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Diabetes Research
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abstract
Article history:
Aims: To evaluate the associations between inflammatory cytokines and adiponectin and
Methods: A total of 761 patients with T2DM were divided into a non-obese group and an
4 October 2015
obese group to enable the effects of obesity and T2DM on vascular complications to be
differentiated. The serum levels of circulating inflammatory cytokines, that is, tumor
necrosis factor (TNF)-a, and interleukin (IL)-6, total adiponectin, and high molecular weight
(HMW) adiponectin were measured, and carotid intima media thickness (IMT), the presence
Keywords:
of carotid plaque, and the severities of retinopathy and nephropathy, were assessed.
Results: The obese group had significantly lower serum total and HMW adiponectin levels
Vascular complication
than the non-obese group. In the obese group, serum levels of total and HMW adiponectin,
and TNF-a were significantly higher in patients with proliferative retinopathy than in those
without retinopathy after adjusting for covariates. In the non-obese group, only IL-6 levels
were significantly higher in patients with proliferative retinopathy than in those without.
Serum levels of total and HMW adiponectin were significantly higher in patients with
macroalbuminuria than in those with normoalbuminuria. No significant difference of three
cytokines levels were observed depending on the carotid IMT or the presence of plaque.
Logistic regression analysis revealed that serum total adiponectin (OR = 1.209, P = 0.038),
diabetes duration (OR = 1.230, P = 0.014), and HbA1c (OR = 2.359, P = 0.006) were significantly
associated with proliferative retinopathy in the obese group.
Conclusion: The study shows total adiponectin may influence proliferative retinopathy in
obese patient with T2DM.
# 2015 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author at: Department of Endocrinology, Inha University School of Medicine, 7-206 3rd St. Shinheung-Dong, Jung-gu,
Incheon 400-711, Republic of Korea. Tel.: +82 32 890 1101; fax: +82 32 890 1120.
E-mail address: namms@inha.ac.kr (M. Nam).
1
Seong Bin Hong and Jung Jin Lee contributed equally to this work.
http://dx.doi.org/10.1016/j.diabres.2015.10.017
0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
2.
2.1.
Study population
This study was conducted using a cross-sectional, observational design. The patient population consisted of 761 subjects
with type 2 diabetes recruited from the outpatient clinic at the
Diabetes Center of Inha University Hospital from March 2007
to December 2009. Inclusion criteria for the patients with
T2DM included; older than 20 year of age, newly diagnosed
with T2DM using American Diabetes Association criteria
(2003) [7] and/or was being treated with oral hypoglycemic
agents or insulin, or lifestyle modification for known T2DM. All
patients were Korean. Patients were allocated to an obese
or non-obese groups using the classification used in the
redefined Asian-Pacific Region guideline [8]; non-obese group
(body mass index (BMI) <25 kg/m2) and obese group (BMI
25 kg/m2). The exclusion criteria applied were as follows:
congestive heart failure, severe infection, uncontrolled hypertension, severe dyslipidemia (total cholesterol >400 mg/d), or
59
2.2.
Measurements
Evaluations comprised detailed medical history taking, anthropometric measurements, physical examination, laboratory measurements, and diabetic vascular complication
studies.
2.2.1.
2.2.2.
2.2.3.
60
2.2.4.
2.3.
Statistical analysis
3.
Results
The study population comprised 468 men and 293 women with
type 2 diabetes. Study subjects were divided into two groups:
335 non-obese (BMI <25 kg/m2) patients and 426 obese (BMI
25 kg/m2) patients. The baseline clinical characteristics of
the two groups are shown in Table 1. Systolic and diastolic
blood pressures were higher in the obese group (P = 0.017 and
0.002, respectively). Triglyceride, HOMA-IR, and high sensitivity C reactive protein (hs-CRP) were higher (P < 0.0001,
P < 0.0001 and P = 0.001, respectively), and high density
lipoprotein (HDL) cholesterol and total and HMW adiponectin
levels were lower in the obese group (P = 0.01 and P < 0.0001,
respectively) (Table 1).
Mean and maximum cIMT, and the prevalence of diabetic
nephropathy were similar in the obese and non-obese groups.
More non-obese patients had retinopathy (30.2 vs. 21.2%,
P = 0.044), and more obese patients had carotid plaque (49.7 vs.
57.1%, P = 0.054) (Table 2).
N
Age (years)
Gender (M/F)
BMI (kg/m2)
Waist to hip ratio
Diabetes duration (years)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Fasting glucose (mg/dl)
HbA1c (%)
Total cholesterol (mg/dl)
Triglyceride (mg/dl)
HDL (mg/dl)
LDL (mg/dl)
hsCRP (mg/L)
HOMA-IR
Baseline levels of adipokines (N)
TNF-a (pg/ml)
IL-6 (pg/ml)
Total adiponectin (ng/ml)
HMW adiponectin (ng/ml)
Total
Non-obese
Obese
761
52 (4760)
468/293
25.4 (23.527.4)
0.91 (0.890.94)
4(19)
125 (114135)
77 (7085)
139 (117168)
7.4 (6.88.6)
179 (156204)
142 (96201)
45 (3952)
117 (95144)
0.1 (0.050.21)
2.7 (1.674.15)
750
1.29 (0.842.07)
0.95 (0.581.63)
3.94 (2.786.12)
1.29 (0.612.39)
335
52 (4660)
207/128
23.2 (22.024.1)
0.90 (0.870.92)
5 (111)
122 (113133)
76 (6982)
139 (116178)
7.6 (6.89.0)
177 (155202)
126 (18380)
46 (4054)
115 (94143)
0.08 (0.040.19)
2.11 (1.253.42)
328
1.37 (0.872.09)
0.92 (0.561.47)
4.21 (3.186.84)
1.52 (0.832.85)
426
53 (4861)
261/165
27.1 (25.928.8)
0.92 (0.900.96)
4 (18)
126 (116136)
79 (7286)
138 (118163)
7.35 (6.78.4)
180 (157208)
153 (109215)
44 (3851)
118 (96146)
0.11 (0.060.23)
3.13 (2.114.78)
422
1.25 (0.832.06)
0.96 (0.591.70)
3.64 (2.585.46)
1.07 (0.511.97)
P valuea
0.247
0.883
<0.0001
<0.0001
0.002
0.017
0.002
0.65
0.22
0.22
<0.0001
0.01
0.15
0.001
<0.0001
0.778
0.068
<0.0001
<0.0001
61
Nephropathy
Normoalbuinuria
Microalbuminuria
Macroalbuminuria
Retinopathy
No apparent
Retinopathy (+)
Mild NPDR
Moderate NPDR
Severe NPDR
PDR
Total patients
Non-obese patients
Obese patients
n = 726
n = 315
n = 411
418 (57.7%)
274 (37.8%)
33 (4.6%)
186 (59.0%)
116 (36.8%)
13 (4.1%)
232 (56.4%)
158 (38.4%)
20 (4.9%)
Total patients
Non-obese patients
Obese patients
n = 634
n = 285
n = 348
474 (74.8%)
160 (34%)
86 (13.6%)
23 (3.6%)
30 (4.7%)
21(3.3%)
199
86
43
16
15
12
(69.8%)
(30.2%)
(15.1%)
(5.6%)
(5.3%)
(4.2%)
274
74
43
7
15
9
(78.8%)
(21.2%)
(12.3%)
(2.0%)
(4.3%)
(2.6%)
Total patients
Non-obese patients
Obese patients
n = 678
n = 298
n = 380
365 (53.8%)
313 (46.2%)
0.68 (0.610.79)
0.80 (0.710.93)
148 (49.7%)
150 (50.3%)
0.68 (0.600.78)
0.79 (0.690.91)
217 (57.1%)
163 (42.9%)
0.67 (0.610.78)
0.79 (0.710.93)
P valuea
0.867
P valuea
0.044
P valuea
0.054
0.54
0.48
4.
Discussion
62
Table 3 Comparison of cytokines levels at different stages of diabetic retinopathy in obese and non-obese patients.
TNF-a (pg/ml)
Non-obese patients
No apparent
n = 199
Mild NPDR
N = 43
Moderate NPDR
n = 16
Severe NPDR
n = 15
PDR
n = 12
Obese patients
No apparent
n = 274
Mild NPDR
N = 43
Moderate NPDR
n=7
Severe NPDR
n = 15
PDR
n=9
Pa
IL-6 (pg/ml)
1.28 (0.851.93)
Pa
Total
adiponectin
(ng/ml)
0.88 (0.541.42)
Pa
4.16 (3.116.36)
HMW
adiponectin
(ng/ml)
Pa
1.48 (0.692.73)
1.42 (0.752.14)
1.000
0.77 (0.491.40)
1.000
4.69 (3.417.06)
1.000
1.60 (0.983.07)
1.000
2.24 (1.072.88)
0.652
1.17 (0.781.50)
1.000
4.60 (2.956.57)
1.000
1.54 (0.722.21)
1.000
1.42 (1.032.33)
1.000
1.12 (0.782.57)
0.508
3.97 (3.096.12)
1.000
1.36 (1.033.45)
1.000
2.41 (1.073.00)
0.208
1.66 (0.992.69)
0.02
4.97 (3.777.86)
1.000
1.89 (1.234.88)
1.000
1.21 (0.822.00)
0.93 (0.581.63)
3.47 (2.424.86)
1.03 (0.451.82)
1.29 (0.892.07)
1.000
0.99 (0.621.54)
1.000
4.27 (2.848.49)
0.124
1.20 (0.592.40)
0.756
1.07 (0.852.29)
1.000
1.23 (0.961.85)
0.840
3.61 (1.8412.52)
1.000
1.61 (0.487.22)
1.000
1.25 (0.862.67)
1.000
1.86 (1.022.36)
0.148
3.65 (2.924.64)
0.996
1.04 (0.821.77)
0.428
2.27 (1.728.64)
0.012
1.58 (1.042.34)
0.196
8.98 (6.6711.35)
<0.001
2.52 (1.605.75)
0.001
Table 4 Comparison of cytokines levels at different stages of diabetic nephropathy in obese and non-obese patients.
TNF-a (pg/ml)
Non-obese patients
Normoalbuminuria
n = 186
Microalbuminuria
n = 116
Macroalbuminuria
n = 13
Obese patients
Normoalbuminuria
n = 232
Microalbuminuria
n = 158
Macroalbuminuria
n = 21
Pa
1.22 (0.871.85)
IL-6 (pg/ml)
Pa
0.87 (0.541.42)
Total
adiponectin
(ng/ml)
Pa
4.15 (3.176.80)
HMW
adiponectin
(ng/ml)
Pa
1.52 (0.812.75)
1.44 (0.862.33)
1.000
0.95 (0.581.63)
1.000
4.20 (3.096.23)
1.000
1.44 (0.732.79)
0.576
2.33 (0.953.63)
0.053
1.27 (0.895.52)
0.120
5.90 (4.429.41)
0.111
2.64 (1.435.36)
0.115
1.15 (0.821.96)
0.94 (0.611.81)
3.61 (2.545.29)
1.07 (0.521.90)
1.37 (0.872.29)
0.176
1.02 (0.581.53)
1.000
3.69 (2.585.73)
1.000
1.05 (0.511.96)
1.000
1.48 (0.892.34)
1.000
1.19 (0.622.16)
1.000
3.95 (3.047.69)
0.006
1.42 (0.842.43)
0.001
63
Age (years)
Gender (M/F)
Diabetes duration (years)
HbA1c (%)
Total adiponectin (ng/ml)
TNF-a (pg/ml)
IL-6 (pg/ml)
Obese
Non-obese
OR
P value
OR
P value
OR
P value
0.927
0.689
1.182
1.468
1.126
1.035
1.051
0.024
1.000
<0.0001
0.006
0.066
0.934
1.000
0.89
0.230
1.233
2.359
1.209
1.117
.949
0.074
0.532
0.014
0.006
0.038
0.184
1.000
0.938
1.177
1.181
1.186
.967
.950
1.095
0.208
1.000
<0.0001
0.608
1.000
1.000
1.000
Multiple logistic regression analysis was performed using no apparent retinopathy group as a reference.
OR: Odds ratio adjusting for other covariates in the logistic regression model.
Bonferronis multiple testing correction was applied for the subgroup analysis.
64
[8]
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Conflict of interest
All of the authors have read and approved this manuscript and
have no conflict of interest to disclose and industry relationship.
Acknowledgement
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