Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.

The pathologies of diabetic micro- and macroangiopathy are different, suggesting that diabetes affects these two types of vascular tissue in a dissimilar manner. We have compared insulin receptors and the effects of insulin on cultured endothelium from calf retinal capillaries and aorta, and the vascular supporting cells, retinal pericytes, and aortic smooth muscle cells. 125I-insulin binds to high affinity insulin receptors on all four cell types. Receptor concentrations were similar except for aortic smooth muscle cells, which have 10-fold fewer receptors than the other cell types. Insulin at a concentration of 10 ng/ml stimulated [14C]glucose incorporation into glycogen in retinal endothelial cells and pericytes and aortic smooth muscle cells, but had no effect on aortic endothelium. Insulin over a concentration range of 10 ng/ml-10 microgram/ml, stimulated [3H]thymidine incorporation into the DNA of retinal pericytes, and endothelial cells and aortic smooth muscle cells but had no effect on aortic endothelial cells. These data suggested that a differential response to insulin may exist between endothelium of micro- and macrovasculature, and suggest that retinal capillary endothelium and retinal pericytes are both very insulin-sensitive tissues.

Risk factors for progression of background retinopathy in long-standing IDDM.

Risk factors for the development of severe forms of diabetic retinopathy were examined prospectively in a group of 153 patients with long-standing insulin-dependent diabetes mellitus. During a 4-yr follow-up study, 34 individuals progressed to preproliferative and proliferative retinopathy. The risk of progression to severe forms of diabetic retinopathy was determined by the degree of background diabetic retinopathy and several systemic factors. It increased steeply with hemoglobin A1c, declined proportionally with increasing age, and was dramatically different in patients with diastolic blood pressure below versus above 70 mmHg. Although the mechanisms of action of these systemic factors are unclear, the findings emphasize the multifactorial nature of the pathogenesis of severe forms of eye lesions.

Risk of early-onset proliferative retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy.

Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates greater than 30 micrograms/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinal vascular reactivity to norepinephrine and angiotensin II in normals and diabetics.

Retinal arterial vasoconstriction induced by an infusion of angiotensin II or norepinephrine was investigated in eight normal controls (N), nine diabetics without retinopathy (DNR), and 10 diabetics with retinopathy (DR) by color fundus photographs taken before and after the infusions. Image analysis was done by a semiautomated computerized microdensitometer using a videoscanner. Normal controls and diabetics without retinopathy had a significant reduction in diameter compared with diabetics with retinopathy, who failed to constrict arterioles in response to either vasopressor. The mechanism of this phenomenon is unclear. Semiautomated computerized microdensitometry is reproducible and appears to be a sensitive technique to evaluate the vascular reactivity of the retinal vasculature.

Financial implications of implementing standards of care for diabetic eye disease.

This article reviews practical financial issues surrounding the implementation of published standards of care for diabetic patients concerning examination for detection of retinopathy. Issues such as the financial basis of referral patterns and the fear of patient loss are raised. The role of the primary physician in coordinating care is discussed. The strategies of ophthalmic screening at the site of primary care are presented as alternatives to published standards. There is a need for development of low-cost screening for low-risk patient groups. All effective means of detecting retinopathy and implementing sight-saving therapy in a timely manner is cost-effective compared with the cost saved of disability payment alone.

Psychosocial adjustment to advanced proliferative diabetic retinopathy.

OBJECTIVE: To identify the major problems with adjustment to the advanced stages of proliferative diabetic retinopathy and to examine the relationship between adjustment and visual acuity. RESEARCH DESIGN AND METHODS: A cross-sectional descriptive cohort study was conducted at the referral-based eye unit at Joslin Diabetes Center in Boston, Massachusetts. We studied 47 adults with IDDM and advanced proliferative diabetic retinopathy. Thirty reported recent visual loss, and 17 had more stable vision. RESULTS: Psychosocial Adjustment to Illness Scale scores were significantly elevated relative to a normative diabetic sample (t = 2.94, P < 0.01). Our proliferative diabetic retinopathy sample reported the most difficulties in the domain of health-care orientation. No significant differences were observed in adjustment scores between those with recent partial visual loss and those with more stable vision. However, visual acuity in the best eye correlated significantly with the proliferative diabetic retinopathy sample's total adjustment score (r = -0.34, P = 0.02) and with 4 of 7 adjustment subscales. CONCLUSIONS: These results suggest that advanced proliferative diabetic retinopathy may be associated with particular difficulties in adjustment that are more related to best visual acuity than to recent visual loss. Relatively mild visual impairment may have significant psychosocial impact.

Psychosocial aspects of diabetic retinopathy.

Diabetic retinopathy, particularly in the more advanced stages, poses many difficult psychosocial problems and demands major adjustments by the patient. Our review of this literature has identified specific problems relevant to patient care, future research, and public policy. For example, proliferative retinopathy often leads to at least partial visual impairment, psychiatric symptoms, and difficulties with glycemic control. Partial visual impairment appears to cause as much psychosocial disruption as severe blindness. This suggests that most rehabilitation programs that serve the legally blind may come too late in the course of this illness. This review emphasizes the paucity of past research on psychosocial aspects of diabetic retinopathy and raises some questions for future research.

Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40-yr follow-up study.

The development of proliferative diabetic retinopathy was studied in three cohorts consisting of 292 patients with recent juvenile-onset, type I (insulin-dependent) diabetes who were followed 20-40 yr beginning in 1939, 1949, and 1959. The risk of this severe eye complication was almost nonexistent during the first 10 yr of diabetes, rose abruptly to its maximum level (approximately 30/100 person-years), and remained at that level for the next 25 yr. This pattern did not vary with sex, age at onset of diabetes, or level of glycemic control during the first 5 yr of diabetes. However, the risk of proliferative retinopathy was strongly related to the level of glycemic control during the several years preceding onset of this complication. This was a dose-dependent relationship, with patients in the highest quartile of the distribution of the index of frequency of hyperglycemia having a 10-fold higher risk than individuals in the lowest quartile. A virtually identical pattern was observed in patients who developed diabetes in 1959 as was observed in those who developed diabetes in 1949 or 1939. In contrast, diabetic nephropathy as evidenced by persistent proteinuria showed a lower incidence in the 1959 than in the 1939 cohort. In conclusion, these incidence data do not support the notion that the risk of proliferative retinopathy is mainly a function of duration of diabetes. Instead, the pattern of occurrence of this severe eye complication in type I diabetes suggests that the process leading to the development of proliferative retinopathy consists of two or more stages and that progression through each stage may be governed by different factors.

Diabetic retinopathy: can we modify its course?

With the exception of panretinal laser photocoagulation, no therapy has been shown to modify the course of diabetic retinopathy. Success in developing new therapies for diabetic retinopathy will depend on how well the disease process is understood and on whether interventions can be identified that ameliorate or circumvent critical stages in the development of the disease. A model of the disease process is presented to serve as a frame-work on which pieces of the puzzle can be placed and new areas of potential interventional therapy can be conceptualized.

Recent advances in diabetic retinopathy.

Despite the fact that we still do not understand what causes the development of retinopathy in diabetic subjects, major advances in its treatment have taken place. Photocoagulation clearly reduces the retinopathy although how early treatment should be initiated has not been clearly defined. Vitrectomy is capable of restoring vision in many already blind eyes but at some risk. We are inching closer to an understanding of the pathophysiology of retinopathy with development of retinal endothelial and pericyte cell culture techniques, studies of vascular permeability, flow and angiogenesis. Diabetic retinopathy is more common at early durations of diabetes than previously realized. This may allow for prospective intervention studies, using development of retinopathy as an endpoint. Diabetic retinopathy may be a reasonable index of short-term survival.

Factors influencing the development of visual loss in advanced diabetic retinopathy. Diabetic Retinopathy Study (DRS) Report No. 10.

Natural history data from the Diabetic Retinopathy Study were examined by multivariate methods to determine which baseline characteristics could predict the occurrence of severe visual loss (SVL) in eyes originally assigned to no treatment. The presence and extent of new blood vessels on the optic disc (NVD) had the strongest association with SVL. Several other ocular characteristics also were strongly associated with visual outcome. In the absence of NVD at baseline, the degree of intraretinal hemorrhages and microaneurysms (HMA) had the strongest association with development of SVL. Macular edema was a factor in determining visual loss to 20/200 but not SVL (less than 5/200). Among systemic characteristics, urinary protein was the best predictor of visual outcome, but none were as good as the major ocular variables.

Laser light scattering spectroscopy of in vivo human lenses.

Laser light scattering spectroscopy measures the thermal random movement of protein as characterized by the diffusion coefficient. This technique has been used in assessing cataract formation in animals. The changes detected appear to predict the later development of lens opacities. The sensitivity and quantitative aspects of this technique offer advantages over other presently available methods of detecting cataract formation. First studies in humans indicated a significant correlation between the diffusion coefficient and age (P less than 0.05). The age adjusted mean diffusion coefficient for nondiabetics (4.60 +/- 0.29; mean +/- SEM) was significantly higher compared to diabetics without retinopathy (3.59 +/- 0.41; P = 0.0473), diabetics with background or preproliferative retinopathy (2.73 +/- 0.27; P = 0.0001), or to diabetics with preproliferative or proliferative retinopathy receiving laser photocoagulation within 1 year of measurement (3.02 +/- 0.37; P = 0.0012). Diabetics with laser treatment more than 1 year prior to measurement (3.96 +/- 0.51) did not differ significantly from nondiabetics.

Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus.

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.

Different determinants of neovascularization on the optic disc and on the retina in patients with severe nonproliferative diabetic retinopathy.

Almost all patients with type I and many with type II diabetes develop proliferative retinopathy. This entity consists of two components: new blood vessels on the optic disc (NVD), which frequently lead to visual loss, and new blood vessels elsewhere on the retina (NVE), which do not pose such a serious threat to vision. This study examined determinants of neovascularization specifically on the optic disc in eyes with severe nonproliferative retinopathy. The study eyes were under surveillance as the untreated control eyes of participants in the Diabetic Retinopathy Study. During the 5-year follow-up period, NVE developed in almost all of the eyes, whereas the cumulative incidence of NVD in these same eyes was 64% and varied according to several factors. The risk of NVD in a study eye was increased if the contralateral treated eye had NVD rather than NVE or severe nonproliferative retinopathy (odds ratio [OR], 6.1; P < .0001). It was also increased if the study eye had, at the baseline examination, soft exudates and intraretinal microvascular abnormalities (OR, 5.7; P = .002) or soft exudates alone (OR, 4.0; P = .04). Nephropathy and poor glycemic control were each associated with a two-fold increase in risk but neither was statistically significant. Eyes of individuals over 40 years of age were protected from the development of NVD (OR, 0.5; P < .05). The findings of this study support the hypothesis that, in patients with diabetes, the development of NVD is determined by different factors than the development of NVE.

Cardiovascular autonomic neuropathy and proliferative diabetic retinopathy.

PURPOSE: To determine prospectively whether cardiovascular autonomic neuropathy is a risk factor for proliferative diabetic retinopathy. METHODS: A five-year follow-up study of 88 diabetic persons was performed at a center providing primary and specialized care for diabetes. Participants were white, insulin-dependent patients with diabetes of 15 to 21 years' duration. The primary end point was the presence of proliferative diabetic retinopathy, seen either on fundus photography or ophthalmologic examination. Cardiovascular autonomic neuropathy was measured at baseline by using a standard protocol. RESULTS: Fourteen patients developed proliferative diabetic retinopathy during follow-up. One measure of cardiovascular autonomic neuropathy, the 30:15 ratio, the heart rate variation at the 30th beat compared with that at the 15th beat, was lower among patients with proliferative diabetic retinopathy (P = .0049) The risk of proliferative diabetic retinopathy in patients with an abnormal cardiovascular autonomic neuropathy index was 2.59, although the estimate was not statistically significant because of the small number of patients who developed proliferative diabetic retinopathy. CONCLUSIONS: This study provides prospective evidence that cardiovascular autonomic neuropathy is associated with proliferative diabetic retinopathy. In addition to ocular determinants of proliferative diabetic retinopathy, systemic risk factors also should be considered when examining patients with diabetes mellitus.

Influence of HLA-DR phenotype and myopia on the risk of nonproliferative and proliferative diabetic retinopathy.

The relationship between HLA-DR phenotype, refractive error, and risk of both nonproliferative and proliferative diabetic retinopathy was studied among 227 insulin-dependent diabetics participating in a case-control study of diabetic retinopathy. In the absence of myopia, risk of both proliferative and nonproliferative diabetic retinopathy was increased for HLA-DR phenotypes 4/0, 3/0, and X/X (HLA susceptible) compared to HLA-DR phenotypes 3/4, 3/X, and 4/X (HLA nonsusceptible). Odds ratios equalled 11.8 and 7.4 respectively. In the presence of myopia this increased risk associated with HLA status was abolished. Myopia decreased the risk of proliferative and nonproliferative diabetic retinopathy among HLA-susceptible individuals, odds ratio equalled .09 and .09, but had no protective influence among HLA-nonsusceptible individuals.

Psychologic stress and glycemic control: a comparison of patients with and without proliferative diabetic retinopathy.

Using a case/control design, patients with (cases) and without (controls) proliferative diabetic retinopathy were compared using three psychosocial measures: life events, psychiatric symptomatology, and ego development. Cases reported significantly more symptoms. They also demonstrated a modest and significant correlation of negative life events with HgbA1c that was not shown in the controls. When the relationship of life events with glycemic control was explored in cases of varying durations of proliferative retinopathy, we found that the association between negative life events and HgbA1c was accounted for by the cases with a recent onset of retinopathy. Patients in this recent group showed a trend towards more negative life events that decreased with longer duration of proliferative retinopathy. This study suggests that the onset of proliferative retinopathy portends a life crisis during which metabolic control is sensitive to additional life stress and that this association is not found among patients whose illness is more stable.

Psychosocial correlates of mild visual loss.

Studies of the psychosocial aspects of visual impairment have emphasized the effects of blindness, giving relatively little attention to the effects of mild or partial visual impairment. Consequently, we know little about when in the course of visual loss significant psychosocial dysfunction develops. To address this question, we assessed psychosocial functioning at three times over eight months in 31 adults with proliferative diabetic retinopathy and mild to moderate visual impairment in at least one eye. Examination of the correlations between visual and psychosocial measures revealed strong and significant correlations between visual acuity and adjustment (range of r = -0.45 to -0.68), between visual acuity and psychological symptoms (range of r = -0.39 to -0.50), and between visual acuity and emotion-focused coping (range of r = -0.38 to -0.53). The strength of these correlations and their occurrence in three independent measures of psychosocial functioning suggest a clinically meaningful relationship between visual and psychosocial functioning in the range of mild to moderate visual impairment. Psychosocial dysfunction related to visual impairment develops long before blindness. Further prospective research on the psychosocial aspects of partial visual impairment will clarify this relationship and may help justify early intervention with rehabilitation in the visually impaired who do not qualify for services for the blind.

Risk for cardiovascular autonomic neuropathy is associated with the HLA-DR3/4 phenotype in type I diabetes mellitus.

OBJECTIVE: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus. DESIGN: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes. SETTING: Outpatient diabetes clinic. PATIENTS: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years. MEASUREMENTS: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function. RESULTS: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemic control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% CI, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy. CONCLUSIONS: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the development of this complication.

Reproducibility of the densitometric analysis of fluorescein angiograms.

Computer-aided operator-interactive densitometry was applied to assess the reproducibility or retinal-fluorescein angiograms. To achieve this, the fundus camera images of glass tubings of various diameter filled with fluorescein of varying concentrations were subjected to densitometric analysis. These studies were carried out repeatedly at 9-micrometer and 29-micrometer scanning resolutions by three observers and thus the inter- and intra-operator errors could be estimated. The scanned data were analyzed as both optical densities and intensities for some of the measurements. In both analyzing modes good linearity was obtained when the densitometric response was plotted against tubing diameter for various concentrations. To determine the reproducibility of transit time and retinal circulation time analyses, a randomly selected patient's angiogram was repeatedly analyzed by three observers and compared. From these data the inter- and intra-operator errors were also determined for successive frames and the reproducibility of the area under the dye dilution curves for both arteries and veins was computed. The overall densitometric reproducibility was found to be good; however, practical usefulness of the retinal circulation time remains to be established.