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Annals of Clinical & Laboratory Science 38:361-367 (2008)
© 2008 Association of Clinical Scientists

Cytokine Profile of Peripheral Blood in Type 2 Diabetes Mellitus Patients with Diabetic Retinopathy

Jong-Han Lee1, Woonhyung Lee1, Oh Hun Kwon1, Jeong-Ho Kim1, Oh Woong Kwon2, Kyung Hwan Kim3 and Jong-Baeck Lim1
1 Departments of Laboratory Medicine, 2 Ophthalmology, and 3 Pharmacology, Yonsei University College of Medicine, Seoul, Korea

Address correspondence to Jong-Baeck Lim, M.D., Ph.D., Department of Laboratory Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, Korea 120-752; tel 82 2 2228 2447; fax 82 2 364 1583; e-mail jlim{at}yuhs.ac.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To evaluate the usefulness of cytokine levels of peripheral blood in diabetic retinopathy (DR), demographic and biochemical parameters including low-density lipoprotein (LDL) diameter as well as cytokine profiles were analyzed in 74 patients with type 2 diabetes mellitus (DM), with DR (n = 46) or without DR (n = 28). DM duration was longer in the patients with DR than without (p <0.001). Serum glucose (p = 0.005) and total cholesterol (p = 0.029) levels were higher in DM patients with DR than DM patients without DR. Plasma LDL diameter, interleukin-6 (IL-6), and interleukin-8 (IL-8) showed significant differences among the different degrees of DR severity in analysis of variance (ANOVA) with no definite trend. The risk of DR in DM patients was decreased by an increase of interleukin-10 (IL-10) level [odds ratio (OR) = 0.152; confidence interval (CI): 0.028–0.817]. Plasma LDL diameter was smaller and IL-6 and tumor necrosis factor-alpha (TNF-{alpha}) levels were higher in DM patients with proliferative diabetic retinopathy (PDR) compared to those with non-proliferative diabetic retinopathy (NPDR) (p <0.05). We found that higher IL-10 levels were related to lower risk of DR in DM patients. Levels of IL-6 and TNF-{alpha} as well as LDL diameter may be helpful in the prediction of PDR in DM patients with DR.

Keywords: plasma cytokine levels, plasma LDL diameter, proliferative diabetic retinopathy


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Diabetic retinopathy (DR), a common micro-vascular complication of diabetes mellitus (DM), results in blindness in >10,000 diabetic patients per yr [1]. If DR goes undetected or is untreated, it can have an adverse impact on patients’ quality of life and be a significant burden on health care costs [2]. Accordingly, early diagnosis and proper management of DR can improve the outcome in DM patients.

There are many methods to diagnose DR, such as ophthalmoscopy, fluorescein angiography, and fundus photography. The grading of stereoscopic color fundus photographs in 7 standard fields (SSFs), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) group, is a recognized standard for the detection of DR [3]. All of these ophthalmic diagnostic approaches must be conducted by ophthalmologists and require invasive and expensive procedures. The identification of peripheral blood biochemical parameters including a cytokine profile for DR could be helpful for early detection and management of DM patients with DR. Recent studies on cytokine profiles in vitreous or ocular fluid suggest that some cytokines, such as monocyte chemoatrractant protein-1 (MCP-1) [4], vascular endothelial growth factor (VEGF) [5,6], and hepatocyte growth factor (HGF) [7], could be involved the process of DR or PDR. Few studies on cytokine levels in peripheral blood have been performed in DM patients with DR or PDR [8,9]. Analysis of cytokine profiles in vitreous fluid would not be practical in a clinical laboratory because it is an invasive and costly procedure that requires extensive sample preparation. In this study, we evaluated the clinical usefulness of cytokine profiles in peripheral blood, as well as some biochemical parameters that might be helpful in the prediction and management of DR in type 2 DM patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study subjects  Seventy-four patients were enrolled who had been diagnosed with type 2 DM at least 6 mo prior and had been continuously receiving insulin therapy for at least 3 mo at Yonsei University Health System in Seoul, Korea. We obtained age- and sex-matched samples from DM patients with and without DR. Of the 74 patients (mean age ± SD, 59.2 ± 8.8 yr), there were 28 DM patients without DR (58.0 ± 8.6 yr) and 46 DM patients with DR (59.9 ± 9.0). Patients’ ages ranged from 37–77 yr (median, 60 yr). DM patients with DR were classified according to the degree of DR severity: mild (n = 21), moderate (n = 8), severe (n = 10), and PDR (n = 7). DM diagnosis was based on the 1985 World Health Organization criteria [10]. Exclusion criteria included other eye disorders that could interfere with the diagnosis of DR, acute myocardial infarction, any organ failure, liver disease, stroke, systemic and recent infection, and laser photocoagulation therapy. We also excluded patients who had taken lipid-lowering agents. The study protocol was approved by the Institutional Review Board (IRB) of Yonsei University Health System.

Diagnosis of DR  DR was diagnosed by ophthalmoscopy and fluorescein angiography through dilated pupils by an ophthalmologist at Yonsei University Health System. Patients were classified according to the presence or absence of DR and degree of severity using the final scale of the ETDRS Classification [3], as follows: 0, absent DR (DM patients without DR); 1, DM patients with mild DR; 2, DM patients with moderate DR; 3, DM patients with severe DR; and 4, DM patients with PDR.

Blood collection  From March 2006 to January 2007, overnight fasting EDTA plasma and serum samples were taken from the patients, aliquotted, and frozen at –76°C until analysis. EDTA plasma samples were thawed at room temperature and used for cytokine assays and LDL diameter (peak particle diameter). Serum samples were thawed at room temperature and used for biochemical assays.

Biochemical assays  All parameters were analyzed by spectrophotometry using a Hitachi-7600 D-module automatic Analyzer (Hitachi Ltd., Tokyo, Japan). Serum glucose was assayed by a hexokinase method with Gluco-quant Glucose/HK reagent (Roche Diagnostics, Mannheim, Germany). Serum urea nitrogen (BUN) was measured by a urease and glutamate dehydrogenase (GLDH) method with Wako L-type UN reagent (Wako Pure Chemicals, Osaka, Japan). Creatinine was assayed by the Jaffe picrate reaction using Daiichi Clinimate CREA reagent (Daiichi Pure Chemicals, Tokyo, Japan). Lactate dehydrogenase (LDH) was measured by spectrophotometric enzyme assay with Wako L-type LDH reagents (Wako Pure Chemicals). Total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured enzymatically with Daiichi reagents (Daiichi Pure Chemicals). Triglycerides were measured enzymatically using Roche triglyceride GPO-PAP reagents (Roche Diagnostics).

Measurement of LDL diameter  To evaluate LDL diameter, LDL was isolated from plasma according to the method of Griffin et al [11]. We isolated LDL from plasma at a density of 1.019–1.063 g/ml by density gradient ultracentrifugation. Then we performed electrophoresis using a pore-gradient lipoprotein system (CBS Scientific, Del Mar, CA) with commercially available non-denaturing 2–16% polyacrylamide gels (Alamo Gels, San Antonio, TX). After electrophoresis, the gels were fixed for 30 min in sulphosalicyclic acid and stained with Coomassie blue for 1 hr. The gels were destained in 7.5% acetic acid for 24 hr and standardized against markers: polystyrene latex beads (36 nm), thyroglobulin (17 nm), apoferritin (12.2 nm), and catalase (10.4 nm). The gels were scanned using GS-800 Calibrated Imaging Densitometer (Bio-Rad Laboratories, Graz, Austria).

Cytokine assays  Biochip array and evidence investigator cytokines and growth factors array (RANDOX Laboratories, Crumlin, UK) were used to perform simultaneous quantitative detection of multiple analytes from a single patient sample [12]. The evidence investigator array quantitatively tested for interleukin-1 alpha (IL-1{alpha}), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-4 (IL-4), IL-6, IL-8, IL-10, epidermal growth factor (EGF), VEGF, interferon-gamma (IFN-{gamma}), TNF-{alpha}, and MCP-1 by sandwich chemiluminescent immunoassay. Increased levels of cytokines in a specimen led to increased binding of an antibody labeled with horseradish peroxidase, and thus an increase in the chemiluminescence being emitted. The light signal generated from each of the test regions on the biochip was detected using digital imaging technology and compared with that from a stored calibration curve. The concentrations of analytes present in the sample were calculated from the calibration curve. Calibration and quality control (QC) procedures were performed according to the manufacturer’s instructions (RANDOX), QC materials, and guide. All QC parameters of cytokine assays passed acceptance criteria with good performance.

Statistical analyses  Data were expressed as mean ± SD or median and range. Comparisons of DM patients with and without DR were conducted by independent samples t-test. We evaluated the differences of biochemical parameters among the groups with different degrees of DR severity by analysis of variance (1-way ANOVA) with post-hoc Scheffe test. The risk factors of cytokines independently associated with the presence of DR in DM patients were analyzed by logistic regression using the backward Wald variable selection method. In the 46 DM patients with DR, comparisons of LDL diameter and cytokines between 39 DM patients with NPDR and 7 DM patients with PDR were performed by the Mann-Whitney U test. SPSS 12.0 (SPSS Inc., Chicago, IL) and Analyse-it (Analyse-it Software Ltd., Leeds, UK) were used for statistical analyses. A p-value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical characteristics and biochemical assays in DM patients with and without DR  Biochemical and demographic parameters were investigated. DM duration was longer in patients with DR (mean ± SD, range, 15.2 ± 6.9 yr, 3–35) than without DR (9.0 ± 5.4 yr, 1–23) (p <0.001). Serum glucose (p = 0.005) and total cholesterol (p = 0.029) levels were higher in DM patients with DR than without DR (Table 1Go). Other analytes such as serum urea, creatinine, HDL-C, LDL-C, triglycerides, and LDH did not show significant differences (p >0.05) between the 2 groups.


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  		Table 1. Clinical parameters of 74 DM patients with and without DR.
 
LDL diameter in DM patients with and without DR  In comparisons of LDL diameter, there was no significant difference between DM patients with DR (26.95 ± 1.08 nm) (p = 0.724) and without (26.85 ± 1.12 nm) (Table 1Go).

Cytokine profiles in DM patients with and without DR  Circulating levels of 12 plasma cytokines (IL-1{alpha}, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, EGF, VEGF, IFN-{gamma}, TNF-{alpha}, and MCP-1) were compared in DM patients with and without DR. None of the plasma cytokine concentrations were significantly different in DM patients with and without DR (p >0.05) (Table 1Go).

Plasma LDL diameter and cytokine profiles according to the degree of DR severity  Statistical significance was determined via 1-way ANOVA with post-hoc Scheffe test. LDL diameter, IL-6, and IL-8 showed significant differences among the different degrees of DR severity (p <0.05) (Table 2Go). The LDL diameter of DM patients with PDR was smaller than that of DM patients with severe DR. Plasma IL-6 level of DM patients with PDR was higher than those without DR, DM patients with mild DR, and DM patients with severe DR. Plasma IL-8 level of DM patients with moderate DR was higher than those without DR, DM patients with mild DR, and DM patients with severe DR. In trend analysis, LDL diameter and cytokines were analyzed according to the degree of DR severity via simple linear regression test. There was no significant linear association with increasing DR severity (p >0.05) (data not shown).


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  		Table 2. Characteristics of plasma LDL diameter and cytokine levels according to the degrees of DR severity.
 
Risk factor assessment of cytokines independently associated with presence of DR in DM patients  Logistic regression was performed to identify the risk factors of DR in DM patients using the backward Wald variable selection method. EGF, IL-6, IL-8, and IFN-{gamma} were ruled out sequentially in the course of variable selection. Among the cytokine parameters, only IL-10 (OR = 0.152; 95% CI: 0.028–0.817) was identified as a possible negative risk factor of DR (p = 0.028) (Table 3Go).


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  		Table 3. Risk factor assessment of cytokines independently associated with presence of DR in DM patients.
 
Comparisons of LDL diameter and cytokine profiles between DM with NPDR and DM with PDR  In DM patients with PDR, LDL diameter was smaller (p = 0.002) compared to DM patients with NPDR. In addition, in DM patients with PDR, IL-6 (p = 0.001) and TNF-{alpha} (p = 0.037) levels were higher compared to DM patients with NPDR (Table 4Go).


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  		Table 4. Comparison of plasma LDL diameter and cytokine levels between DM with NPDR and DM with PDR.
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we measured biochemical parameters, LDL diameter, and cytokine profiles in peripheral blood of 74 type 2 DM patients to compare the levels in DM patients with and without DR. There have been several reports of elevated inflammatory proteins, cytokines, or adhesion molecules in the vitreous fluid [4–7,13–15] or circulating blood [8,9] of DM patients with DR or PDR. In our results, the duration of DM in patients with DR was longer than in patients without DR. In addition, the levels of serum glucose and total cholesterol in DM patients with DR were higher than in DM patients without DR (p <0.05). In recent studies, dyslipidemia was reported to be a risk factor for diabetic renal disease but the effect of serum lipids on DR and macular edema is still under investigation; there have been several studies with conflicting results for lipid profiles in DR patients [16–18]. The EURODIAB IDDM Complications Study Group [19] reported that cholesterol levels were related to all levels of retinopathy and triglycerides were associated with moderately severe NPDR and PDR. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) [20] reported that average LDL particle diameter was negatively associated with DR of type 1 DM in 540 males. We found that LDL diameter was smaller in type 2 DM patients with PDR than type 2 DM patients with NPDR, but was not associated with the presence of DR. The different results between our study and the DCCT/EDIC study may be due to sample size and subjects’ characteristics such as DM type, because all patients in our study had type 2 DM. LDL diameter was not a decisive risk factor for PDR but could be screened in laboratory tests for PDR in DM patients.

In our analyses of plasma cytokine profiles, there was no cytokine that showed a statistically significant different level between DM patients with and without DR. Jacqueminet et al [8] suggested that peripheral blood MMP-9 level might serve as a surrogate biomarker of retinopathy in type 1 diabetic patients free of other vascular complications.

The degree of severity should be evaluated to decide the management of DM patients. LDL diameter, IL-6, and IL-8 showed significant differences among the different degrees of DR severity using ANOVA with post-hoc Scheffe analysis (Table 2Go). There was no significant linear trend between cytokine levels and degrees of DR severity in trend analysis, however MCP-1 (p for trend = 0.054), IL-10 (p for trend = 0.09), and IL-6 (p for trend = 0.116) showed relatively lower p-values than the other cytokines. We speculate that these three cytokines might show significant associations with the degrees of DR severity, if further large scale-studies were to be performed.

We also analyzed independent risk factors of all tested parameters associated with the presence of DR. IL-6, IL-8, EGF and IFN-{gamma} were ruled out sequentially through logistic regression analyses using the backward Wald variable selection method. There remained 8 variables among the cytokine parameters after logistic regression (Table 3Go). However, only plasma IL-10 level was negatively related to the incidence of DR in DM patients (p = 0.028). This result might be caused by the function of IL-10 as a potent anti-inflammatory cytokine [21]. There are few studies investigating the relationship between IL-10 and DR or PDR. Mysliwiec et al [22] suggested that IL-10 levels in DM type 1 patients presenting with various stages of DR allow higher secreting activity of IL-10 and seem to correlate with protective function against development of late diabetic complications. Hernández et al [23] reported that serum IL-10 levels were lower in diabetic patients with PDR than control subjects, but there were no differences in vitreous IL-10 levels between PDR patients and the control group.

We compared the plasma cytokine levels and LDL diameter in NPDR and PDR patients. The IL-6 and TNF-{alpha} levels were higher and LDL diameter was smaller in DM patients with PDR compared to those with NPDR. There have been reports [24,25] that suggested a significant role of the vitreous level of IL-6 in the pathogenesis of PDR, but there are few studies of the plasma level of IL-6 in PDR. Demircan et al [26] reported that vitreous TNF-{alpha} levels may play an important role in the pathogenesis of PDR, and Doganay et al [27] reported that the serum TNF-{alpha} level is higher in PDR patients, just as we have found. Therefore, the plasma levels of IL-6 and TNF-{alpha} might be useful cytokines for evaluation of PDR.

Our study has limitations since it included a relatively small number of DR patients (n = 46) and there was numerical discordance between NPDR (n = 39) and PDR (n = 7) cases. Prospective studies of larger study populations are necessary to clarify various suggestive peripheral blood biochemical parameters of DR or PDR, such as LDL diameter, cytokines, and other biomarkers.

In conclusion, we found that plasma IL-10 level was negatively related to the incidence of DR in DM patients. Plasma LDL diameter was smaller and IL-6 and TNF-{alpha} levels were higher in DM patients with PDR compared to those with NPDR.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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