoint between the
lowest rib and the iliac crest. Waist-hip ratio (WHR) defined as the ratio of
waist girth to the circumference of the hips measured at the trochanter [12].
BIOCHEMICAL ANALYSIS
Blood sampling
Participants
were asked to fast for 12 h before blood sampling. Venous blood samples were
collected in sampling tube with aseptic precautions. After 2 h of collections
sample was centrifuged at 3000 rpm for 5 min. Serum was separated and collected
in polythene tube with cork. The sera with no sign of haemolysis used for the
estimation of all biochemical parameters.
Biochemical
Estimation
Insulin resistance markers
HbA1c concentration is measured based on
a specific chemical reaction to the glycated N-terminal valine of the β-chain
using by Quo-Lab A1C Analyzer. Fasting blood glucose was measured after
overnight fasting by Glucose Oxidase-Peroxidase Method using BECKMAN COULTER
Analyzer Model AU680.
Lipid parameters analysis
Serum
Total Cholesterol was determined by the enzymatic colorimetric cholesterol
oxidase-peroxidase method, Serum High Density Lipoprotein was estimated by the
cholesterol esterase-peroxidase precipitation method and Serum Triglycerides
was estimated by the GPO-PAP-enzymatic colorimetric method. All these
parameters optical density (absorbance) were done on BECKMAN COULTER Analyzer
Model AU680. Serum level of Low-Density Lipoprotein Cholesterol levels were calculated
by Fried Wald equation.
Adiponectin
analysis
Serum
level of adiponectin was measured using ALPCO, USA, High Molecular Weight (HMW)
& Serum Adiponectin ELISA kit for research use only.
Leptin analysis
Serum level of Leptin was estimated
using by Diagnostic Automation, Inc., USA, Micro-well ELISA kit for research
use only.
Free fatty acid analysis
Serum level of Free Fatty Acid was
estimated using SIGMA ALDRICH, USA, Free Fatty Acid Quantitation kit, ELISA kit
for research use only.
Cytokine ELISA assay
The levels of interleukin-17A and
interleukin-23 in the serum were measured using an Enzyme Linked Immunosorbent
Assay via Human cytokine ELISA set (R&D Systems, USA) and serum levels of
IL-6, IL-17 and IL-23 were measured using kits from The Bio-Plex Pro Human
Cytikine Assay, Bio-Rad Laboratories In. USA. The serum was isolated and stored
at -80ºC until further analysis. ELISA was performed according to the
manufacturer’s protocol. The absorbance was read at 450 nm with a microtiter
plate reader (Thermo Scientific-MULTISKAN FC). Cytokine levels were determined
with the help of standard curve and concentration was expressed as pg/ml.
Statistical
data analysis
All numerical
data were presented in terms of mean ± SD. Statistical analysis of results was
completed by normal distribution ‘Z’ test. In this data analysis, variables
showing p- value less than 0.05 and 0.001 were considered to be significant
statistically and highly significant respectively. Correlation coefficient (r
value) was calculated for final finding correlation between two parameters by
using Pearson two-tailed analysis. All statistics were done using SPSS software
version 15.
RESULTS
Clinical data of Met-S with T2DM
patients
The clinical and demographic data of metabolic syndrome patients with
type 2 diabetes in this study were shown in Table
1. Age and sex distributions were similar between patients and control
subjects. Among the 45 recruited patients, all men. The average age of the
patients was 36.92
± 2.40 years. Healthy controls were 45 subjects with mean age 37.28 ± 2.05 years,
only male subjects. Exclusively, metabolic syndrome patients with onset of
type 2 diabetes were involved by markedly higher levels of fasting blood glucose
(FBG), glycosylated haemoglobin (HbAlc) along with anthropometric parameter
under IDF
definition criteria [12] compared to control subjects.
Determination of anthropometric
parameters with serum level of Adipokines
Table 1 shows the anthropometric
measurements of the patients with metabolic syndrome (N=45) as cases and
subjects without metabolic syndrome as healthy control (N=45). As expected,
mean anthropometric parameters of
BMI, Waist Circumference, Waist to Hip Ratio, Systolic blood pressure,
Diastolic blood pressure were showed highly statistically significantly
increased (P<0.001) in both the groups.
Additionally, biochemical parameters of the participants in the present study are given in the Table 1. Serum Fasting Glucose, HbAlc, Triglycerides, Total Cholesterol, LDL-C, VLDL-C, Leptin and Free Fatty Acid levels were significantly increased (P<0.001) and HDL-C, adiponectin levels were significantly reduced (P<0.001) patients with Met-S and healthy compared to controls (Table 1, Figures 1,2 and 3).
Determination of serum level of Th1
specific pro-inflammatory cytokines IL-6 and Th17 specific pro-inflammatory
cytokines IL-17and IL-23
Table 1 and Figure 4 show that IL-6 level in metabolic syndrome patients with type 2 diabetes was tremendously higher than their respective healthy control subjects in males (p<0.001). There was a significant increase in serum IL-17 concentration in Met-S with onset of T2D aged below 40 years male as compared to controls and the age associated augmentation in IL-17 levels was also highly significant (p<0.001) (Figure 5). A similar increasing pattern was found in the serum levels of IL-6, another Th1 specific pro-inflammatory cytokine (Table 1).
The increased level of pro-inflammatory cytokines suggests that innate immune system also plays a crucial role in the pathogenesis of type 2 diabetes. So, it might be indicating that the IL-17 related cytokines may also be involved in the pathogenesis of type 2 diabetes. Furthermore, the level of IL-23 was found to be significantly increased in Met-S with type 2 DM patients of age groups as compared to healthy controls (p<0.001) (Table 1 and Figure 6). Statistical analysis showed a significant difference between serum levels of IL-6, IL-17 and IL-in metabolic syndrome patients with type 2 diabetes and healthy controls (𝑃<0.001) (Table 1, Figures 4, 5 and 6).
Baseline correlation between anthropometric
variables and markers of Met-S with T2DM Cases (Table 2)
BMI and WC were correlated significantly with age, BMI, WC, WHR, SBP, DBP, Fasting blood sugar, HbA1c, Total Cholesterol, Triglycerides, HDL, LDL, VLDL , Adiponectin, Leptin and Free fatty acid with respectively (BMI;WC) all correlation were found to be statistically significant at the 0.01 level (Table 2).
DISCUSSION
Metabolic
syndrome is defined by constellation of inter-connected with clinical,
biochemical and metabolic factors that strongly increases the risk of
cardiovascular disease, type 2 diabetes and all causes of mortality [8]. The metabolic
syndrome represents a combination of risk factors, which include atherogenic
dyslipidemia, hypertension, hyperglycaemia, prothrombotic state and a
pro-inflammatory state [7].
The relationships between inflammatory
biomarkers such as IL-6, IL-17, IL-23 and adipokinesin metabolic syndrome
patients with type 2 diabetes have not been thoroughly investigated. This study
was designed to investigate that the circulating levels of serum IL-6, IL-17, IL-23
and adipokines in metabolic syndrome with onset of type 2 diabetes mellitus.
First, we have found that significantly elevated in the circulating serum
levels of pro-inflammatory cytokines IL-6, IL-17, IL-23 in Met-S patients with
type 2 diabetes were compared to healthy subjects. Second, we have attempted to
establish a relationship of between age and sex with anthropometric and serum
adiponectin, leptin, HbA1c, fasting blood sugar, lipid profile levels of metabolic
syndrome cases with onset of Type 2 diabetes mellitus were investigated. We
observed significant decrease Adiponectin level. While, serum level of leptin,
fasting blood sugar, waist circumference and BMI with all anthrppometric
feathers were significantly higher in metabolic syndrome patients with type 2
diabetes than in the controls. Moreover, BMI and WC significantly correlate
with anthropometric parameter, adiponecctin, leptin, free fatty acid, HbA1c,
fasting blood sugar, lipid profile levels. These results suggested that serum
IL-6, IL-17, IL-23 and adipokines might participate in the inflammatory process
of type 2 diabetes and have a crucial role in the pathogenesis of in Met-S with
onset of type 2 diabetes mellitus.
The relation
between IL-6 and inflammation-induced obesity in type 2 diabetic patients
Over the past decades many studies have
suggested that low-grade inflammation related to central obesity might be the
key regulator in pathogenesis of type 2 diabetes mellitus [13]. It has been
confirmed that enlargement of adipose tissue is associated with increases of
number of adipose tissue macrophages, which are responsible for increases in
serum concentration of pro-inflammatory cytokines, especially IL-6 and TNF-α
expression. IL-6 is released from macrophages of adipose tissue as well as from
adipocytes and skeletal muscle [9,14].
In addition, previous studies revealed an
association between IL-6 and systemic inflammation causing Met-S [15]. This
study showed that serum IL-6 levels were significantly greater in Met-S
patients than in controls. No significant correlations between serum IL-6 levels
and Met-S components were observed. Previous studies showed that IL-6 is
positively associated with BMI, fasting insulin, hypertension and type 2 diabetes;
however, such results disagree with our findings [16]. Sarbijani et al. [17]
reported that IL-6 serum levels were significantly greater in men with Met-S
than in controls. They also observed a lack of correlation between IL-6 and
Met-S components, which agrees with our findings. Additionally, Kitsios et al.
[18] showed that obese and overweight adolescents and children with Met-S had
significantly greater serum IL-6 levels than their counterparts without Met-S.
Moreover, recent study Mojgan et al. [19] reported
that serum
IL-6 and TNF-α levels were significantly greater in metabolic syndrome patients
with type 2 diabetes than in controls, supporting the evidence that
inflammation plays an important role in the immune-pathogenesis of the disease.
However, no correlation was found between Met-S components and IL-6 or TNF-α
serum level. Rehman et al. [20] and Victoria et al. [21] studies were observed
similarly serum IL-6 were significantly higher in the diabetic patients
than in the related controls. These all studies supported by our study results
and these data support a possible role for inflammation in diabetogenesis. Thus, our results have confirmed
these findings in metabolic syndrome patients with type 2 diabetes had
significantly increased serum levels of IL-6 with other pro-inflammatory
cytokines than healthy controls. These results support the evidence that
inflammation plays an important role in the immune-pathogenesis of the disease.
Additionally, we suggest that IL-6 and other pro-inflammatory cytokines serum
levels be measured as valuable predicting factors for Met-S.
The relation between IL-17, IL-23 and inflammation-induced obesity
in patients with type 2 diabetes
Our data indicated that serum IL-17, IL-23
levels were higher in metabolic syndrome patients with type 2 diabetes group in
comparison with the healthy control group. Recent studies indicated that IL-17
has a crucial role in the creation of inflammation in adipose tissues of obese
individuals [22]. In animal model, obesity has been correlated with elevated
levels of IL-17 and increased inflammation [22]. Importantly, Jagannathan B et
al. [23] concluded that patients with type 2 diabetes showed increased Th17
cells with activated Th17 signature genes. Obese patients who have insulin
resistance showed elevated blood levels of IL-17. Moreover, it has been demonstrated
that circulating levels of IL-17 are elevated significantly in patients with
diabetes [23] and obese women [24]. Therefore, both IL-17 and IL-23 are
introduced as additional markers for inflammation that accompanies obesity. In
addition, earlier findings confirmed the increase in leptin and macrophage
migration inhibitory factor levels in obese humans [25].
Role of
IL-17 in type 2 diabetes mellitus development
Recent
studies have demonstrated an association between Th17 cells and T2D
development. Several investigators have suggested that T2D and its
complications are immune-dependent conditions that can alter patterns of
cytokines expression [25]. Chen et al. [26] reported that IL-17 levels are
elevated in newly diagnosed Type 2 diabetic patients than control subjects.
Moreover, they found an increase in IL-17 mRNA expression and ROR γt in
peripheral blood mononuclear cells (PBMCs) of type 2 diabetic patients and such
increase in IL-17 gene expression was associated with TNF-α gene expression.
Such findings indicate that IL-17 plays a crucial role in the inflammatory
process and type 2 diabetes mellitus development. Additionally, treatment with
anti-IL-17 neutralizing antibodies elevated serum adiponectin concentration,
decreased serum levels of TNF-α and enhanced adipocyte-differentiation markers.
These data indicate that IL-17 could possess a crucial role in development of
insulin resistance and type 2 diabetes mellitus [27].
Several
results concluded that dys-regulation of IL-17 production can result in
excessive pro-inflammatory cytokines expression and chronic inflammation. Such
inflammatory conditions may have a vital role in progression of insulin
resistance [25]. Based on the above-mentioned findings, it can speculate that
IL-17 involves in type 2 diabetes mellitus pathogenesis, however the exact
mechanistic pathways are unclear yet. Previous studies suggested some probable
mechanisms regarding the potential role of IL-17 in type 2 diabetes mellitus
pathogenesis. Briefly, IL-17 activates nuclear factor-kappa B (NF-κB) pathway
which up-regulates inflammatory cytokine genes expression [28].
IL-17A
is a potential inflammatory cytokine which contributes to several autoimmune
and inflammatory diseases including type 2 diabetes mellitus [29]. Several
studies showed that Interleukin-17A could be considered as a potent inducer of
type 2 diabetes mellitus. This present study revealed that the circulating
levels of serum IL-6, IL-17, IL-23 and adipokines in metabolic syndrome with
onset of type 2 diabetes mellitus. We have found that significantly elevated in
the circulating serum levels of pro-inflammatory cytokines IL-6, IL-17, IL-23
in Met-S diagnosed patients with type 2 DM were compared to healthy subjects in
Indian population.
Adipose tissue has been postulated to play a prominent role in both
insulin resistance and the clinical expression of the metabolic syndrome, most
likely mediated by increased release and peripheral tissue action of NEFA and
by dys regulated production of adipocyte-secreted proteins, including leptin,
adiponectin, resistin, TNF-α and IL-6 [30].
Our previous study, we observed the serum
levels of adipokines, biochemical markers with anthropometric features were
significantly higher in metabolic
syndrome patients with type 2diabetes compare to healthy control subjects. These findings were also
consistently similar with present study [31].
CONCLUSION
The current data of the present study suggest
a strong association between advancement of metabolic syndrome with elevated level of pro-inflammatory
cytokines as well as significant altered serum levels of adipokines. The results of the present study clearly
demonstrate that the circulating serum levels of pro-inflammatory cytokines
IL-6, IL-17 and IL-23 are primary mediators of inflammation in Met-S with type
2 diabetes. The role of Th17 cytokines also seems to be inevitable. IL-17 and
IL-23 can be considered as a novel cytokine involved in the inflammatory
process ensued in Met-S with type 2 diabetes. Furthermore, cytokines
produced by the Th17 path-ways might be implicated in clinical manifestation of
diabetes and could be used as markers to distinguish between T1D and T2D at
different age of diabetes onset. The results of this study indicate a close
association between age and gender of T2D patients with adipokines and
inflammatory markers specially IL-6, IL-23 and IL-17A. The study also suggests
an age-related inflammatory change in T2D with metabolic syndrome subjects as
compared to healthy individuals. Additionally, to the best of our knowledge,
the present work for the first time shows correlation between pro-inflammatory
cytokines and adipokines along with metabolic anthropometric with age, BMI and
WC in onset of type 2 diabetic human subjects having poor glycemic control with
average HbA1c values above 8.2%. The cytokines viz. IL-6, IL-23 and IL-17A are
believed to contribute to the pathogenesis of type 2 diabetes with Met-S on the
basis of age and glycemic condition of the patients.
Furthermore, the adiponectin and leptin were
significantly altered in patients with metabolic syndrome and type 2 diabetes.
A significant and positive relationship between adipokines, free fatty acid and
other parameters of metabolic syndrome, including BP values in normo-tensive
subjects with central obesity were also observed. Further, prospective in-depth
studies are needed to validate this threshold and may provide new insights into
the immunological and metabolic events which occur during type 2 diabetes with
Met-S on. Furthermore, research and investigations are necessary to determine
the efficacy of applying these biochemical markers to diagnosis and treatment
in all clinical setting.
DISCLOSURE STATEMENT
This study is investigator initiated. The
authors declare that they have no competing/conflict of interests in relation
to this research work.
FUNDING
No financial support from an external agency was used for this study.
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