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Diabetes Care 25:2328-2334, 2002
© 2002 by the American Diabetes Association, Inc.

Pathophysiology/Complications
Original Article

Macular Edema Reflects Generalized Vascular Hyperpermeability in Type 2 Diabetic Patients With Retinopathy

Søren T. Knudsen, MD, PHD1, Toke Bek, MD, DMSC2, Per L. Poulsen, MD, PHD1, Marianne N. Hove, MD2, Michael Rehling, MD, DMSC3 and Carl E. Mogensen, MD, DMSC1

1 Medical Department M (Diabetes & Endocrinology), Aarhus Kommunehospital, Aarhus, Denmark
2 Department of Ophthalmology, Aarhus Kommunehospital, Aarhus, Denmark
3 Department of Clinical Physiology and Nuclear Medicine, Aarhus Kommunehospital, Aarhus, Denmark


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS—
 CONCLUSIONS—
 References
 
OBJECTIVE—Diabetic maculopathy (DMa) is the most prevalent sight-threatening type of retinopathy in type 2 diabetes and a leading cause of visual loss in the western world. The disease is characterized by hyperpermeability of retinal blood vessels and subsequent formation of hard exudates and macular edema, the degree of which can be estimated by measurement of retinal thickness. We examined associations between retinal thickness as evaluated by optical coherence tomography scanning (OCT), glomerular leakage as evaluated by urinary albumin excretion rate (UAE), and general vascular leakage as evaluated by the transcapillary escape rate of albumin (TERalb) in type 2 diabetic patients with and without DMa.

RESEARCH DESIGN AND METHODS—In 20 type 2 diabetic patients with DMa and 20 type 2 diabetic patients without retinopathy matched for age, sex, and duration of diabetes, we performed OCT, fundus photography, fluorescein angiography, and 24-h ambulatory blood pressure measurement. UAE was determined by radioimmunoassay. TERalb was determined as the initial disappearance of intravenously injected 125I-labeled human serum albumin.

RESULTS—Patients with diabetic maculopathy had higher HbA1c (8.5 ± 1.5 vs. 7.4 ± 1.2%, P < 0.05) and higher total cholesterol (5.8 ± 0.7 vs. 5.2 ± 0.9 mmol/l, P < 0.05) than patients without retinopathy. UAE was higher in the DMa group than in the group with no retinopathy (9.3 x/÷ 3.1 vs. 3.9 x/÷ 1.9 µg/min, P < 0.01). There was no difference in TERalb between the two groups (6.0 ± 1.6 vs. 6.6 ± 1.5%, NS). In the group with DMa, OCT, TERalb, and UAE correlated significantly (OCT versus TERalb: r = 0.55, P < 0.05; OCT versus UAE: r = 0.58, P < 0.01; UAE versus TERalb: r = 0.81, P < 0.01). Conversely, there were no correlations between these three parameters in the group without retinopathy.

CONCLUSIONS—Macular edema seems to reflect a generalized vascular leakage in type 2 diabetic patients.

Abbreviations: AMBP, 24-h ambulatory blood pressure • BP, blood pressure • DMa, diabetic maculopathy • OCT, optical coherence tomography scanning • TERalb, transcapillary escape rate of albumin • UAE, urinary albumin excretion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS—
 CONCLUSIONS—
 References
 
Diabetic retinopathy remains a leading cause of vision loss in the western world (1). Diabetic maculopathy (DMa) is the most prevalent sight-threatening manifestation of retinopathy in type 2 diabetes (2). Therefore, this type of retinopathy is anticipated to predominate in the future, as the number of type 2 diabetic patients escalates (3). DMa is characterized by a variety of morphological changes in the retina, including hemorrhages, cotton wool spots, exudates, and edema. The pathogenic mechanisms initiating this eye disease are unknown, but lesions such as hard exudates and edema can be ascribed to a pathologically increased permeability of retinal blood vessels.

Retinal edema is considered the most important indicator of retinal damage leading to visual impairment. Hitherto, quantitative assessment of retinal edema has been difficult. However, with the advent of the new diagnostic modality, optical coherence tomography scanning (OCT) (4), measurement of retinal thickness, and thereby quantification of retinal edema, has become feasible. Several studies have introduced OCT for evaluation of diabetic retinopathy (5,6).

Whether the vascular hyperpermeability leading to macular edema is an isolated retinal phenomenon or an ocular manifestation of a generalized vascular hyperpermeability is currently unknown. Therefore, the purpose of our study was to evaluate the association between the degree of macular edema, as assessed by OCT, and two measures of vascular permeability in the systemic circulation, namely urinary albumin excretion (UAE) rate and transcapillary escape rate of albumin (TERalb) (7) in type 2 diabetic patients with and without DMa. Furthermore, study patients were characterized with regard to glycemic control (8), blood lipid levels (9), ambulatory blood pressure (AMBP) (10), and autonomic neuropathy (11).


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS—
 CONCLUSIONS—
 References
 
Patients
Case group.
A total of 20 type 2 diabetic patients with DMa, defined as retinal hemorrhages and/or microaneurysms combined with hard exudates and/or retinal edema in the macular area, were identified in the database of eye examinations in our screening clinic for diabetic retinopathy. For each patient in the case group, we defined the study eye as the eye with the most severe degree of retinopathy.

Control group.
A total of 20 type 2 diabetic patients with no signs of retinopathy were identified in the above-mentioned database. For each patient in the DMa group, we identified and ranked the 10 patients in the database with no retinopathy that matched best with regard to age, sex, and known duration of diabetes. The patients were invited to participate in the study according to rank. For each control patient, we included the eye corresponding to the study eye of the matching case.

Patients were considered to have type 2 diabetes if they had onset of diabetes after age 30 years, had no need for insulin treatment for at least 1 year after the diagnosis of diabetes, and had no history of ketoacidosis. Because ACE inhibitors are known to affect UAE and have been suggested to affect TERalb (12) and retinal vascular permeability (13), patients treated with ACE inhibitors or angiotensin II receptor antagonists were not included. Likewise, patients previously treated with laser photocoagulation were not included.

Leisure time physical activity was graded as follows: passive (not participants), moderate (physical exercise once or twice a week), and active (physical exercise more than twice a week). Patients were classified as nonsmokers (without daily use of tobacco for the preceding year), moderate smokers (<15 cigarettes per day), or heavy smokers (>15 cigarettes per day). Patients were classified as having macrovascular disease if one or more of the following were present: symptoms of angina pectoris; history of myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty; symptoms of or operation for intermittent claudication; or history of amputation, transient ischemic attack, or stroke. All subjects included in the study were Caucasian.

Eye examinations
The patients underwent routine ophthalmological examinations for diabetic retinopathy, including measurement of visual acuity, slit-lamp examination, fundus photography, fluorescein angiography, as well as OCT of the central retina.

Retinal photography.
Fundus photography was performed using a Canon 60UV fundus camera on Kodak Ektachrome 64 color diapositive film. In each eye, one 60° image centered on the fovea and a nasally displaced field centered on the optic disk were taken. Fluorescein angiography was performed using Ilford Delta 400 black/white film. A fast sequence was taken during the filling phase of the retinal vessels of the study eye, and late-phase images were taken of both eyes 5–10 min after injection of fluorescein. The fluorescein angiograms verified that all maculopathies were of an exudative type.

OCT.
The OCT method is analogous to ultrasound B-scanning, in that distance information is extracted from the time delays of reflected signals. Optical (laser) instead of acoustic waves are used in OCT, which allows a much higher resolution (10 µm) and thereby a more precise assessment of retinal thickness (14). Therefore, this method is very sensitive and, in addition, noninvasive. In this study, we used the Humphrey optical coherence tomography scanner (version A4.1; Humphrey Instruments, San Leandro, CA). Six radial scans centered on the fixation point were performed with a 30° interval (Fig. 1). Each scan had a length of 2.83 mm, and the sequence of scanning was the same for all patients, as performed using the default settings of the scanner.



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  		Figure 1— Horizontal OCT scans (length 2.83 mm) through the fovea from two different type 2 diabetic patients. Points used for measurements of retinal thickness are indicated by white, horizontal bars. A: OCT scan of a patient with no diabetic retinopathy. B: OCT scan of a patient with macular edema. Note the diffuse thickening of the retina and the disappearance of the foveal depression.

 
Analysis of OCT scans was performed by an ophthalmologist who had not participated in the examination of study patients. Therefore, this ophthalmologist had no knowledge of the patients’ clinical or laboratory data and did not know whether individual patients were case or control subjects. The scans were displayed on the OCT monitor, and the distance from the retinal surface to the zone with highest reflectivity at the choriocapillaris/pigment epithelium was measured with a ruler. The measured distances on the monitor were converted to distances on the retinal plane using the standard calibration of the OCT apparatus. For each scan, five thickness measurements were obtained, at points 10, 30, 50, 70, and 90% of the length of the scan from its beginning (Fig. 1) (15,16). The average thickness of a scan was calculated as the mean of the five measured thicknesses, and the average retinal thickness in the macular area was then calculated as the mean thickness of the six scans. One patient in the control group had no identifiable high reflectivity zone at the choriocapillaris/pigment epithelium, and for this reason, we were not able to measure retinal thickness in this patient. The OCT scans of this patient were excluded, leaving 20 sets of OCT scans in the case group and 19 sets in the control group for analysis.

TERalb
In the first 15 patients included in each group, we measured the TERalb as described by Parving et al. (17,18). We were unable to perform this examination in the last five patients in each group because of a sudden withdrawal of 125I-labeled albumin from the market.

The examination was performed in the morning after an overnight fast. After resting for 1 h in the supine position, the patient received an intravenous bolus injection containing 0.2 MBq 125I-labeled human albumin (HSA for metabolic studies, IsoPharma IT.23S). Blood samples were collected from a cubital vein in the other arm before and 10, 15, 20, 30, 40, 50, 55, and 60 min after the injection for counting of plasma radioactivity and measurement of total plasma protein concentration in duplicate by refractometry (Bellingham & Stanley, Tunbridge Wells, U.K.). Radioactivity was corrected for total plasma protein concentration, and the slope of the linear regression of radioactivity on time was used to calculate TERalb (i.e., the plasma tracer disappearance rate). TERalb measurements were accepted only if the correlation coefficient between the time points for blood collection and the corresponding values of a specific radioactivity exceeded 0.85. On the basis of this criterium, two TERalb examinations (one case subject and one control subject) were excluded from the analyses.

24-h blood pressure measurements
AMBP was measured using an oscillometric technique (Spacelabs 90207, validated by the British Hypertension Society) (19). Readings were obtained at 20-min intervals over 24 h. Individually reported sleeping times were implemented in the calculation of day and night blood pressure (BP).

Autonomic function tests
Three bedside cardiovascular reflex tests were performed: heart rate variation to deep breathing (inspiration/expiration difference, average of two determinations), heart rate response to standing up (30:15 ratio), and blood pressure response to standing up. These tests were performed and evaluated as described by Ewing et al. (20).

Biochemical analyses
UAE was measured by radioimmunoassay and expressed as the geometric mean of three overnight collections made within 1 week. HbA1c was determined by high-performance liquid chromatography (nondiabetic range 4.4–6.4%). Blood glucose was determined using the Reflolux II (Boehringer Mannheim, Mannheim, Germany).

All subjects included in the study gave their written informed consent to participate. The study was approved by the regional ethics committee.

Statistical analysis
To approximate normal distribution, UAE measurements were log-transformed before analysis. Differences between groups were tested by the unpaired Student’s t test. For noncontinuous variables, the {chi}2 test with Yates’ correction was used. Correlations were analyzed using Pearson’s test. A two-tailed P value <0.05 was considered significant. Results for normally distributed variables are expressed as mean ± SD, whereas UAE values are expressed as geometric mean x/÷ tolerance factor.


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS—
CONCLUSIONS—
 References
 
Clinical characteristics, retinal thicknesses, UAE, TERalb, and AMBP values of the patients are shown in Table 1.


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  		Table 1— Clinical characteristics, retinal thickness, UAE, TERalb, and AMBP values of type 2 diabetic patients without retinopathy or DMa

 
The groups were well matched with regard to age, sex, and known duration of diabetes. The median pairwise difference was 1.4 years for age and 1.2 years for duration of diabetes. Values of HbA1c and total cholesterol were significantly higher in the patients with DMa than in the patients without retinopathy. Interestingly, the level of physical activity was higher in the control group than in the case group, whereas there were no differences in use of antidiabetic medication, prevalence of macrovascular disease, smoking habits, BMI, or serum creatinine level between the groups. The cardiovascular reflex tests revealed no statistically significant differences in autonomic function between the groups (data not shown).

Average UAE and retinal thickness, as measured by OCT, were higher in the group with DMa than in the control group. There was no significant difference in TERalb between the groups. AMBP values, pulse pressures, and night/day ratios were uniformly higher in the case group than in the control group, although the differences between groups did not reach the level of statistical significance (all data not shown). Because more case subjects than control subjects received antihypertensive treatment, true differences in BP between the groups might have been missed. Restricting the analysis to the subgroup of patients not receiving antihypertensive treatment (10 case subjects, 14 control subjects), BP values were still uniformly higher in the case group than in the control group, but the differences were numerically larger, reaching statistical significance for night systolic BP (131 ± 14 vs. 117 ± 14 mmHg, P < 0.05) and night pulse pressure (60 ± 9 vs. 49 ± 9 mmHg, P < 0.01).

In the total group of patients (n = 40), retinal thickness (OCT), UAE, and TERalb showed a significant correlation (OCT versus UAE: r = 0.56, P < 0.01; OCT versus TERalb: r = 0.36, P = 0.069; UAE versus TERalb: r = 0.38, P < 0.05). In a subgroup analysis, there was a strong correlation between OCT, UAE, and TERalb in the group with DMa (\?\Figs. 2–4) (OCT versus UAE: r = 0.58, P < 0.01; OCT versus TERalb: r = 0.55, P < 0.05; UAE versus TERalb: r = 0.81, P < 0.01), whereas there were no correlations between these three parameters in the group without retinopathy (OCT versus UAE: r = 0.04, P = 0.86; OCT versus TERalb: r = 0.37, P = 0.22; UAE versus TERalb: r = 0.14, P = 0.63).



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  		Figure 2— UAE versus average retinal thickness as measured by OCT in type 2 diabetic patients with DMa.

 


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  		Figure 4— UAE versus TERalb in type 2 diabetic patients with DMa.

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS—
 CONCLUSIONS—
References
 
Our study is the first to examine associations between retinal thickness as assessed by OCT and measures of glomerular and vascular permeability in diabetes. In type 2 diabetic patients with DMa, we found significant correlations between retinal thickness, UAE, and TERalb, whereas no such association was seen in type 2 diabetic patients without retinopathy. Increased retinal thickness has previously been shown to coincide with increased leakage of retinal blood vessels in type 2 diabetes (21). Therefore, our findings indicate that in type 2 diabetic patients with DMa, the pathologically increased permeability of the retinal vessels, as reflected by increased retinal thickness, corresponds to equivalent permeability changes in kidney capillaries and in small vessels throughout the circulation of the diabetic patient.

A decade ago, the hypothesis of albuminuria as a marker of widespread endothelial damage was introduced (22). Several studies have established a relationship between abnormal UAE and increased TERalb (23,24,25). Because retinopathy and nephropathy are often coexisting in diabetes, it has been difficult to establish an independent association between the presence of retinopathy and increased TERalb (24,25). In the present study, we were not able to demonstrate differences in TERalb between the groups with and without retinopathy. This could be because the included cases had varying degrees of DMa, ranging from a single hard exudate to macular edema. However, when considering the varying degree of macular edema, as evaluated by OCT measurements of retinal thickness, we found a significant association between retinal thickening and TERalb.

Several studies have established a statistical association between retinopathy and nephropathy in type 1 diabetes (26) as well as in type 2 diabetes (27), and these complications were also strongly correlated in the present study. Both DMa and diabetic nephropathy are characterized by a pathologically increased permeability of a vascular barrier. In DMa, leakage of lipoproteins and water from the retinal vessels results in formation of hard exudates and macular edema, whereas increased permeability of glomerular capillaries in diabetic nephropathy leads to an increased UAE. Hemodynamic as well as structural abnormalities are believed to initiate these changes. It is well known that systemic hypertension is a risk factor for development of both retinopathy and nephropathy in diabetes (28,29), conceivably because elevated blood pressure is transmitted to the microcirculation, thus resulting in capillary/glomerular hyperperfusion and hypertension (30,–32). Because the retinal vessels have no autonomic innervation, blood flow in response to increased blood pressure is dependent on local factors, e.g., autoregulation. As the autoregulatory capacity of the retinal circulation is impaired when blood glucose is elevated (33), simultaneous hypertension and hyperglycemia is anticipated to be particularly detrimental for the microvasculature.

In accordance with this hypothesis, our patients without retinopathy had significantly better glycemic control and also tended to have lower blood pressure than patients with DMa. These findings are in line with results from the U.K. Prospective Diabetes Study, in which poor glycemic control and elevated blood pressure have been pointed out as major risk factors for development of diabetic complications (34). We have recently shown that increased pulse pressure is associated with a higher frequency of complications in type 2 diabetic patients (35). Furthermore, lowering of blood pressure and glycemia has been proven to slow the development and progression of microvascular complications in diabetes (36,–40).

In several studies, treatment with ACE inhibitors has been proposed to provide specific organ-protective effects beyond what would be expected from the relatively modest reductions in BP achieved in these studies (38,41,42). A study in type 2 diabetic patients with nephropathy comparing 12 months of treatment with either lisinopril or atenolol showed a reduction in albuminuria and TERalb in patients treated with ACE inhibitors, whereas this was not seen in the patients treated with atenolol, even though reduction in BP was similar in the two groups (12). This finding indicates that ACE inhibitors have direct effects on the microvasculature, thus reestablishing the barrier function of the leaky capillaries in diabetes. This theory is supported by the fact that retinal blood vessels have receptors for angiotensin II (43) and that ACE inhibition reduces the permeability of these vessels (13,44). Our patients with DMa seemed to have a systemic microvascular hyperpermeability, the degree of which was reflected by retinal thickness. Because treatment with ACE inhibitors is known to have beneficial effects on UAE and TERalb, treatment with ACE inhibitors or angiotensin II receptor antagonists could be a promising treatment modality for this group of patients. OCT might then be the instrument of choice to evaluate the efficacy of such intervention in reducing macular edema.

In conclusion, our data show that retinal thickness in the macular area is associated with a glomerular and generalized vascular leakage in type 2 diabetic patients with DMa. Therefore, hyperpermeability of blood vessels seems to coexist in different organs in diabetic patients, and this pathological feature might represent a common target for medical intervention. Quantitative assessment of retinal thickness, e.g., by OCT, may become a useful instrument in evaluating such intervention effects in DMa.



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  		Figure 3— TERalb versus average retinal thickness as measured by OCT in type 2 diabetic patients with DMa.

 

   Acknowledgments
 
Financial support for this study was received from the Sehested Hansen Foundation, the Novo Nordisk Foundation, the Beckett Foundation, the Jochum Jensen Memorial Grant, and the Illum Foundation.

We thank Theis Bacher, Merete Møller, Hanne Petersen, Lisbet Vester, and Helle Hedegaard for their excellent technical assistance.


   Footnotes
 
Address correspondence and reprint requests to Søren Tang Knudsen, Medical Department M (Diabetes & Endocrinology), Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark. E-mail: stk{at}dadlnet.dk.

Received for publication 30 January 2002 and accepted in revised form 23 August 2002.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS—
 CONCLUSIONS—
 References
 

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