Unraveling the Impact of High Glucose on the Retina: Insights from Human Retinal Organoids
Diabetic retinopathy (DR) remains a leading cause of vision loss worldwide, yet despite significant advancements in ophthalmology and diabetes research, there is still much to uncover about its early onset and progression. Traditionally viewed as a vascular disease, recent studies—including ours—suggest that neurodegeneration may occur even before vascular damage. But what exactly happens at a cellular and molecular level when the retina is exposed to high glucose?
In our latest study, now online at bioRxiv, we used human retinal organoids to investigate how chronic hyperglycemia affects different stages of retinal development. Our findings shed light on key molecular and cellular mechanisms that may drive early diabetic retinopathy, offering new insights for potential therapies.
Why Retinal Organoids? Bridging the Gap Between Models and Human Biology
Most DR research relies on animal models, such as diabetic mice or rats. While these models have contributed significantly to our understanding of DR, they fail to fully replicate human retinal physiology, particularly in aspects like photoreceptor development, cellular interactions, and metabolic responses.
To address these challenges, we turned to human induced pluripotent stem cell (iPSC)-derived retinal organoids, which closely mimic the complexity of the human retina. These self-organizing 3D structures contain multiple retinal cell types, including:
✔️ Photoreceptors (rods and cones)
✔️ Retinal ganglion cells
✔️ Bipolar cells
✔️ Müller glia
This system allowed us to study retinal development and function under hyperglycemic conditions in a controlled environment, revealing how diabetes-related changes affect specific cell types.
What We Did: Modeling Hyperglycemia in the Retina
We differentiated human retinal organoids for 30, 90, and 150 days, corresponding to different stages of retinal development. Then, we exposed them to high glucose (25mM D-glucose) for 28 days, mimicking chronic hyperglycemia.
What We Found: Early Resilience, But Long-Term Damage
🔹 Early-stage retinal organoids (D30, D90) showed remarkable resilience to high glucose, maintaining normal morphology, gene expression, and viability.
🔹 Advanced-stage organoids (D150+28) showed significant disruptions, particularly in photoreceptors. We observed:
✔️ Shortened outer segments, a key structure for light detection.
✔️ Downregulation of photoreceptor-specific genes, including those involved in phototransduction and visual perception.
✔️ Increased oxidative stress response, suggesting metabolic stress.
🔹 Interestingly, other retinal cell types like bipolar cells, Müller glia, and retinal ganglion cells showed greater resilience, but we detected signs of glial activation, indicating an adaptive stress response.
Transcriptomic Insights: Uncovering the Molecular Drivers of DR
We performed RNA sequencing to analyze how gene expression changes under hyperglycemic conditions. Our findings revealed:
🧬 Disruption of phototransduction-related pathways, including G protein-coupled receptor signaling and sensory perception—suggesting that glucose directly impacts the ability of photoreceptors to function properly.
⚠️ Evidence of oxidative stress, a known driver of diabetic retinal damage.
🔍 Comparison with human DR datasets confirmed key overlaps in pathways related to photoreceptor dysfunction, gliogenesis, and metabolic stress—validating our organoid model as a powerful tool for studying early DR progression.
What Does This Mean for Diabetic Retinopathy Research?
These findings challenge the traditional vascular-first model of DR. Instead, they support the emerging concept that retinal neurodegeneration occurs early, potentially setting the stage for later microvascular damage.
Our study also raises important therapeutic questions:
🔹 Could targeting photoreceptor metabolism help prevent vision loss in diabetes?
🔹 Are there ways to enhance retinal resilience to hyperglycemia?
🔹 Could we intervene early—before microvascular damage begins—to slow or stop DR progression?
Next Steps: Toward Translational Impact
While this study provides new mechanistic insights, there is still much to explore. Future research will focus on:
✔️ Testing potential neuroprotective strategies in retinal organoids.
✔️ Investigating the role of glucose metabolism in photoreceptor survival.
✔️ Exploring how longer-term exposure to hyperglycemia affects cellular function.
Final Thoughts: A Step Closer to Precision Medicine for DR
By using human-derived retinal models, we are moving closer to understanding DR in a way that is clinically relevant and translatable to human patients. These findings pave the way for targeted interventions that could one day prevent vision loss in individuals with diabetes.
🔗 Read the full study here: https://doi.org/10.1101/2025.02.24.639921
#DiabeticRetinopathy #Ophthalmology #Neuroscience #RetinalOrganoids #DiabetesResearch #VisionScience #StemCells #PrecisionMedicine
