COBRE: INSULIN RECEPTOR SIGNALING IN DIABETIC RETINOPATHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic retinopathy is the most common complication of diabetes and the leading cause of vision loss in the working age population. A growing body of evidence suggests that the neural retina undergoes significant deterioration early in the course of diabetes. Insulin receptor (IR) activation has been shown to rescue retinal neurons from apoptosis through a phosphoinositide 3-kinase cascade. Retinal IR is constitutively active; however, this constitutive activation is impaired in diabetic retinopathy. We report a novel finding that cytoplasmic actin associates with and activates the retinal IR in vivo. We also observed that the association of actin with the IR, as well as the constitutive IR activation, is reduced under hyperglycemic conditions, in vivo. This is the first study which demonstrates that cytoplasmic actin regulates the autophosphorylation of the retinal IR. The loss of association between IR and actin may be an important contributory factor for the initial pathology of diabetic retinopathy.