Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1α and VEGF

Clinical trials have demonstrated that acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients (1–5). The worsening results, in part, from hard exudates and macular edema — pathologies that are manifestations of blood-retinal barrier breakdown. However, continued intensive insulin therapy eventually leads to a marked reduction in the risk of diabetic retinopathy onset and progression (5, 6). Patients with type 2 diabetes converting to acute intensive insulin therapy also show a marked increase in retinopathy risk when compared with patients on oral hypoglycemic drugs. The effect is insulin dose–dependent (7), and the progression of retinopathy is seen at multiple levels, ranging from no retinopathy to moderate background retinopathy (8). While hyperglycemia is an independent risk factor, the change from oral hypoglycemic drugs to insulin is associated with a 100% increased risk of retinopathy progression and a threefold increased risk of visual impairment (9). As in type 1 diabetes, long-term intensive therapy (more than 6 years) eventually reduces the risk of retinopathy development and progression (10). The mechanisms underlying the early deterioration of retinopathy following the institution of acute intensive insulin therapy remain unknown. VEGF is a family of angiogenic and vascular permeability–enhancing peptides derived from alternatively spliced mRNAs. VEGF bioactivity is primarily mediated via two high-affinity cognate receptors, kinase insert domain receptor (KDR)/Flk-1 and Flt-1 (11, 12). Preclinical and clinical studies have shown that VEGF is operative in the pathogenesis of both background and proliferative diabetic retinopathy (13–15). Intraocular VEGF levels are increased in diabetic human eyes with blood-retinal barrier breakdown and neovascularization (13, 15–17), and notably, the specific inhibition of VEGF bioactivity prevents neovascularization and blood-retinal barrier breakdown in various relevant animal models (14–18).