Orexin Blockers’ Role in Glucose Homeostasis and Diabetic Retinopathy

Background: Diabetic retinopathy (DR) is the most common complication of diabetes and can lead to blindness if untreated. Orexin is a neuropeptide produced by the hypothalamus that regulates the sleep/wake cycle. Orexin-blockers are prescribed for insomnia, which recent studies have shown to decrease blood glucose levels, suggesting a potential therapeutic for DR. This study aims to explore orexin-blockers’ role in glucose homeostasis and diabetic retinopathy through in-vitro, in-vivo, and chart-review methods. Methods: In-vitro: Glucose uptake by human retinal endothelial cells (HRECs) was determined by exposure to varying levels of suvorexant, a commonly prescribed orexin blocker, and orexin-A. Additionally, Orexin expression under high glucose concentrations was examined using fluorescent staining. Pre-clinical: Diabetic (db/db) and non-diabetic (db/m) mice were injected with suvorexant daily. Mice weights and blood glucose were regularly compared with the vehicle control. Clinical Chart-review: A review that examines individuals retrospectively to determine if orexin-blockers decrease percentages of developing vision-threatening DR or macular edema compared to patients NOT taking orexin-blockers. Results: In-vitro: HRECs exposed to suvorexant had increased glucose uptake, while those exposed to orexin had a decreased glucose uptake. There were no significant changes in orexin expression in HRECs exposed to high glucose. Pre-clinical: Mice treated with suvorexant showed a downward trend in body weight, food intake, and better glucose tolerance than vehicle control diabetic mice. Clinical Chart-review: 41 patients treated with orexin blockers were identified. Fewer patients taking suvorexant developed vision-threatening DR than those without treatment. Additionally, there was a trend of decreasing HbA1c while taking suvorexant. Conclusion: The results of the in-vitro, pre-clinical, and clinical chart review studies indicate suvorexant has blood glucose-lowering properties. Data will continue to be collected for the clinical chart review to further determine the effects of orexin blockers on diabetic retinopathy and HbA1c.