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bioRxiv · 10.1101/2025.07.23.666398

Intranasal Insulin Mediates Neurodegeneration in Diabetic Retinopathy via Regulation of Inflammatory and Apoptotic Pathways

Ong, S. S.·Konstantopoulos, J.·Suarez, M. K.·Rigdon, J.·Ma, J.-X.·Sappington, R.
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Abstract

Neurodegenerative changes predominate in early stages of diabetic retinopathy but effective therapies are lacking. Insulin treatment decreases neurodegeneration and intranasal insulin has been shown to reach the central nervous system in neurodegenerative diseases like dementia. We tested the hypothesis that intranasal insulin can decrease retinal neurodegeneration using the C57BL/KsJ-db/db transgenic diabetic (db/db) mouse model. Compared to the non-diabetic wildtype mice given intranasal saline, we observed decreased electroretinogram b-wave and oscillatory potential amplitudes in db/db mice treated with intranasal saline but not in the db/db mice treated with 2 units of intranasal insulin daily over 10 weeks. When compared to the non-diabetic intranasal saline control, we also observed decreased outer retinal thickness in the db/db mice given intranasal saline but this effect was attenuated in the db/db mice treated with intranasal insulin. GFAP immunoreactivity and caspase cell count were similarly elevated in the db/db mice treated with intranasal saline but not intranasal insulin. Mean blood glucose measurements increased 30 minutes after both intranasal saline and insulin treatment. Transcriptomic analysis revealed downregulation of inflammatory and apoptotic genes in the retina of db/db mice treated with intranasal insulin when compared to saline. In summary, treatment with intranasal insulin prevents the depression of b-waves and oscillatory potentials, decreases the attenuation of outer retinal thickness, reduces caspase cell count and GFAP immunostaining, and downregulates the transcription of inflammatory and apoptotic genes in the retina of db/db mice without exerting peripheral glucose lowering effects. Taken together, our results suggest that intranasal insulin can reduce neurodegeneration in diabetic retinopathy by improving retinal neuronal function, decreasing reactive gliosis and cell death, and modulating the expression of inflammatory and apoptotic genes.

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Ong, S. S., Konstantopoulos, J., Suarez, M. K., Rigdon, J., Ma, J.-X., Sappington, R.. 2025-07-26. Intranasal Insulin Mediates Neurodegeneration in Diabetic Retinopathy via Regulation of Inflammatory and Apoptotic Pathways. https://doi.org/10.1101/2025.07.23.666398

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