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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4371-4376
Copyright © 2004 by The Endocrine Society

Insulin Resistance and Proliferative Retinopathy: A Cross-Sectional, Case-Control Study in 115 Patients with Type 2 Diabetes

Aneliya Parvanova, Ilian Iliev, Marco Filipponi, Borislav D. Dimitrov, Monica Vedovato, Antonio Tiengo, Roberto Trevisan, Giuseppe Remuzzi and Piero Ruggenenti

Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research (A.P., I.I., B.D.D., G.R., P.R.), Ranica (Bergamo), Italy; Units of Ophtalmology (M.F.), Diabetology (R.T.), and Nephrology (G.R., P.R.), Azienda Ospedaliera, Ospedali Riuniti, 24125 Bergamo, Italy; Section Information Services, University Hospital Saint George (B.D.D.), Plovdiv, 4000 Bulgaria; and Department of Clinical and Experimental Medicine, University of Padova (M.V., A.T.), Padova, 35100 Italy

Address all correspondence and requests for reprints to: Dr. Piero Ruggenenti, Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: manuelap{at}marionegri.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In this cross-sectional, case-control study we explored the association of proliferative diabetic retinopathy (PDR) with insulin resistance (IR) in type 2 diabetics with serum creatinine less than 2.0 mg/dl. For each PDR case, one reference case with background diabetic retinopathy (BDR) and two controls without retinopathy were identified. IR was evaluated by hyperinsulinemic euglycemic clamp; retinopathy was evaluated by indirect ophthalmoscopy and photography. Patients were matched by age, gender, and body mass index. PDR patients (n = 28) had higher IR and low-density lipoprotein cholesterol and triglyceride levels than BDR patients (n = 29), but comparable levels of glycosylated hemoglobin. Compared with patients without retinopathy (n = 58), those with PDR had higher IR, low-density lipoprotein cholesterol, and albuminuria (P < 0.05); those with BDR had higher glycosylated hemoglobin (P < 0.05), but comparable IR. At multivariate regression analysis, IR was the only independent marker of PDR among patients with retinopathy (P = 0.016). IR also retained its independent predictive value at multiple comparison among all groups (by Kruskal-Wallis test, P = 0.019). In type 2 diabetes, IR is an independent specific marker of proliferative retinopathy that may characterize patients at increased risk for blindness who may benefit most from early screening and therapeutic intervention. Longitudinal studies are needed to evaluate the role of IR in the pathogenesis of proliferative retinopathy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
VASCULAR DISEASE OF the retina (diabetic retinopathy) typifies the long-term diabetic state (1). Retinopathy lesions are divided into two large categories, background (simple or nonproliferative) and proliferative. Background diabetic retinopathy (BDR), a less severe form characterized by microvascular changes restricted to the retina that seldom influence visual acuity, can ultimately be identified in virtually all people with type 1 and in a high proportion of those with type 2 diabetes mellitus (1, 2, 3).

Proliferative diabetic retinopathy (PDR), a more severe disease characterized by ischemia-induced proliferation of new retinal vessels (4, 5), affects up to 25% of type 1 and type 2 diabetic patients over 15–25 yr of disease duration (2, 3). It usually progresses to visual impairment, being the leading cause of new cases of blindness in persons aged 20–74 yr in the United States (6) and the most common cause of blindness among people in their working years of life in the United Kingdom (7, 8). PDR accounts for almost the entire dramatic (~25-fold) excess of blindness in diabetic subjects compared with those without diabetes (9).

Diabetes duration (3), poor metabolic control (10), and high blood pressure (11) are risk factors for both forms of retinopathy and promote their progression over time. However, why PDR, unlike BDR, affects only a subgroup of diabetic patients during their lifetime remains elusive.

Insulin resistance and associated metabolic and hemodynamic abnormalities are now established features of type 2 diabetes and associated macrovascular complications (12, 13, 14). Insulin resistance has also been associated with microalbuminuria in patients with type 1 diabetes (15, 16). There is now clear evidence that the insulin resistance syndrome (or metabolic syndrome) is an independent predictor of cardiovascular disease and mortality in the diabetic population (17, 18). Evidence that PDR is associated with increased cardiovascular morbidity and mortality, albuminuria and other hallmarks of the metabolic syndrome suggests that retinopathy also might cluster with insulin resistance (19).

To test this hypothesis, we studied the association of insulin responsiveness, assessed by a hyperinsulinemic euglycemic clamp, with the degree of retinopathy along with other components of the metabolic syndrome in a large cohort of type 2 diabetic patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patient selection

Twenty-eight consecutive patients with PDR were selected among type 2 diabetic patients referred to the Department of Renal Medicine of the Clinical Research Center for Rare Diseases Aldo e Cele Daccò of Ranica (Bergamo, Italy) and to the Unit of Metabolic Diseases of the University of Padova, Italy. Inclusion criteria were diagnosis of type 2 diabetes according to American Diabetes Association criteria (20), age 18–75 yr, serum creatinine concentration below 2.0 mg/dl, and glycosylated hemoglobin below 11%. Exclusion criteria were any evidence of nondiabetic renal disease, obstructive uropathy, severe heart failure (New York Heart Association class III or more), liver disease, cancer, autoimmune disease, antidiabetic treatment with glitazones, and any other condition that in the investigator’s judgment could confound data interpretation or prevent a reliable ophthalmological evaluation.

For each patient with PDR (case), one patient with BDR (reference case) and two patients without retinopathy (controls) who satisfied the same inclusion/exclusion criteria were identified among the same population of diabetic patients. Reference cases and controls were matched with cases for gender, age (±5 yr), and body mass index (BMI; ±2 kg/m2). Diabetes duration was established through interview of the patient and, whenever possible, evaluation of previous clinical reports and medical charts.

Normotension was defined as systolic/diastolic blood pressure less than 140/90 mm Hg without antihypertensive therapy. Patients receiving antihypertensive therapy were considered hypertensive regardless of their actual blood pressure values.

No change in diet, lifestyle, or pharmacological treatment was introduced during the 3 months before patient selection. All patients provided written informed consent to study participation according to Declaration of Helsinki guidelines. The ethical committee of the Clinical Research Center approved the study protocol.

Study design

This was a cross-sectional, case-control study. The aim was to include an equivalent number of patients with PDR (cases, n = 30) or BDR (reference cases, n = 30) and without (n = 60) retinopathy (controls). At screening evaluation, the patients were seen by one diabetologist and two ophthalmologists. All relevant demographic, clinical, and laboratory data were reported in a dedicated case record form. In addition to the ophthalmological evaluation, all patients had their insulin sensitivity, albumin excretion rate (AER), and glomerular filtration rate (GFR) evaluated as specified below.

Clinical and laboratory evaluations

Ophthalmological examination. The retina was evaluated by indirect ophthalmoscopy and photography. The examinations were performed independently by two ophthalmologists, who were masked to the clinical and laboratory data of the patients. The diagnoses were compared for consistency. Patients with an inconsistent diagnosis were evaluated by a third independent ophthalmologist (in 2% of the cases), and the diagnosis was recorded and considered for data analysis.

Photographs of four standard 30° fields of each eye were taken through dilated pupils in stereo pairs (lateral to macula, macula, disc, and nasal) with a Canon CF 60 UV fundus camera (Tokyo, Japan) as described by Kohner and Porta (21). The pictures were printed on Kodak Ectachrome 100-color slide film (Eastman Kodak Co., Rochester, NY). Photographs were initially assessed for quality and adherence to the protocol. Inadequate photographs were discharged. The eye with the most severe involvement was used for categorization of retinal involvement. BDR was defined by the presence of microaneurisms, hemorrhages, hard exudates, venous congestion, cotton wool spots, or intraretinal microvascular abnormalities. PDR was diagnosed when new vessels, glial proliferation, preretinal hemorrhage, vitreous hemorrhage, scars of photocoagulation (known to have been directed at new vessels), and/or retinal detachment were found. Patients with none of these abnormalities were classified as not having retinopathy (22, 23).

Hyperinsulinemic euglycemic clamp. Selected patients were admitted to the metabolic ward at 0730 h. Weight and height were measured without shoes. After 15 min of rest, sitting blood pressure was measured three times to the nearest 2 mm Hg in the dominant arm with a random-zero sphygmomanometer, and the average of the three readings was recorded.

Peripheral insulin responsiveness was assessed during a hyperinsulinemic euglycemic clamp (24) performed in the morning after an overnight fast. Antidiabetic therapy was withdrawn on the evening before the clamp. One polyethylene cannula was inserted into an antecubital vein (for infusion of insulin and glucose), and another one was placed retrogradely into a wrist vein surrounded by heated box at 55 C (for sampling of arterialized venous blood). Fasting blood samples were taken for measurements of plasma insulin, creatinine, glycosylated hemoglobin (HbA1c), and lipids. The infusion of short-acting human insulin (Humulin R; Eli Lilly & Co., Indianapolis, IN) was performed at a rate of 4 mU/kg·min for 10 min and then decreased to 2 mU/kg·min. This infusion rate was maintained throughout the duration of the study. As soon as the blood glucose concentration decreased to 5.0 ± 0.28 mmol/liter, the euglycemic clamp was started (time zero). From time zero, the blood glucose concentration was measured every 5 min by the glucose oxidase method, and it was maintained within 5.0 ± 0.28 mmol/liter by adjusting the infusion of a 20% glucose solution through a pump (IVAC 560; IVAC, San Diego, CA). During the last 30 min of the clamp (and therefore after at least 120 min of sustained euglycemia), three blood samples were taken every 10 min for insulin measurements to confirm a steady state plasma insulin concentration. Thus, the insulin infusion was targeted at 200 mU/liter mean insulin levels (from 120–150 min of the clamp). At these levels, hepatic glucose production is totally suppressed (25), and the amount of glucose required to maintain steady state euglycemia is assumed be equal the total body glucose disposal. The total body glucose disposal rate (milligrams per kilograms per minute) was calculated as the mean glucose infusion rate during the last 30 min of the hyperinsulinemic euglycemic clamp.

GFR. The GFR was measured by the plasma clearance of unlabeled iohexol after a single iv injection of 5 ml iohexol solution (647 mg/ml; Omnipaque 300, Nycomed Amersham Sorin, Milan, Italy) (26). Blood samples were taken from the contralateral arm at 120, 150, 180, 210, and 240 min after the injection. After centrifugation (3000 min–1 for 10 min) at room temperature, plasma was separated and stored at –20 C for HPLC determination.

AER. The AER was measured in three consecutive overnight urine collections. The albumin concentration was determined by rate nephelometry (Array 360 System; Beckman Coulter, Milan, Italy) in fresh urine samples. The sensitivity of the assay was 2 mg/liter. Normo-, micro-, and macroalbuminuria were defined as AER less than 20, 20–200, and more than 200 µg/min, respectively, in at least two of the three urine collections (27).

Other laboratory tests. Serum creatinine, potassium, and lipid concentrations and other routine laboratory parameters were measured by automatic analyzer Synchron CX5 (Beckman Coulter). HbA1c was measured by HPLC (normal laboratory range, 3.53–5.21%; Beckman System Gold Chromatograph).

Statistical analyses The analytical approach consisted of descriptive statistics, comparative analyses, and regression modeling. All categorical variables were analyzed for frequency distribution (number and percentage), and all numeric variables were analyzed for the type of probability distribution by Kolmogorov-Smirnov and Shapiro-Wilk tests. The characteristics between different groups were compared by unpaired t test, Wilcoxon rank-sum test, or {chi}2 test, as appropriate. Multiple comparisons were performed by Kruskal-Wallis test. This test is nonparametric and compares the mean ranks in a multiple way, whereas the grouping variable combines the three study groups using {chi}2 statistic and asymptotic significance. The logistic regression modeling to analyze the presence of diabetic retinopathy and its severity (PDR or BDR) was applied by entry and stepwise methods with adjustment for covariate effects. The odds ratio and its 95% confidence intervals were computed by the Wald method of asymptotic normality from the coefficients of logistic regression. The level of statistical significance of the results from the analyses and tests was assumed at P < 0.05. Before the analyses, the skewed distribution of diabetes duration, AER, and triglycerides was normalized by log transformation, and data were presented as the mean (±SD) or median (interquartile range) as appropriate or as the number and percent frequency, unless otherwise stated. All evaluations were performed with SAS software (version 8.0, SAS Institute, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patient characteristics

From 120 identified type 2 diabetic patients, five patients, two with PDR, one with BDR, and two without retinopathy, denied consent to participate in the study because of difficulties in attending the planned visits. Thus, 115 patients (107 males) completed the study.

Among the three study groups, age, gender distribution, BMI, and smoking habits were comparable (Table 1Go). Diabetes duration was not significantly different in the three groups; however, there was a trend for a longer duration in patients with PDR or BDR compared with those without retinopathy. HbA1c was higher in patients with retinopathy than in those without, although the difference vs. patients without retinopathy achieved statistical significance only in those with BDR. Details on antidiabetic treatment in the three study groups are given in Table 2Go. As expected, patients with retinopathy were more frequently receiving insulin therapy (alone or combined with oral antidiabetic drugs) than those without retinopathy. However, the proportions of patients receiving insulin therapy in the PDR and BDR groups were comparable. The distribution of patients receiving metformin in the three groups was comparable as well. All patients were on a hypocaloric diet and had similar physical activity. No patient was involved in competitive sports.


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  		TABLE 1. Main characteristics of type 2 diabetic patients with PDR or BDR and without retinopathy

 

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  		TABLE 2. Percentage of patients with different types of diabetes treatment

 
The proportions of patients on angiotensin-converting enzyme inhibitors, alone or combined with other antihypertensive drugs, were comparable in the different groups (Table 1Go). No patient was taking angiotensin II receptor antagonists. On the average, blood pressure was well controlled and comparable in all groups. Plasma levels of low-density lipoprotein (LDL) cholesterol or triglycerides were significantly higher in patients with PDR than in the other two groups. Serum creatinine concentration and GFR were comparable in all groups. The AER was higher in patients with PDR than in those with BDR or without retinopathy. Multiple comparison between the groups showed marginal statistical significance for LDL cholesterol (P = 0.061), triglycerides (P = 0.055), and AER (P = 0.046).

All patients had decreased insulin sensitivity; their average whole body glucose disposal rate was about 50% lower than that evaluated in 20 nondiabetic subjects matched for age and sex evaluated under the same conditions and considered as healthy controls (11 ± 1.5 mg/kg·min). However, type 2 diabetic patients with PDR had a significantly lower (P < 0.05) whole body glucose disposal rate (4.53 ± 2.14 mg/kg·min) than those with BDR (6.05 ± 2.14 mg/kg·min) or without retinopathy (5.74 ± 2.24 mg/kg·min). The multiple comparison between the groups supported not only the paired differences, but also indicated a significant trend in insulin resistance (P = 0.019) (Fig. 1Go).



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  		FIG. 1. Total body glucose disposal rate in type 2 diabetic patients with PDR or BDR or without retinopathy. Data are the mean ± SE, P = 0.019, by Kruskal-Wallis test for multiple comparisons. DR-No, Without retinopathy.

 
Multifactorial logistic regression analysis

To further evaluate the independent association between insulin sensitivity and diabetic retinopathy, we performed a multifactorial logistic regression analysis considering all parameters listed in Table 1Go. In the comparison between patients with PDR vs. those with BDR, only a decreased glucose disposal rate was significantly and independently associated with PDR (accuracy, 64.9%; P = 0.008; Table 3Go). Of note, each increase in glucose disposal rate of 1.52 mg/kg·min was associated with a 30% decreased risk of PDR (odds ratio, 0.70; 95% confidence interval, 0.53–0.94). When the patients with PDR were compared with those without retinopathy, the glucose disposal rate, diabetes duration, and LDL cholesterol were the only covariates that retained a significant and independent association with PDR (accuracy, 75.6%; P = 0.002; Table 3Go). In the analysis of the patients with BDR vs. those without retinopathy, HbA1c was the only covariate significantly associated with BDR (accuracy, 67.8%; P = 0.037; Table 3Go).


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  		TABLE 3. Multifactorial logistic regression analysis of PDR and BDR

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study we found that insulin resistance was much more severe in type 2 diabetic patients with PDR than in those with BDR or no evidence of diabetic retinal involvement. At a multiple comparison among the three study groups, insulin resistance was the only considered marker to retain a statistically significant association with the severity of retinopathy. Of note, at multivariate analysis, insulin resistance was significantly and independently associated with PDR, but not with BDR.

Within the limits of the cross-sectional design of the study, these findings suggest that insulin resistance may play a central role in type 2 diabetic patients who, regardless of the level of actual blood glucose control, eventually develop PDR. Our study together with previous evidence that insulin resistance is often associated with renal and cardiovascular complications of type 2 diabetes (15, 16, 17, 18) corroborates the hypothesis that insulin resistance may predispose to micro- and macrovascular complications of diabetes, possibly by enhancing vascular susceptibility to the long-term effects of chronic hyperglycemia. This is also consistent with our finding that hallmarks of insulin resistance, such as increased LDL cholesterol or triglycerides levels and albuminuria, clustered with PDR.

The association of BDR with HbA1c, but not with insulin resistance, combined with the finding that insulin responsiveness was comparable in patients with BDR and in those without retinal involvement, suggests that the diabetic milieu per se, regardless of the level of insulin responsiveness, is the key factor that promotes the development of BDR (10).

Of note, the above findings were obtained in a large cohort of patients with type 2 diabetes mellitus through gold standard procedures not only for the evaluation of insulin responsiveness (by hyperinsulinemic euglycemic clamp) (24), but also for the measurement of GFR and AER [by unlabeled iohexol plasma clearance) (26) and three consecutive overnight urine collections (27), respectively]. The retinal changes were evaluated by two complementary methods, such as indirect ophthalmoscopy (to explore areas uncovered by the photographic technique) and retinal photography (allowing records for later comparative evaluations) (21), as applied by two independent ophthalmologists who were blinded to the clinical status of the patients.

Careful matching for age, gender, and BMI, combined with comparable lifestyle (diet, physical activity, and smoking habits), renal function, and treatment with different antidiabetic (in particular, metformin therapy) and antihypertensive drugs in different study groups excluded any major role of these potential confounders. Furthermore, the mean serum creatinine concentration and GFR were almost identical and within normal ranges in all considered groups, which ruled out the possibility that in patients with PDR, higher insulin resistance might be merely an effect of reduced renal function. Although there were no significant differences in reported diabetes duration among the three groups, patients with retinopathy tended to have a longer duration than those without. However, the finding that diabetes duration was comparable in patients with PDR and BDR conceivably ruled out the possibility that this factor might have contributed to more insulin resistance in those with PDR. This consideration is also in line with previous evidence that diabetes duration is not per se a major determinant of insulin resistance (28, 29). As expected, insulin therapy was more frequent in patients with retinopathy than in those without. However, the finding that the proportion of patients receiving insulin therapy was comparable in the PDR and BDR groups combined with previous evidence that insulin therapy may induce a small increase in the total glucose disposal rate as assessed by euglycemic clamp (30) suggest that this factor was also unlikely to affect the study findings. Metformin treatment could not be a major confounder, because it was similarly distributed in the three study groups, and as recently reported (31), it does not directly affect insulin sensitivity, as assessed by the clamp method.

Furthermore, comparable HbA1c levels in patients with PDR and BDR provided the evidence that differences in metabolic control, at least over the last 2 months, could not account for differences in insulin responsiveness between the two study groups. Although higher blood pressure values are reported to be associated with more insulin resistance (32), in our patients targeting antihypertensive therapy to blood pressure levels of 140/90 mm Hg or less resulted in well controlled and comparable blood pressure levels in all groups regardless of their insulin responsiveness.

Notably, our results confirm and extend previous observations (33, 34, 35), including the report by Maneschi et al. (36) showing that in a relatively small group of type 2 diabetic patients, those with retinopathy tended to be more insulin resistant than those without. These studies, however, did not provide information about the severity of retinal involvement. Our results are also in agreement with recent evidence that in type 1 diabetes the risk of retinopathy, either PDR or BDR, is strongly associated with serum triglycerides levels, waist to hip ratio (37), and BMI (38, 39), which are well recognized markers of insulin resistance.

Insulin responsiveness is quite heterogeneous within the diabetic phenotype, and acquired factors, such as obesity and physical activity, the two most important lifestyle variables modulating insulin action, account for no more than 50% of this heterogeneity (14, 40). Clustering of insulin resistance in families suggests that the remaining proportion of interindividual variability in insulin action may depend on a genetic component (41). In this regard, finding that both insulin resistance and micro- and macrovascular complications of diabetes tend to cluster in families (42) suggests a link between an inherited familial defect leading to insulin resistance syndrome and an increased susceptibility to chronic complications.

Several factors related to insulin resistance may be involved in the pathogenesis of PDR. Defective fibrinolysis caused by excess plasminogen activator inhibitor-1 (PAI-1) activity and selective inhibition of some antiatherogenic effects of insulin may promote the occlusion of retinal capillaries and secondary ischemia-induced neovascularization (43). The ischemic damage can be further amplified by insulin resistance that has been related to a lower ability of insulin to induce vasodilatation through impaired nitric oxide endothelial production or accelerated inactivation (44).

Regardless of the involved mechanisms, our findings suggest that a greater insulin resistance may be a risk factor for PDR in type 2 diabetic patients. However, ad hoc longitudinal studies are needed to test the hypothesis of an independent role of insulin resistance in the pathogenesis of this microvascular complication of diabetes.

In conclusion, more severe insulin resistance is associated with PDR in type 2 diabetic patients and clusters with other renal and cardiovascular risk factors. Early screening for insulin resistance may identify high risk patients who may benefit the most from established and experimental preventive and therapeutic interventions, including amelioration of insulin responsiveness.


   Acknowledgments
 
We thank Drs. Stefano Zenoni and Stefano Tadini (Unit of Ophthalmology, Ospedali Riuniti, Bergamo, Italy) for logistic support and counseling for controversial diagnostic cases; Dr. Anna Fassi (Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy) for recruiting and examining patients for the study; Mrs. Federica Arnoldi, Res. Nurse (Clinical Research Center Aldo e Cele Daccò, Ranica, Italy) for patients’ support, data entry, and validation; and Dr. Annalisa Perna, StatSciD (Laboratory of Biostatistics), for statistical advice. Mrs. Manuela Passera helped to prepare the manuscript.


   Footnotes
 
Abbreviations: AER, Albumin excretion rate; BDR, background diabetic retinopathy; BMI, body mass index; GFR, glomerular filtration rate; HbA1c, glycosylated hemoglobin; IR, insulin resistance; LDL, low-density lipoprotein; PDR, proliferative diabetic retinopathy.

Received December 3, 2003.

Accepted June 4, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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