Pharmacokinetics of insulin uptake by ocular tissues and the role of cerebrospinal fluid in optic nerve insulin accumulation following topical insulin application

Abstract

As part of our ongoing studies concerning the efficacy of using topically applied medications to treat retinal and optic nerve diseases, we previously showed that insulin accumulated in the retina, optic nerve, and cerebrospinal fluid (CSF) following topical application. The purpose of this study was to investigate which route insulin takes to get to the posterior segment of the eye, and to specifically assess the role of the CSF in optic nerve insulin accumulation. Lewis rats that received 125I-insulin eye drops were killed at different time points and their ocular tissues counted in a gamma counter. In order to determine whether elevated levels of CSF insulin could lead to optic nerve insulin accumulation, a separate cohort of animals was injected in their lumbar cistern with unlabeled insulin and their optic nerves later assessed for the presence of insulin by enzyme-linked immunosorbent assay. All ocular tissues (except the lens) showed at least one significant time point elevation in 125I-insulin compared to baseline. Both the combined cornea/iris/ciliary body and the sclera showed a notable, overall increase in counts over baseline, with values at 20 and 30 minutes being significantly elevated. The highest numbers of counts were seen in the aqueous humor. Animals injected intralumbar cisternally with insulin showed elevated insulin concentrations in their optic nerves and cisterna magna-derived CSF that did not appear to be due to uptake of insulin from the circulation. These results support the hypothesis that the insulin that accumulates in the retina and optic nerve following topical application arrives there after diffusing through the sclera, though an intraocular route--while unlikely--cannot be ruled out.