Abstract Diabetic retinopathy (DR) is a leading cause of preventable blindness in developed countries. Breakdown of the blood retinal barrier (BRB) in DR leads to macular edema and is one of the earliest events during the development of disease. The blood retinal barrier is comprised of inner and outer components: the outer barrier is formed by tight junctions between the retinal pigment epithelial (RPE) cells, and the inner barrier is formed by tight junctions between the retinal vascular endothelial cells. While the inner blood retinal barrier has been well studied, the development and regulation of the outer blood retinal barrier has not been carefully examined in the context of DR. Tight junction protein, Claudin-19, is the predominant claudin in the RPE, and has been shown to play a role in the barrier properties of the RPE. Additionally, previous work from our laboratory suggest that hyperinsulinemia (as seen in type 2 diabetes) may lead to disruption of the outer BRB. The purpose of this study is to identify the spatial localization and functions of claudins in the RPE and test the hypothesis that regulation of RPE claudins with hyperglycemia/hyperinsulinemia leads to breakdown of the blood retinal barrier. Understanding the molecular mechanisms involved in breakdown of the outer blood retinal barrier will help identify therapeutic targets for macular edema in diabetic retinopathy.