Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

Abstract

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.

Keywords: CNS; PI3K/Akt; RGC; glaucoma; insulin; neurodegeneration; neuroprotection.

Figure 1

Possible influence of insulin resistance on the pathogenesis of glaucoma. Loss of the insulin signaling pathway reduces activation of Akt pathway. In the RGC, insulin resistance promotes dendritic retraction, mitochondrial dysfunction, tau hyperphosphorylation, and apoptosis. A decrease in insulin signaling in microglia induces the expression of pro-inflammatory mediators. It additionally contributes to vascular dysfunction by causing nitric oxide/endothelin-1 imbalance and endothelial cell apoptosis. In astrocytes, decreased insulin signaling causes depletion of glycogen stores, impairing metabolite redistribution. RGC: Retinal ganglion cell, PI3K: phosphoinositide-3 kinase, Akt: protein kinase B, mTORC: mammalian target of rapamycin complex, Bad: bcl-2 agonist of cell death, GSK3β: glycogen synthase kinase 3- beta, GLUT-4: glucose transporter type 4, NO: nitric oxide, GS: glycogen synthase, IκB: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells.