Original article
157
Fetuin-A and type II diabetes mellitus
Lamyaa Ismail Ahmeda, Sabila Gomaa Mousaa, Nagwa Abd El-Ghaffar
Mohamedb, Zeinab Ahmed Yousrya, Mayada Rabea Abd-El Khalaaa
a
Department of Internal Medicine,
Faculty of Medicine for Girls,
Al-Azhar University bDepartment of Clinical and
Chemical Pathology, National Research Center,
Cairo, Egypt
Correspondence to Lamyaa Ismail Ahmed, MD,
145c Shoubra Street, Cairo, Egypt
Tel: +20 100 570 0578;
e-mail: lamyaa.harb@yahoo.com
Received 22 August 2014
Accepted 01 October 2014
The Egyptian Society of Internal Medicine
2014, 26:157–161
Background
The pathophysiology of type II DM is complex; in addition to impaired insulin secretion from
Beta-cells, reduced insulin sensitivity was found to play a predominant role in the pathogenesis
of the disease. Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits
insulin action both in vivo and in vitro.
Objective
Our aim was to investigate whether serum fetuin-A levels predict the incidence of insulin
resistance in type II DM.
Patient and methods
The present study included 40 patients who had type II diabetes mellitus served as patients
group and 40 apparently normal individuals served as control group. All patient and control
groups were subjected to the following: full medical history and thorough physical examination,
fasting & post prandial blood glucose, urea, creatinine, lipid profile, CRP, insulin and fetuin-A.
Results
There was highly significant increase in serum insulin, serum fetuin A and HOMA-IR in diabetic
group compared with control group. There was significant positive correlation between serum
fetuin A and serum insulin, FBG, HbA1c and serum CRP. Also a significant positive correlation
between HOMA-IR and serum fetuin A, serum insulin and HbA1c were found.
Conclusion
We concluded that fetuin-A may play a role in the pathogenesis of type II DM, and high serum
fetuin-A has a strong association with IR and glycemic control in type II diabetic patients. Future
studies are recommended to establish the possibility of using fetuin-A as a predictor of insulin
resistance in type II diabetic patients.
Keywords:
C-reactive protein, diabetes mellitus, fetuin-A, insulin resistance
Egypt J Intern Med 26:157–161
© 2014 The Egyptian Society of Internal Medicine
1110-7782
Introduction
Diabetes mellitus (DM) is one of the most serious
diseases [1]. The pathophysiologies of type II DM
are reduced insulin sensitivity and increased insulin
resistance associated with enhanced hepatic glucose
output and impaired insulin secretion due to a
progressive decline of b-cell function [2].
Several circulating proteins have been shown to be
involved in the regulation of insulin sensitivity, such
as fetuin-A, which is an endogenous inhibitor of the
insulin-stimulated receptor tyrosine kinase; high levels
of fetuin-A are associated with insulin resistance [3–6].
Fetuin-A located on chromosome 3q27; this region
was mapped as a type II DM and metabolic syndrome
susceptibility locus [7].
Aim of the work
Our aim was to investigate whether serum fetuin-A levels
predict the incidence of insulin resistance in type II DM.
1110-7782 © 2014 The Egyptian Society of Internal Medicine
Patients and methods
The present study included 40 patients who had type
II DM (20 females and 20 males) who served as the
patients group; their ages ranged from 37 to 63 years with
mean age of 47.45 ± 6.70 years. Forty apparently healthy
individuals served as the control group (20 females and
20 males); their ages ranged from 37 to 58 years with
mean age of 45 ± 6.03. All patients were selected from
Al-Zhraa University Hospital and Almokatam Hospital
during the period between January 2012 and May 2012.
Written consent was obtained from all participants before
the start of the research in addition to approval of ethical
committee of Faculty of Medicine, Al-Azhar University.
All patients and control group were subjected to the
following: full medical history and thorough physical
examination were performed. The following laboratory
parameters were estimated in blood samples: fasting and
postprandial blood glucose, glycosylated haemoglobin
(HbA1c), urea, creatinine, lipid profile (total cholesterol,
triglyceride, HDL, LDL), C-reactive protein (CRP),
insulin, and fetuin-A. Abdominal ultrasound was
performed to all patients.
DOI: 10.4103/1110-7782.148140
158
The Egyptian Society of Internal Medicine
Exclusion criteria
Individuals were excluded if they had a known history
of cardiovascular disease, stroke or transient ischemic
attacks, uncontrolled hypertension, liver disease, renal
disease, severe dyslipidemia (triglycerides >600 mg/dl
or cholesterol >350 mg/dl); pregnant diabetic women
and individuals taking lipid-lowering agents during the
last 3 months, glucocorticoids, antineoplastic agents,
psychoactive agents, or bronchodilators on a regular
basis were also excluded.
Fasting venous blood samples of 5 ml was taken from
each participant in the study and divided into two
parts: the first part (1 ml) of venous blood was added to
a tube containing EDTA for determination of HbA1c
by cation exchange resin [8]. The rest of blood was left
to clot (the second part) and centrifuged at 3000 xg for
5 min for separation of serum. Fasting blood glucose
(FBG) was determined immediately using the glucose
oxidase method on Hitachi 912 autoanalyzer (Hitachi,
Roche, Japan). The rest of serum was stored at −20°C
for determination of CRP, urea, creatinine, cholesterol,
triglyceride, insulin, and fetuin-A.
The determination of fasting and postprandial
blood glucose, serum cholesterol, serum triglyceride,
serum urea, and serum creatinine was carried out on
Hitachi 912 autoanalyzer (Hitachi) by colorimetric
methods. For determination of HDL-cholesterol,
phosphotungstic acid and magnesium ions are used for
precipitating all lipoprotein except the HDL fraction,
which was present in the supernatant and measured
by autoanalyzer 912. LDL-cholesterol was calculated
using the Friedwald formula [9].
Direct detection of serum CRP was performed in
serum by rapid latex agglutination procedure [10].
Serum insulin was determined using radioimmunoassay
[11]. Insulin resistance was calculated as homeostasis
model assessment of insulin resistance (HOMA-IR)
using the following equation: HOMA-IR=fasting
blood glucose (mg/dl)×fasting serum insulin (mIU/
ml)/405 [12].
The determination of serum fetuin-A was carried out
using quantitative sandwich enzyme immunoassay
technique [13], and the kit was supplied from R & D
Systems Europe Ltd (19 Barton Lane, UK).
Statistical analysis
The results were performed using statistical package
for social science software, version 17.0 (SPSS Inc.,
Chicago, Illinois, USA). Continuous variables were
expressed as mean ± SD. Comparison between two sets
of patients was performed by the independent t-test, but
more than two sets of patients were compared by oneway analysis of variance. Pearson correlation coefficient
‘r’ was used to describe the association between serum
fetuin-A and the variables of interest. P values less than
0.05 were considered statistically significant.
Results
The present study was carried out on 80 Egyptian
persons and were classified into two groups.
Group 1 included 40 healthy age-matched and sexmatched individuals who served as the control group
(20 females and 20 males). Their mean age was 45 ±
6.03 years.
Group 2 included 40 type II diabetic patients (20
females and 20 males). Their mean age was 47.45 ±
6.70 years.
Table 1 reveals highly significant increase in FBG,
HbA1c, serum urea, cholesterol, and CRP in the
diabetic group compared with the control group
(P < 0.01). There was nonsignificant difference
with respect to age and systolic and diastolic blood
pressure.
Table 2 shows highly significant increase in serum
insulin, serum fetuin-A, and HOMA-IR in the
diabetic group compared with the control group (P <
0.01).
Tables 3 and 4 and Figs 1–3 shows a significant positive
correlation between HOMA-IR and serum fetuin-A,
serum insulin, and HbA1c in diabetic patients. In
Table 1 Clinical and laboratory data of diabetic patients
(group 2) and the control group (group 1) (mean ± SD)
Parameters
Age (years)
Systolic blood
pressure (mmHg)
Diastolic blood
pressure (mmHg)
FBG (mg/dl)
HbA1c (%)
Urea (mg/dl)
Creatinine (mg/dl)
Cholesterol (mg/dl)
Triglycerides (mg/dl)
LDL (mg/dl)
HDL (mg/dl)
CRP (mg/l)
Diabetic patients
(group 2)
47.45 ± 6.70
121.67 ± 5.87
87.67 ± 3.43
111.93
6.64
31.92
0.83
208.08
125.10
128.24
51.40
7.65
±
±
±
±
±
±
±
±
±
27.64
2.96
12.33
0.19
45.43
64.77
40.49
14.52
9.31
Groups
Control
(group 1)
45.03 ± 6.03
119.5 ± 6.05
>0.05
>0.05
78.5 ± 3.66
>0.05
82.10
5.23
23.11
0.77
175.43
127.70
107.23
49.28
0.30
±
±
±
±
±
±
±
±
±
13.50
0.12
8.67
0.18
47.92
62.44
42.72
18.20
1.90
CRP, C-reactive protein; FBG, fasting blood glucose; HbA1c,
glycosylated hemoglobin or the hemoglobin A1c; P > 0.05 =
nonsignificant; P < 0.01 = highly significant.
P
<0.01
<0.01
<0.01
>0.05
<0.01
>0.05
>0.05
>0.05
<0.01
Fetuin A and type II diabetes mellitus Ahmed et al. 159
Figure 1
Table 2 Serum insulin, serum fetuin-A, and HOMA-IR in
different groups (Mean ± SD)
Parameters
Insulin (mIU/ml)
Fetuin-A (µg/ml)
HOMA-IR
Diabetic group
30.48 ± 8.99
339.59 ± 33.91
8.77 ± 4.23
Groups
Control group
9.05 ± 1.65
284.33 ± 14.60
1.82 ± 0.37
P
<0.01
<0.01
<0.01
HOMA-IR, homeostasis assessment model for insulin resistance.
Table 3 Correlation between HOMA-IR and other laboratory
parameters in the diabetic group
The correlation between HOMA-IR and serum fetuin-A in the
diabetic group. HOMA-IR, homeostasis assessment model for insulin
resistance.
Figure 2
Diabetic group
Fetuin-A
Insulin
Urea
Creatinine
FBG
HbA1c
Cholesterol
Triglyceride
HDL
LDL
HOMA-IR
0.796
0.889
0.000
0.191
0.872
0.561
0.113
−0.136
0.188
0.003
P
<0.01
<0.01
>0.05
>0.05
>0.05
<0.01
>0.05
>0.05
>0.05
>0.05
FBG, fasting blood glucose; HbA1c, glycosylated hemoglobin or the
hemoglobin A1c.
Table 4 Correlation between fetuin-A and other laboratory
parameters in the diabetic group
Diabetic group
Insulin
Urea
Creatinine
FBG
HbA1c
CRP
Cholesterol
Triglyceride
HDL
LDL
The correlation between serum fetuin-A and serum insulin in the
diabetic group.
Figure 3
Fetuin-A
0.842
−0.015
0.118
0.576
0.485
0.786
−0.053
−0.263
−0.214
−0.127
P
<0.01
>0.05
>0.05
<0.01
<0.01
<0.01
>0.05
>0.05
>0.05
>0.05
CRP, C-reactive protein; FBG, fasting blood glucose; HbA1c,
glycosylated hemoglobin or the hemoglobin A1c.
addition, there was significant positive correlation
between serum fetuin-A and serum insulin, FBG,
HbA1c, and serum CRP.
Discussion
Type II diabetes is characterized by inadequate insulin
secretion and insulin resistance in the target tissues.
Insulin mediates its action through phosphorylation of
the insulin receptor. Fetuin-A inhibits insulin receptor
autophosphorylation [14].
The correlation between serum fetuin-A and FBG in the diabetic group.
FBG, fasting blood glucose.
The present study showed highly significant increase
in serum insulin, serum fetuin-A, and HOMA-IR in
the diabetic group compared with the control group.
Our results showed significant positive correlations
160
The Egyptian Society of Internal Medicine
between fetuin-A levels and both fasting insulin levels
and HOMA-IR in patients with type II diabetes
and this agreed with the studies conducted by Jung
et al. [15] who demonstrated that serum fetuin-A is
significantly associated with IR, and Graham et al. [4]
who showed that fetuin-A is positively correlated with
insulin resistance.
These results were previously reported by Wallace
et al. [12], who demonstrated that fetuin-A levels were
correlated with fasting insulin levels and HOMA-IR
in obese patients, suggesting a potential link between
fetuin-A and insulin resistance. Stefen et al. [16] had
demonstrated that fetuin-A was correlated with insulin
resistance and fat accumulation in the liver. Li et al.
[17] reported that fetuin-A, which is predominantly
secreted by the liver, is found to be related to the
accumulation of fat in the liver, insulin resistance, type
II diabetes, and cardiovascular diseases.
Dasgupta and colleagues reported that the liversecreted protein fetuin-A induces insulin resistance,
and circulating fetuin-A is elevated in insulin resistance
and fatty liver in humans. In agreement with these
data, Emoto et al. [18] had shown that high levels
of circulating fetuin-A are associated with insulin
resistance in humans, suggesting that fetuin-A may
represent a mechanism involved in the pathophysiology
of type II diabetes.
Looking at lipid profile and their relationship with
fetuin-A, our study showed highly significant increase
in total cholesterol level in group 2 when compared
with group 1 and insignificant difference in serum
triglycerides, LDL, and HDL levels between two
groups. Kotronen and Yki-Järvinen [20] showed that
fetuin-A levels were negatively correlated with HDLcholesterol.
Khalil and Kuobaili [21] reported that elevated serum
fetuin-a levels found in type II diabetic patients were
significantly associated with atherogenic dyslipidemia,
thus indicating that fetuin-a may be one of the
contributing factors to the increased incidence of
coronary heart diseases in type II diabetic patients. Ix
et al., [22] reported that higher level of fetuin-A was
associated with higher triglycerides, LDL-cholesterol,
BMI, and insulin resistance.
In our results, CRP also showed marked increase in
group 2 when compared with group 1. This agrees with
a study reported by Kotronen and Yki-Järvinen [20],
which showed that serum fetuin-A levels were increased
in diabetic patients when compared with case–control
individuals and demonstrated a positive correlation
between serum fetuin-A and CRP levels. These
results agreed with our results, as there was a positive
correlation between serum fetuin-A and CRP levels
(r = 0.786, P < 0.01).
These data further suggest a potential role for fetuin-A
as a marker associated with inflammation in both type
II DM and obesity [20]. Baumann and colleagues
found that fetuin-A participates in the inflammatory
response. In support of its inflammatory profile,
fetuin-A has been shown to increase transcriptional
events leading to an increased expression of several
proinflammatory cytokines including interleukin-1,
interleukin-6, interleukin-12, and tumor necrosis
factor-A [23].
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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