Robert N. Mames

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell-derived factor-1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses. Treatment of patients with triamcinolone decreases SDF-1 levels in the vitreous, with marked disease improvement. SDF-1 induces human retinal endothelial cells to increase expression of VCAM-1, a receptor for very late antigen-4 found on many hematopoietic progenitors, and reduce tight cellular junctions by reducing occludin expression. Both changes would serve to recruit hematopoietic and endothelial progenitor cells along an SDF-1 gradient. We have shown, using a murine model of proliferative adult retinopathy, that the majority of new vessels formed in response to oxygen starvation originate from hematopoietic stem cell-derived endothelial progenitor cells. We now show that the levels of SDF-1 found in patients with proliferative retinopathy induce retinopathy in our murine model. Intravitreal injection of blocking antibodies to SDF-1 prevented retinal neovascularization in our murine model, even in the presence of exogenous VEGF. Together, these data demonstrate that SDF-1 plays a major role in proliferative retinopathy and may be an ideal target for the prevention of proliferative retinopathy.

OBJECTIVE: The pilot study examined the ability of octreotide to retard progression of diabetic retinopathy (DR) and delay the need for panretinal photocoagulation (PRP) in patients with advanced stages of retinal disease. RESEARCH DESIGN AND METHODS: Patients with severe nonproliferative DR (NPDR) or early non-high-risk proliferative DR (PDR) were randomly assigned to conventional diabetes management (control group, 12 patients) or to treatment with maximally tolerated doses of octreotide (200-5,000 microg/day subcutaneously; 11 patients). Ocular changes in each eye were assessed at a minimum of every 3 months for 15 months or until disease progressed to high-risk PDR requiring laser surgery. Endocrine assessments occurred at 3-month intervals during the study RESULTS: Only 1 of 22 eyes from patients treated with octreotide reached high-risk PDR requiring PRP, compared with control patients, in whom 9 of 24 eyes required PRP. The decreased incidence of progression requiring laser surgery was statistically significant if events were considered independently (P < 0.006). The incidence of ocular disease progression was only 27% in patients treated with octreotide compared with 42% in patients with conventional diabetes management. This treatment effect on whether the retina worsened approached statistical significance using repeated measures analysis (P = 0.0605). Endocrine management was similar between treatment groups. Thyroxine replacement therapy was administered to maintain a euthyroid state for all octreotide-treated patients and 7 of 12 control patients. CONCLUSIONS: Our results suggest that octreotide treatment in euthyroid patients may retard progression of advanced DR and may delay the time to laser surgery.

Diabetic retinopathy (DR) is the most severe of several ocular complications of diabetes. The earliest clinical signs of DR are microaneurysms and haemorrhages. Later signs include dilated, tortuous irregular veins and retinal non-profusion, leading to retinal ischaemia that ultimately results in neovascularisation. Diabetic macular oedema, which involves the breakdown of the blood-retinal barrier, also occurs and is responsible for a major part of vision loss, particularly in Type 2 diabetes. The pathogenesis of DR is very complex. Many biochemical mechanisms have been proposed as explanations for the development and progression of DR. Chronic hyperglycaemia leads to oxidative injury, microthrombi formation, cell adhesion molecule activation, leukostasis and cytokine activation. Next, ischaemia-mediated overexpression of growth factors and cytokines occurs. These factors include vascular endothelial growth factor, insulin-like growth factor-1, angiopoetin-1 and -2, stromal-derived factor-1, fibroblast growth factor-2 and tumour necrosis factor. Because of the complex interplay between these factors, targeting a single growth factor will be unlikely to result in therapeutic inhibition of angiogenesis. These growth factors no doubt act in synergy to mediate the steps of angiogenesis, including protease production, endothelial cell proliferation, migration and tube formation. This review attempts to provide an overview of perspectives regarding the pathogenesis of this disease. The focus, however, is on describing the unique features of selected relevant factors and how each growth factor may act in a synergistic manner with other factors.