The effect of insulin and glucose levels on retinal glial cellactivation and pigment epithelium-derived fibroblast growth factor-2

摘要

Purpose: The diabetic retina exhibits decreases in endogenousnonangiogenic neurotrophins. This study hypothesized that deficienciesin systemic and retinal pigment epithelium-derived (RPE) neurotrophicfactors also influence retinal changes in diabetes.Methods: Diabetes was established in Listar hooded rats withstreptozotocin. Reverse transcriptase coupled polymerase chain reaction(RT-PCR) and immunoblotting were used to determine the expression offibroblast growth factor-2 (FGF-2) in the retina and RPE, and glialfibrillary acid protein (GFAP) in the retina. In addition, primary humanRPE cultures and a transformed Müller cell line were used to determinethe effect of insulin, glucose, and insulin-like growth factor (IGF) onthe expression of these substances.Results: FGF-2 and GFAP were increased in retina, but FGF-2 wasdecreased in the RPE of diabetic animals. Retinal GFAP correlated withRPE FGF-2 expression in these animals. Insulin produced a dose-dependentincrease in FGF-2 in RPE cells and decrease in GFAP in Müller cellsgrown in 15 mM glucose. In 5 mM glucose, insulin had no effect onexpression of either protein. Physiological levels of insulin inhibitedchanges induced by 15 mM glucose. The effect of 9 nM insulin on eachculture was mimicked by 1 nM IGF, and blocked with an IGFR-1 inhibitor.Conclusions: It is suggested that decreased systemic insulin andhigh glucose levels contribute to decreased FGF-2 production in the RPEand increased glial cell activation in the diabetic retina. Addition ofinsulin and IGF act to reverse this effect through the IGFR-1. Thesemechanisms may contribute to the development of diabetic retinopathy.