Endogenous insulin signaling in the RPE contributes to the maintenance of rod photoreceptor function in diabetes

Abstract

In diabetes, there are two major physiological aberrations: (i) Loss of insulin signaling due to absence of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) and (ii) increased blood glucose levels. The retina has a high proclivity to damage following diabetes, and much of the pathology seen in diabetic retinopathy has been ascribed to hyperglycemia and downstream cascades activated by increased blood glucose. However, less attention has been focused on the direct role of insulin on retinal physiology, likely due to the fact that uptake of glucose in retinal cells is not insulin-dependent. The retinal pigment epithelium (RPE) is instrumental in maintaining the structural and functional integrity of the retina. Recent studies have suggested that RPE dysfunction is a precursor of, and contributes to, the development of diabetic retinopathy. To evaluate the role of insulin on RPE cell function directly, we generated a RPE specific insulin receptor (IR) knockout (RPEIRKO) mouse using the Cre-loxP system. Using this mouse, we sought to determine the impact of insulin-mediated signaling in the RPE on retinal function under physiological control conditions as well as in streptozotocin (STZ)induced diabetes. We demonstrate that loss of RPE-specific IR expression resulted in lower a-and bwave electroretinogram amplitudes in diabetic mice as compared to diabetic mice that expressed IR on the RPE. Interestingly, RPEIRKO mice did not exhibit significant differences in the amplitude of the RPEdependent electroretinogram c-wave as compared to diabetic controls. However, loss of

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

“…Very curiously, other two deregulated lncRNAs, CRNDE (down-expressed) and CYTOR (over-expressed), interact with the already cited ARF1 and AKT1, and with CAP1 and ACACA, also involved in insulin-related pathways [89,90]. Recently, it was experimentally proved that insulin signaling in the RPE may provide a paracrine signal to the retina for maintenance of photoreceptor function and survival, even if partially able to induce oxidative stress [91]. Additionally, high glucose level influences the synthesis of IGF-1, PEDF, advanced glycosylation end (AGE) products and their receptors (RAGE).…”

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

“…During DR, where high levels of glucose are present, neurodegenerative changes occur in the retina affecting glial cells, ganglion cells, pericytes and vascular endothelial cells. RPE is also affected by hyperglycemia and its dysfunction is a contributing factor to early DR [33]. All these changes are produced before they can be detected clinically [34,35].…”

Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases

“…In this context, high glycemic index (GI) of the diet and diabetes have been implicated as risk factors for AMD [99,100]. Although the uptake of glucose in retinal pigment epithelium (RPE) cells is not insulin-dependent, the signaling pathways modulated by the insulin receptor (IR) in RPE cells regulate the generation of reactive oxygen species and the expression of pro-inflammatory cytokines in mice retina [101]. Considering that ceramide is proposed to mediate insulin-resistance in skeletal muscle by blocking Akt signaling [94], it may be possible that higher ceramide levels in AMD influence the retinal homeostasis in part through an alteration of insulin signaling in the RPE.…”