Purchase this article with an account.
Muneeb Ahmad Faiq, Tanuj Dada, Trina Sengupta, Madhu Nath, Thirumurthy Velpandian, Kevin Chan; Role of Central Insulin Resistance in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):682.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Central insulin resistance (CIR) has been implicated in many neurodegenerative conditions. CIR was recently suggested to be a major risk factor for glaucoma also but this supposition lacks coherent scientific evidence. In order to examine this hypothesis, we used intracerebral injection of S961 (a potent blocker of insulin receptor; IR) in rodents to test if CIR lead to pathological changes akin to glaucoma.
A guide cannula (24 gauge, 15mm long) was stereotaxically implanted either in the left or right lateral ventricle in Wistar rats weighing 200g-250g through a burr hole 0.5 mm posterior to the coronal suture, 2mm lateral to the sagittal suture and 3mm below the dura mater according to the coordinates 5.4 mm A, 2mm L, 4mmV as per De Groot atlas. A post-surgical recovery period of 7 days was given to the animals before S961 (Group 1, n=6) or control buffer (Group 2, n=6) was injected. Intraocular pressure (IOP) measurements were taken with TonoPen XL over 24 days. Histology was done on the retina using H&E and crystal violet staining at Day-0, Day-14 and Day-24 post-S961 or buffer injection. Retinal insulin receptor expression was performed by immunohistochemistry (IHC), gene expression profile was done using real-time polymer chain reaction (PCR) and protein expression with western blotting.
While no significant change in IOP in the control group was observed (13.4 ± 2.6 mmHg on Day-0 to 14.6±2.1 mmHg on Day-24; p=0.06), intracerebral injection of S961 led to an increase in IOP from 12.2±2 mmHg on Day-0 to 28.1±3.4 mmHg on Day-24 (p<0.05) with decrease in the cell density and IR expression in the retinal ganglion cell (RGC) layer. These changes were accompanied with upregulation of IL2, IL4, FGFR1, GSK3a, and GSK3b with fold change of 1.98, 2.78, 1.53, 1.6, 1.22 respectively and downregulation of IGF2, MAPK15, NFKB1A, PI3K, NRG1, BCL2L11, IGF1, RARB and IR with 2.35, 1.65, 2.39, 2.07, 2.05, 1.94, 1.55, 2.14, 3.3 fold changes respectively. Western blot showed elevation of TNF-α and GFAP in the retina after S961 injection.
These results indicate that blocking IR in the central nervous system is associated with elevation in IOP, loss of RGCs and changes in gene and protein expression relevant to RGC apoptosis. This study indicates that CIR may have an etiopathogenic role to play in glaucomatous neurodegeneration and targeting insulin signaling may hold promise as potential therapeutic modality for glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only