Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects.

Vascular responsiveness to infused angiotensin II and to norepinephrine was determined in 14 normal subjects and two groups of diabetic subjects, 16 with no clinically detectable diabetic complications and 14 with diabetic retinopathy but no clinical evidence of nephropathy. All were maintained on a 100-mEq. -Na- 100-mEq. -K diet. Serum electrolytes, 24-hour urinary sodium, creatinine clearance, and plasma renin activity did not differ significantly among the groups. Group mean baseline diastolic pressure in those with retinopathy was higher than in normal subjects but no significantly different from that of uncomplicated diabetics. The pressor dose of angiotensin II (ng./kg./min. to increase diastolic blood pressure 20 mm. Hg) for each group respectively was 11.5 +/-0.9, 12.9+/- 1.3, and 8.3 +/- 1.3, and the slope of the dose-response curve (mm. Hg rise in blood pressure resulting from the infusion of 1 ng./kg./min. following the initial increment in blood pressure) was 2.0 +/-0.2, 1.6+/-0.2, 3.3+/- 0.6. For norepinephrine, the pressor doses were 163 +/- 24, 212+/-21, and123 +/- 11 and slopes were 0.17 +/- 0.03, 0.13 +/- 0.02, and 0.20 +/-0.02. Neither diabetic group differed significantly from normal subjects. Diabetics with retinopathy were more sensitive to angiotensin II, pressor dose (P less than 0.059) and slope (P less than 0.02), and to norepinephrine, pressor dose (P less than 0.006) and slope (P =0.05) than those without complications. These data suggest that vascular reactivity is enhanced in diabetics with retinopathy.

Ocular surgery in patients with diabetic nephropathy.

Patients with severe diabetic nephropathy often have diabetic retinopathy requiring eye surgery. During the course of their nephropathy, which was treated medically (group A, N = 34), with dialysis (group B, N = 18), or with renal transplantation (group C, N = 2), 54 diabetic patients have had eye surgery. The ophthalmologic procedures included cataract extraction, vitrectomy, scleral buckling, and cyclocryosurgery. The complications included postoperative hemorrhagic glaucoma and persistent retinal detachment. These were encountered in two patients of group A and in two of group B. All other cases showed uneventful intra- and postoperative courses. Major eye surgery can be performed safely during therapy for diabetic nephropathy, including hemodialysis with anticoagulation and transplantation with immunosuppression.

High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes.

OBJECTIVE: To determine the effectiveness of vitamin E treatment in normalizing retinal blood flow and renal function in patients with <10 years of type 1 diabetes. RESEARCH DESIGN AND METHODS: An 8-month randomized double-masked placebo-controlled crossover trial evaluated 36 type 1 diabetic and 9 nondiabetic subjects. Subjects were randomly assigned to either 1,800 IU vitamin E/day or placebo for 4 months and followed, after treatment crossover, for a further 4 months. Retinal blood flow was measured using video fluorescein angiography, and renal function was assessed using normalized creatinine clearance from timed urine collections. RESULTS: After vitamin E treatment, serum levels of vitamin E were significantly elevated (P<0.01) in both type 1 diabetic and control patients. Hemoglobin A1c was not affected by vitamin E treatment. Diabetic patient baseline retinal blood flow (29.1+/-7.5 pixel2/s) was significantly (P = 0.030) decreased compared with that of nondiabetic subjects (35.2+/-7.2 pixel2/s). After vitamin E treatment, diabetic patient retinal blood flow (34.5+/-7.8 pixel2/s) was significantly increased (P<0.001) and was comparable with that of nondiabetic subjects. Additionally, vitamin E treatment significantly (P = 0.039) normalized elevated baseline creatinine clearance in diabetic patients. CONCLUSIONS: Oral vitamin E treatment appears to be effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short disease duration without inducing a significant change in glycemic control. This suggests that vitamin E supplementation may provide an additional benefit in reducing the risks for developing diabetic retinopathy or nephropathy.

Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy.

PURPOSE: The authors investigated retinal blood flow changes in patients with insulin-dependent diabetes mellitus (IDDM) and no diabetic retinopathy compared to age-matched subjects without diabetes. They also investigated whether blood glucose levels could modulate retinal blood flow in these patients with diabetes and whether this modulation would impact retinal blood flow data used in cross-sectional studies assessing changes in retinal blood flow. METHODS: Retinal blood flow was measured using video fluorescein angiography, and blood glucose levels were manipulated using glucose clamp methodologies with continuous basal insulin replacement. Blood glucose levels were clamped at 100, 200, and 300 mg/dl. Retinal blood flow measurements were performed at each blood glucose level after subjects had been stabilized for an hour at each of the different blood glucose levels. RESULTS: Retinal blood flow was found to be significantly decreased (P< 0.01) in the group of patients with no diabetic retinopathy (19.4 +/- 4.6 arbitrary units [AU]) compared to retinal blood flow in subjects without diabetes (28.7 +/- 6.4 AU). During glucose clamp adjustment of blood glucose levels, it was found that as blood glucose levels were increased from euglycemia (100 mg/dl) to 200 mg/dl and to 300 mg/dl, retinal blood flow was significantly increased at the 200 mg/dl level (21.5 +/- 4.7 AU, P < 0.05) and at the 300 mg/dl level (25.9 +/- 8.8 AU, P <0.01) compared to the 100 mg/dl level (16.3 +/- 3.8 AU). In addition, the retinal blood flow at the 100 and 200 mg/dl levels was significantly reduced (P < 0.01) compared to nondiabetic retinal blood flow (28.7 +/- 6.4 AU). CONCLUSIONS: Retinal blood flow was found to be decreased in patients with IDDM with no diabetic retinopathy, and acute elevations in blood glucose levels resulted in increased retinal blood flow in these patients. The acute modulation of retinal blood flow by blood glucose levels should be considered in cross-sectional studies investigating retinal blood flow changes in patients with diabetes. The results from this study indicate that if blood glucose levels are not accounted for in the analyses, larger populations would have to be studied to demonstrate statistically significant differences between groups with and without diabetes.

Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18.

PURPOSE: To identify risk factors for the development of high-risk proliferative diabetic retinopathy (PDR) and for the development of severe visual loss or vitrectomy (SVLV) in eyes assigned to deferral of photocoagulation in the Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: Multivariable Cox models were constructed to evaluate the strength and statistical significance of baseline risk factors for development of high-risk PDR and of SVLV. RESULTS: The baseline characteristics identified as risk factors for high-risk PDR were increased severity of retinopathy, decreased visual acuity (or increased extent of macular edema), higher glycosylated hemoglobin, history of diabetic neuropathy, lower hematocrit, elevated triglycerides, lower serum albumin, and persons with mild to moderate nonproliferative retinopathy, younger age (or type 1 diabetes). The predominant risk factor for development of SVLV was the prior development of high-risk PDR. The only other clearly significant factor was decreased visual acuity at baseline. In the eyes that developed SVLV before high-risk proliferative retinopathy was observed, baseline risk factors were decreased visual acuity (or increased extent of macular edema), older age (or type 2 diabetes), and female gender. CONCLUSIONS: These analyses supported the view that the retinopathy-inhibiting effect of better glycemic control extends across all ages, both diabetes types, and all stages of retinopathy up to and including the severe nonproliferative and early proliferative stages and the possibility that reducing elevated blood lipids and treating anemia slow the progression of retinopathy.

Closed vitreous surgery. XVII. Results and complications of pars plana vitrectomy.

Two hundred consecutive closed vitrectomies through the pars plana were observed for at least five years after operation to determine the results and analyze the complications. Vitrectomy was performed to remove vitreous opacities in 56.5% of the eyes (group 1), as a preliminary procedure in the course of retinal reattachment in 42% (group 2), and to reconstruct the anterior segment in 1.5% (group 3). Of the group 1 eyes for which adequate follow-up data were available, visual acuity improved notably in 64.2% showed no change in 11.3%, and deteriorated in 24.5%. The respective percentages for the other groups were as follows: 23.3%, 19.2%, and 57.5% for group 2; and 0%, +66.7%, and +33.3% for group 3. The most common complication during operation was bleeding in the vitreous, especially in diabetic patients; retinal break, lens injury, and vitreous-base avulsion followed in frequency. Postoperative bleeding occurred in 23% of eyes but usually resolved spontaneously and required no further surgery. There was postoperative glaucoma in 20% of the eyes. Corneal decompensation (15% of all cases) and rubeosis iridis (also 15%) had a propensity to occur in diabetic patients. Multiple procedures seemed to predispose eyes undergoing vitrectomy to rubeosis. Fibrous ingrowth into the vitreous through the sclerotomy was seen in five eyes and was associated with retinal detachment in one.

Optic disc edema in juvenile-onset diabetes.

The clinical and photographic records of patients with juvenile-onset diabetes and nonneurologic disc edema were reviewed to determine the natural history of the disease. Six female and two male patients, 14 to 40 years old, who had had diabetes for seven to 22 years had no visual complaints or mild blurring. All had 6/9 or better visual acuity and normal blood pressure. Visual fields were normal or showed an enlarged blind spot. The edematous discs had superficial, dilated, radially oriented, fluorescein-incontinent capillaries. Two patients had simultaneous neovascularization of the disc. Three received laser photocoagulation, and five received no therapy. In the seven followed up for six months or more, the edema resolved, resulting in 6/6 visual acuity. These findings suggest the edema resulted from a reversible vasculopathy that, due to few symptoms, may be more common than is presently appreciated.

The effects of laser photocoagulation in the retinal capillaries.

Using ruby and argon lasers, we produced multiple lesions on normal rhesus monkey retinas. The clinically used energy levels of both lasers produced identical cellular changes in the retina. Neither laser directly produced obliteration of capillaries. However, after the cellular damage in each burn lesion was repaired, we observed delayed degeneration of capillaries in a small segment at the burned areas. The marked reduction of active retinal cells that reduce vascular activity may beneficially affect laser treatment of diabetic retinopathy. The retinal tissue appears to have excessive photoreceptor cells and the horizontal connection of other cells seems to compensate for visual function after loss of many photoreceptor cells. We demonstrated severe damage in the ganglion cells by argon laser when it was aimed at the thick blood films in the vitreous cavity. Certain precautions must be taken when peripapillary neovascularization is treated by laser beam.

Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma.

Ninety-three patients received ruby laser panretinal photocoagulation in one eye for diabetic retinopathy and we examined them at an average time of 7.1 years later. In 14 patients, the untreated eye developed rubeosis iridis and the contralateral treated eye did not. In seven patients, the untreated eye developed angle neovascularization and the contralateral eye did not. The untreated eye developed neovascular glaucoma and the contralateral treated eye did not in four patients. Our findings suggest that eyes with proliferative retinopathy that received panretinal photocoagulation are less likely to develop rubeosis iridis, angle neovascularization, and probably neovascular glaucoma, than those eyes not receiving panretinal photocoagulation.

Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy.

PURPOSE: To determine the effect of vascular endothelial growth factor and retinopathy level on retinal hemodynamics in nondiabetic and diabetic rats and to evaluate retinal hemodynamics in nondiabetic and diabetic patients. METHODS: Forty-eight diabetic and 22 nondiabetic patients had their diabetic retinopathy levels determined from fundus photographs according to Early Treatment Diabetic Retinopathy Study (ETDRS). Fluorescein angiograms were recorded from the left eye by video fluorescein angiography. Retinal blood flow was calculated from the digitized angiograms. Human recombinant vascular endothelial growth factor or vehicle alone was injected intravitreally into 13 nondiabetic and 11 diabetic rats. RESULTS: Retinal blood flow decreased 33% in patients with ETDRS retinopathy level 10 compared with control patients (P = .001) and increased sequentially in more advanced stages of retinopathy, with a strong correlation between retinal blood flow and retinopathy level (r2 = 0.434, P = .001). In the diabetic rats, retinal blood flow was decreased 35.6% (P = .01). Vascular endothelial growth factor maximally increased retinal blood flow by 36.1% in nondiabetic rats after 25 minutes (P = .001) and by 73.7% in diabetic rats after only 5 minutes (P = .01) and caused a greater response in diabetic than in nondiabetic rats. CONCLUSIONS: Retinal blood flow increases with advancing nonproliferative diabetic retinopathy in humans, and diabetes accentuates the vascular endothelial growth factor-induced increase in retinal blood flow and venous dilation in rats. Vascular endothelial growth factor may contribute to the changes in retinal hemodynamics and morphology observed in early diabetic retinopathy.

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.

Interdisciplinary treatment of diabetes mellitus in a military treatment facility.

The American Diabetes Association emphasizes interdisciplinary management as the standard of care for patients with diabetes. Many times, however, interdisciplinary means various health care professionals treating a patient but not necessarily interacting with each other regarding the patient's care. Recently, Tripler Army Medical Center replicated the Joslin Diabetes Center's diabetes outpatient intensive treatment program as part of a Joslin Diabetes Center/Department of Defense/Veteran's Administration research collaboration. Tripler Army Medical Center named this interdisciplinary program Holopono, which is Hawaiian for success. Holopono is a team of health care professionals providing integrated care and education to a group of diabetes patients over 3.5 days. Individual care management, aided by an Internet-based telemedicine system, then continues for 1 year after entry into the program. This article describes the Holopono program, the role of each team member, and how the team functions together to provide comprehensive diabetes care.