Elevated Vitreous Retinol Binding Protein 3 Concentrations Are Associated with Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy

Abstract

Purpose : The Joslin Medalist Study found increased concentrations of Retinol Binding Protein 3 (RBP3) in people with type 1 diabetes for 50 years or longer with no to mild non-proliferative diabetic retinopathy (DR) versus those with proliferative DR (PDR). RBP3 potentially protects the retina by inhibiting glucose uptake and inflammation. This study correlated inflammatory cytokines and vascular endothelial growth factor (VEGF) in the vitreous and plasma with vitreous RBP3, DR severity, and DR progression in a diverse population of individuals with type 1 and type 2 diabetes.

Methods : Plasma and vitreous samples (N=205) were collected from individuals undergoing retinal surgery at the Joslin Beetham Eye Institute or as part of the Medalist Study, which collected vitreous postmortem. RBP3 and VEGF concentrations were measured by ELISA, and inflammatory cytokines by multiplex assay. Individual neural retinal layer thicknesses in the foveal area were obtained from optical coherence tomography (OCT) images using automated layer segmentation software (Heidelberg v6.0c) for the Medalist subjects.

Results : Elevated vitreous RBP3 concentrations were associated with less severe DR in all eyes (p<0.0001), and in both postmortem Medalist specimens (P<0.0001), and surgical samples from type 1 diabetes of shorter duration and type 2 diabetic patients (P=0.03). No difference in RBP3 concentration was identified between people with type 1 and type 2 diabetes (P=0.19). Higher RBP3 concentration was associated with reduced risk of PDR onset (N=30, P<0.0001), and with increased photoreceptor layer thickness (P=0.04). Higher concentrations of RBP3 were associated with lower levels of TNF-a, TNF-b and VEGF in the vitreous (P<0.05). PDR was associated with lower levels of vitreous IFN-γ (P=0.001) and IL-10 (P=0.007), and higher levels of vitreous IL-6 (P=0.02), IL-15 (P=0.01), and VEGF (P<0.0001), but was not associated with plasma concentrations of these cytokines. Vitreous VEGF levels did not correlate with its plasma levels.

Conclusions : These data suggest that RBP3’s association with less severe DR and slower progression to PDR may be mediated by decreasing diabetes-induced inflammatory cytokines and VEGF in the retina. These findings support RBP3’s potential as both a diagnostic and therapeutic approach to preventing or delaying progression of DR.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.