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Cross‐talk between Lipoprotein and Insulin Receptors in the Retina of Diabetic Mice

Diabetic retinopathy (DR) is a visual complication of diabetes mellitus and a leading cause of visual impairment across the world. Retinal neurodegeneration has been shown to precede the vascular abnormalities of the retina that are used as key clinical indicators of DR. An important feature of retinal neurodegeneration associated with DR is apoptosis of the retinal ganglion cells (RGCs). Our previous in vivo studies with genetically modified db/db mice (mimicking human type 2 diabetes mellitus) indicate a lipid metabolism‐regulated signaling pathway involving lipoprotein receptor‐related protein 1 (LRP‐1) protecting RGCs against apoptosis. Specifically, activation of LRP‐1 by ligand apoEdp (dimerized LRP‐1‐binding apolipoprotein E derived peptide) regulates the PI3K/Akt pathway in the retina, which appears to be involved in cross‐talk with insulin receptor and N‐methyl‐D‐aspartate receptor (NMDAR) signaling. Excess NMDAR activation by neurotransmitter glutamate in DR promotes glutamate excitotoxicity, leading to apoptosis of the cell and thinning of the neuroretina. Recent in vitro studies using cultured RGCs from neonatal mice were conducted and suggest the role of LRP‐1 in regulating glutamate‐induced excitotoxicity in RGCs. Our preliminary data from these in vitro studies suggest that LRP‐1 stimulation via apoEdp results in reduced glutamate‐induced excitotoxicity in RGCs.