All Eyes on Regenerative Insulin for Glaucoma, AKA Diabetes Type 4

Recently browsing on the rather tantalizing website Neurotrophic Keratitis News, I came across an intriguing 2021 study demonstrating topical insulin eye drops successfully treating, you guessed it, neurotrophic keratitis. Delving further, I discovered insulin eye drops are currently being studied as a possible treatment for a number of corneal disorders. 

Today, I'd like to specifically focus on the correlation between insulin and glaucoma, or what researchers are now calling Type 4 Diabetes.

The 2018 glaucoma study Insulin Signaling Promotes Dendrite and Synapse Regeneration and Restores Circuit Function After Axonal Injury is immensely fascinating. The researchers focused on retinal ganglion cells (RGCs), neurons that convey information from the retina to the brain via their axons in the optic nerve. The selective death of RGCs is a crucial element in the pathophysiology of glaucoma, the leading cause of irreversible blindness worldwide. The rapid retraction of RGC dendrites is one of the earliest pathological changes in glaucoma. Their data demonstrated that insulin promotes remarkable dendrite regeneration in adult RGCs after axonal injury. In their optic nerve injury model, RGC dendrites never regenerated unless they were stimulated with insulin, thus providing the first evidence of successful dendritic regeneration in retinal neurons.

Looking into this further, I came across the 2017 Journal of Current Glaucoma Practice article Is Glaucoma a Neurodegeneration Caused by Central Insulin Resistance: Diabetes Type 4?

A few segments of this illuminating article:

"The existence of brain-specific diabetes independent of peripheral diabetes and manifesting as neurodegeneration has been previously reported as diabetes type 3 - Alzheimer's disease - and recently as diabetes type 4- glaucoma." 

"Insulin/insulin signaling is important for neuronal survival, in general, and RGC survival, in particular. Insulin is present in the brain in very high quantities, indicating local production and its important role in cerebral functions. Additionally, insulin is important in trabecular meshwork maintenance and aqueous outflow regulation, thereby playing a role in maintenance of intraocular pressure (IOP). Ameliorating defects in insulin signaling is, therefore, an important therapeutic target to consider for glaucoma therapy."

"In summary, the central insulin resistance theory explains how insulin dysfunction can specifically cause both forms of glaucoma (high pressure and normal pressure) by afflicting outflow pathways via trabecular meshwork, vascular changes (amyloid angiopathy), and trigger glial activation, central neuronal degeneration, and RGC apoptosis through various molecular pathways. Therefore, aberrant insulin signaling in the central nervous system and specifically visual pathways appears to be a cause for glaucoma. Central insulin function enhancement by giving intranasal insulin therapy may help to lower IOP, enhance blood flow, and ameliorate injury to RGCs, preventing RGC apoptosis by positively modulating several cellular pathways like glial activation, glutamate excitotoxicity, ameliorating amyloidopathy/taupathy, and decreasing mitochondrial dysfunction."

Another 2017 paper Diabetes Type 4: A Paradigm Shift in the Understanding of Glaucoma, the Brain Specific Diabetes and the Candidature of Insulin as a Therapeutic Agent states: "At every step, the discussion reveals that insulin and other allied moieties are a sure promise for glaucoma treatment and management," adding: "Immediate application of this analysis points towards glaucoma therapy centered upon improving what we have termed insulin hypofunctionality."

According to the 2014 paper Glaucoma- Diabetes of the Brain: A Radical Hypothesis About Its Nature and Pathogenesis: "Based on the remarkable similarities between glaucoma and diabetes, we propose glaucoma also to be a type of diabetes...Additionally, Alzheimer's disease has already been proposed to be diabetes type 3. We show that Alzheimer's disease is cerebral glaucoma and diabetes at the same time, which, by transitive property of similarities, again leads to our hypothesis that glaucoma is diabetes of the brain...Our proposition may lead to an alternative classification of diabetes as pancreatic and brain diabetes thereby widening the vision arena of the understanding of both these disorders."

The 2021 paper Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration found that: "Studying the insulin pathway in RGCs, glial cells, and endothelial cells and understanding the cross talk between insulin signaling and various pathogenic events in glaucoma are essential to set the stage for future clinical investigations. Several clinical trials that have investigated the potential use of intranasal insulin in the management of Alzheimer's disease have revealed positive outcomes that include improved memory and attention. Thus, stimulating insulin signaling directly using exogenous insulin and enhancing its sensitivity using different anti-diabetic medications may have multiple beneficial outcomes. Targeting insulin signaling may serve not only as a possible neuroprotective therapy in glaucoma, but also as a potential pro-regenerative one."

On a side note, I've been on an ongoing research rabbit hole with taurine's benefits for diabetics for a couple of years now. Taurine has been shown to have a protective effect on RGCs. 

See the studies: Taurine Promotes Retinal Ganglion Cell Survival Through GABA Receptor Activation (2017), Taurine Provides Neuroprotection Against Retinal Ganglion Cell Degeneration (2012), Taurine is a Crucial Factor to Preserve Retinal Ganglion Cell Survival (2013), Taurine Deficiency Damages Retinal Neurones: Cone Photoreceptors and Retinal Ganglion Cells (2012), among others.