Original Paper Ophthalmic Res 2014;51:42–45 DOI: 10.1159/000355323
Received: July 8, 2013 Accepted: August 23, 2013 Published online: November 9, 2013
Body Fat Distribution and Adipokine Secretion Are Not Associated with Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus D. Dossarps a J.M. Petit b B. Guiu c J.P. Cercueil c L. Duvillard d A.M. Bron a C. Creuzot-Garcher a Departments of a Ophthalmology, b Endocrinology, c Radiology and d Biochemistry, CRI INSERM 866, University Hospital, Dijon, France
Abstract Aims: The link between diabetic retinopathy (DR) and adipokines is controversial. Some studies suggest that visceral fat and adipokines could be additional risk factors for DR. The aim of this study was to determine the relationship between abdominal fat or adipokine secretion and DR in patients with type 2 diabetes mellitus (DM). Methods: A total of 179 patients with type 2 DM were included. Each patient underwent measurement of plasma adiponectin and leptin and an evaluation of body fat distribution (visceral and subcutaneous) with MRI. The severity of DR was evaluated according to the classification of the American Academy of Ophthalmology. Patients were classified in 3 groups: absence of DR, mild and moderate DR, and advanced DR (severe, proliferative and laser-treated DR). Results: There were no significant differences between the 3 groups for adiponectin, leptin and visceral or subcutaneous fat accumulation. Patients with DR had a mean duration of diabetes, serum creatinine concentration and percentage of macroalbu-
© 2013 S. Karger AG, Basel 0030–3747/14/0511–0042$39.50/0 E-Mail [email protected] www.karger.com/ore
minuria significantly higher than patients without DR (p < 0.001, p = 0.003 and p < 0.001, respectively). Serum adiponectin increased with the diabetic nephropathy stage (p = 0.007). Conclusions: Our study suggests that body fat distribution and adipokine secretion are not associated with DR in patients with type 2 DM. © 2013 S. Karger AG, Basel
Introduction
In industrialized countries, diabetic retinopathy (DR) is the leading cause of blindness in people aged 50 or less [1] and the third most important cause of vision loss in the elderly [2]. The major risk factors for retinopathy in patients with diabetes are poor glycemic or blood pressure control, duration of diabetes and nephropathy related to the severity of DR [3, 4]. Abdominal obesity and visceral fat are associated with metabolic syndrome and promote the development of diabetes and insulin resistance [5–7]. Several studies suggest that DR is associated with visceral fat accumulation or obesity in type 2 diabetes mellitus (DM) patients [8, 9]. It is important to evaluate whether obesity and visceral fat Catherine Creuzot-Garcher Department of Ophthalmology University Hospital FR–21000 Dijon (France) E-Mail catherine.creuzot-garcher @ chu-dijon.fr
Downloaded by: University of Aberdeen139.133.11.2 - 2/15/2015 5:23:21 AM
Key Words Diabetic retinopathy · Adiponectin · Leptin · Visceral fat · Type 2 diabetes mellitus
Subjects and Methods Study Population This single-center study was approved by the regional ethics committee. Written informed consent was obtained from all patients prior to inclusion in the study. Between February 2008 and November 2010, 179 (89 men and 90 women) patients were screened prospectively at the Endocrinology Department for the following inclusion criteria: type 2 DM, the absence of acute or chronic disease based on the patient’s medical history, physical examination, and standard laboratory tests (blood counts, electrolyte concentrations). Patients who had received thiazolidinediones were excluded.
tion are: no apparent DR, mild DR, moderate DR, severe DR, and proliferative DR. The patients were then classified into 3 groups: absence of DR, simple DR (mild and moderate) and advanced DR (severe, proliferative and laser-treated DR). Grading was done with 2 trained ophthalmologists (D.D. and A.M.B.). In case of disagreement, adjudication was done by a third ophthalmologist (C.C.-G.). Assessment of Diabetic Nephropathy Diabetic nephropathy (DN) was graded as follows: stage 0 for patients with normoalbuminuria (urinary albumin excretion 300 mg/24 h). Statistical Analysis Data were collected on a spreadsheet (Microsoft Office Excel 2007) and all the analyses were performed using StatView 5.0 (SAS Institute, Cary, N.C., USA). A Kolmogorov-Smirnov test was used to evaluate the distribution characteristics of the variables, which were not normally distributed. Comparisons between groups were made using the nonparametric Kruskal-Wallis test for continuous variables and the χ2 test for categorical data. Statistical correlations were determined by the nonparametric Spearman test. The tests were two-tailed, and the significance threshold was set at p < 0.05.
Results
Assessment of DR At inclusion, each patient underwent fundus photography using a Topcon TRC-NW6S nonmydriatic camera (Topcon, Tokyo, Japan). Nonstereoscopic 45° images of four fields were taken for each eye (posterior pole, nasal, temporal and superior) and a fundus examination was carried out by an ophthalmologist. We used the classification of the American Academy of Ophthalmology to evaluate the severity of DR [16]. The different stages of classifica-
A total of 179 patients were included – 110 patients (61.5%) without DR and 69 patients with DR (38.5%). The patients were subdivided according to the severity of retinopathy (table 1). No significant differences in age, sex, HbA1c and BMI were observed for each subgroup. Adiponectin was positively correlated with age (r = 0.198; p < 0.001), negatively correlated with triglycerides (r = –0.281; p < 0.001) and not correlated with BMI (r = 0.107; p = 0.467) and visceral fat (r = –0.047; p = 0.467). Leptin was positively correlated with BMI (r = 0.625; p < 0.0001) and visceral fat (r = 0.236; p < 0.001) and not correlated with triglycerides (r = 0.082; p = 0.162). Adiponectin and leptin were significantly lower in men than in women (p < 0.0001). There were no significant differences between the 3 groups of DR for levels of adiponectin, leptin, visceral fat accumulation and subcutaneous fat. Patients with advanced or simple DR had a mean duration of diabetes, serum creatinine concentration and percentage of macroalbuminuria significantly higher than patients without DR (table 1). Patients with DN stage 2 had a higher adiponectin concentration than patients with DN stage 1 or stage 0, with a median (range) of 6.4 (1.7–29.7) versus 4.4 (0.7– 13.5) and 4.3 (0.6–27.3), respectively (p = 0.007).
Adipokines or Body Fat Distribution and Diabetic Retinopathy
Ophthalmic Res 2014;51:42–45 DOI: 10.1159/000355323
Biochemical Measurements Plasma glucose, HbA1c, fasting serum HDL cholesterol, fasting LDL cholesterol, fasting serum triglycerides, and serum creatinine concentration were determined by standard procedures. Serum adiponectin and serum leptin concentrations were measured by using a commercial ELISA (human adiponectin ELISA kit and human leptin ELISA kit; Quantikine; R&D Systems, Wiesbaden, Germany). Assessment of Body Fat Body mass index (BMI) was measured in all patients, which was calculated as weight/(height)2 (kilograms per square meter). The patients underwent MRI and a single-slice axial T1-weighted image at the level of the L4/L5 intervertebral disk was analyzed to measure the cross sectional area of visceral and subcutaneous fat (cm2) [15].
43
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could be associated with DR, independently of insulin resistance. The modification of adipokine secretion secondary to visceral obesity could be one mechanism involved in the pathogenesis of DR. Several studies have shown that adiponectin increases the sensitivity to insulin [10] and also acts on blood vessels, decreasing inflammation, atherosclerosis [11, 12] and neovascularization [13]. In mice, it was shown that adiponectin suppresses pathological microvessel formation in the retina through modulation of tumor necrosis factor-α expression [14]. We hypothesize that visceral fat distribution and adipokine secretion could have a direct effect on DR. The aim of this study was to determine the relationship between abdominal fat or adipokine secretions and DR in patients with type 2 DM.
Table 1. Characteristics of the patients according to the severity of retinopathy
Sex, M/F Age, years HbA1c, mmol/mol Percent BMI Creatinine, μmol/l Patients with macroalbuminuria, n Duration of diabetes, years Visceral fat, cm2 Subcutaneous fat, cm2 Adiponectin, μg/ml Leptin, ng/ml
No DR (n = 110)
Simple DR (n = 48)
Advanced DR (n = 21)
p
56/54 59.6 (35.3 – 82.2) 73 (32 – 148) 8.8 (5.1 – 15.7) 33.7 (21.8 – 51.7) 81 (48.0 – 141.0) 13 (11.8) 10.0 (1.0 – 50) 272.5 (74.0 – 636.0) 363.0 (164.0 – 957.0) 4.6 (0.7 – 27.3) 18.8 (3.2 – 111.9)
22/26 62.1 (36.3 – 75.6) 68 (39 – 123) 8.4 (5.7 – 13.4) 33.8 (24.7 – 44.9) 85.0 (42.0 – 271.0) 10 (20.8) 16.0 (2.0 – 40.0) 237.5 (114.0 – 634.0) 352.0 (160.5 – 603.0) 4.0 (0.6 – 29.7) 21.5 (4.7 – 70.0)
11/10 63.0 (46.4 – 77.6) 75 (49 – 111) 9.0 (6.6 – 12.3) 33.1 (20.7 – 48.1) 93.0 (53.0 – 219.0) 12 (57.1) 25.0 (6.0 – 48.0) 288.0 (116.0 – 497.0) 339 (76.0 – 601.0) 5.4 (1.0 – 15.7) 25.9 (3.7 – 98.2)
0.814 0.398 0.489 0.796 0.003
Received: July 8, 2013 Accepted: August 23, 2013 Published online: November 9, 2013
Body Fat Distribution and Adipokine Secretion Are Not Associated with Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus D. Dossarps a J.M. Petit b B. Guiu c J.P. Cercueil c L. Duvillard d A.M. Bron a C. Creuzot-Garcher a Departments of a Ophthalmology, b Endocrinology, c Radiology and d Biochemistry, CRI INSERM 866, University Hospital, Dijon, France
Abstract Aims: The link between diabetic retinopathy (DR) and adipokines is controversial. Some studies suggest that visceral fat and adipokines could be additional risk factors for DR. The aim of this study was to determine the relationship between abdominal fat or adipokine secretion and DR in patients with type 2 diabetes mellitus (DM). Methods: A total of 179 patients with type 2 DM were included. Each patient underwent measurement of plasma adiponectin and leptin and an evaluation of body fat distribution (visceral and subcutaneous) with MRI. The severity of DR was evaluated according to the classification of the American Academy of Ophthalmology. Patients were classified in 3 groups: absence of DR, mild and moderate DR, and advanced DR (severe, proliferative and laser-treated DR). Results: There were no significant differences between the 3 groups for adiponectin, leptin and visceral or subcutaneous fat accumulation. Patients with DR had a mean duration of diabetes, serum creatinine concentration and percentage of macroalbu-
© 2013 S. Karger AG, Basel 0030–3747/14/0511–0042$39.50/0 E-Mail [email protected] www.karger.com/ore
minuria significantly higher than patients without DR (p < 0.001, p = 0.003 and p < 0.001, respectively). Serum adiponectin increased with the diabetic nephropathy stage (p = 0.007). Conclusions: Our study suggests that body fat distribution and adipokine secretion are not associated with DR in patients with type 2 DM. © 2013 S. Karger AG, Basel
Introduction
In industrialized countries, diabetic retinopathy (DR) is the leading cause of blindness in people aged 50 or less [1] and the third most important cause of vision loss in the elderly [2]. The major risk factors for retinopathy in patients with diabetes are poor glycemic or blood pressure control, duration of diabetes and nephropathy related to the severity of DR [3, 4]. Abdominal obesity and visceral fat are associated with metabolic syndrome and promote the development of diabetes and insulin resistance [5–7]. Several studies suggest that DR is associated with visceral fat accumulation or obesity in type 2 diabetes mellitus (DM) patients [8, 9]. It is important to evaluate whether obesity and visceral fat Catherine Creuzot-Garcher Department of Ophthalmology University Hospital FR–21000 Dijon (France) E-Mail catherine.creuzot-garcher @ chu-dijon.fr
Downloaded by: University of Aberdeen139.133.11.2 - 2/15/2015 5:23:21 AM
Key Words Diabetic retinopathy · Adiponectin · Leptin · Visceral fat · Type 2 diabetes mellitus
Subjects and Methods Study Population This single-center study was approved by the regional ethics committee. Written informed consent was obtained from all patients prior to inclusion in the study. Between February 2008 and November 2010, 179 (89 men and 90 women) patients were screened prospectively at the Endocrinology Department for the following inclusion criteria: type 2 DM, the absence of acute or chronic disease based on the patient’s medical history, physical examination, and standard laboratory tests (blood counts, electrolyte concentrations). Patients who had received thiazolidinediones were excluded.
tion are: no apparent DR, mild DR, moderate DR, severe DR, and proliferative DR. The patients were then classified into 3 groups: absence of DR, simple DR (mild and moderate) and advanced DR (severe, proliferative and laser-treated DR). Grading was done with 2 trained ophthalmologists (D.D. and A.M.B.). In case of disagreement, adjudication was done by a third ophthalmologist (C.C.-G.). Assessment of Diabetic Nephropathy Diabetic nephropathy (DN) was graded as follows: stage 0 for patients with normoalbuminuria (urinary albumin excretion 300 mg/24 h). Statistical Analysis Data were collected on a spreadsheet (Microsoft Office Excel 2007) and all the analyses were performed using StatView 5.0 (SAS Institute, Cary, N.C., USA). A Kolmogorov-Smirnov test was used to evaluate the distribution characteristics of the variables, which were not normally distributed. Comparisons between groups were made using the nonparametric Kruskal-Wallis test for continuous variables and the χ2 test for categorical data. Statistical correlations were determined by the nonparametric Spearman test. The tests were two-tailed, and the significance threshold was set at p < 0.05.
Results
Assessment of DR At inclusion, each patient underwent fundus photography using a Topcon TRC-NW6S nonmydriatic camera (Topcon, Tokyo, Japan). Nonstereoscopic 45° images of four fields were taken for each eye (posterior pole, nasal, temporal and superior) and a fundus examination was carried out by an ophthalmologist. We used the classification of the American Academy of Ophthalmology to evaluate the severity of DR [16]. The different stages of classifica-
A total of 179 patients were included – 110 patients (61.5%) without DR and 69 patients with DR (38.5%). The patients were subdivided according to the severity of retinopathy (table 1). No significant differences in age, sex, HbA1c and BMI were observed for each subgroup. Adiponectin was positively correlated with age (r = 0.198; p < 0.001), negatively correlated with triglycerides (r = –0.281; p < 0.001) and not correlated with BMI (r = 0.107; p = 0.467) and visceral fat (r = –0.047; p = 0.467). Leptin was positively correlated with BMI (r = 0.625; p < 0.0001) and visceral fat (r = 0.236; p < 0.001) and not correlated with triglycerides (r = 0.082; p = 0.162). Adiponectin and leptin were significantly lower in men than in women (p < 0.0001). There were no significant differences between the 3 groups of DR for levels of adiponectin, leptin, visceral fat accumulation and subcutaneous fat. Patients with advanced or simple DR had a mean duration of diabetes, serum creatinine concentration and percentage of macroalbuminuria significantly higher than patients without DR (table 1). Patients with DN stage 2 had a higher adiponectin concentration than patients with DN stage 1 or stage 0, with a median (range) of 6.4 (1.7–29.7) versus 4.4 (0.7– 13.5) and 4.3 (0.6–27.3), respectively (p = 0.007).
Adipokines or Body Fat Distribution and Diabetic Retinopathy
Ophthalmic Res 2014;51:42–45 DOI: 10.1159/000355323
Biochemical Measurements Plasma glucose, HbA1c, fasting serum HDL cholesterol, fasting LDL cholesterol, fasting serum triglycerides, and serum creatinine concentration were determined by standard procedures. Serum adiponectin and serum leptin concentrations were measured by using a commercial ELISA (human adiponectin ELISA kit and human leptin ELISA kit; Quantikine; R&D Systems, Wiesbaden, Germany). Assessment of Body Fat Body mass index (BMI) was measured in all patients, which was calculated as weight/(height)2 (kilograms per square meter). The patients underwent MRI and a single-slice axial T1-weighted image at the level of the L4/L5 intervertebral disk was analyzed to measure the cross sectional area of visceral and subcutaneous fat (cm2) [15].
43
Downloaded by: University of Aberdeen139.133.11.2 - 2/15/2015 5:23:21 AM
could be associated with DR, independently of insulin resistance. The modification of adipokine secretion secondary to visceral obesity could be one mechanism involved in the pathogenesis of DR. Several studies have shown that adiponectin increases the sensitivity to insulin [10] and also acts on blood vessels, decreasing inflammation, atherosclerosis [11, 12] and neovascularization [13]. In mice, it was shown that adiponectin suppresses pathological microvessel formation in the retina through modulation of tumor necrosis factor-α expression [14]. We hypothesize that visceral fat distribution and adipokine secretion could have a direct effect on DR. The aim of this study was to determine the relationship between abdominal fat or adipokine secretions and DR in patients with type 2 DM.
Table 1. Characteristics of the patients according to the severity of retinopathy
Sex, M/F Age, years HbA1c, mmol/mol Percent BMI Creatinine, μmol/l Patients with macroalbuminuria, n Duration of diabetes, years Visceral fat, cm2 Subcutaneous fat, cm2 Adiponectin, μg/ml Leptin, ng/ml
No DR (n = 110)
Simple DR (n = 48)
Advanced DR (n = 21)
p
56/54 59.6 (35.3 – 82.2) 73 (32 – 148) 8.8 (5.1 – 15.7) 33.7 (21.8 – 51.7) 81 (48.0 – 141.0) 13 (11.8) 10.0 (1.0 – 50) 272.5 (74.0 – 636.0) 363.0 (164.0 – 957.0) 4.6 (0.7 – 27.3) 18.8 (3.2 – 111.9)
22/26 62.1 (36.3 – 75.6) 68 (39 – 123) 8.4 (5.7 – 13.4) 33.8 (24.7 – 44.9) 85.0 (42.0 – 271.0) 10 (20.8) 16.0 (2.0 – 40.0) 237.5 (114.0 – 634.0) 352.0 (160.5 – 603.0) 4.0 (0.6 – 29.7) 21.5 (4.7 – 70.0)
11/10 63.0 (46.4 – 77.6) 75 (49 – 111) 9.0 (6.6 – 12.3) 33.1 (20.7 – 48.1) 93.0 (53.0 – 219.0) 12 (57.1) 25.0 (6.0 – 48.0) 288.0 (116.0 – 497.0) 339 (76.0 – 601.0) 5.4 (1.0 – 15.7) 25.9 (3.7 – 98.2)
0.814 0.398 0.489 0.796 0.003
