Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models
Abstract
1. Introduction
2. Pathophysiology of DR
2.1. Hyperglycemia
2.2. Pericyte Loss and Vascular Dysfunction
2.3. Retinal Ischemia and Inflammation
2.4. Retinal Degeneration
3. Experimental Models of DR
3.1. Streptozotocin
3.2. Alloxan
3.3. Genetic Modulations
3.4. Surgical Methods
3.5. Streptozotocin + UCCAO
3.6. In Vitro
4. Recent Aspects of DR Research
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
DR | diabetic retinopathy |
DM | diabetes mellitus |
ROS | reactive oxygen species |
AGEs | advanced glycation end products |
PKC | protein kinase C |
PEDF | pigment epithelium-derived factor |
NADPH | nicotinamide adenine dinucleotide phosphate |
DAG | diacylglycerol |
PDR | proliferative diabetic retinopathy |
NPDR | non-proliferative diabetic retinopathy |
BRB | blood–retinal barrier |
DME | diabetic macular edema |
VEGF | vascular endothelial growth factor |
HIF-1 | hypoxia-inducible factor 1 |
IGF-1 | insulin-like growth factor 1 |
STZ | streptozotocin |
ICAM-1 | intercellular adhesion molecule-1 |
TNF-α | tumor necrosis factor alpha |
RAGE | receptor for advanced glycation end products |
MCP-1: | monocyte chemoattractant protein-1 |
MMP-2 | matrix metalloproteinase 2 |
MMP-9 | matrix metalloproteinase 9 |
NOD | non-obese diabetic |
UCCAO | unilateral common carotid artery occlusion |
BCCAO | bilateral common carotid artery occlusion |
OIS | ocular ischemic syndrome |
HRMECs | human retinal vascular endothelial cells |
AI | artificial intelligence |
OCT | optical coherence tomography |
fhRPE | fetal human RPE cells |
hESCs | human embryonic stem cells |
hiPSCs | human induced pluripotent stem cells |
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In Vivo Models | |||||
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Model | Type of Diabetes | Onset of Hyperglycemia | Main Retinal Outcomes | Advantages | Disadvantages |
Streptozotocin (STZ) | Type 1 | Within 1 week of injection | Retinal microglial cell activation [79]; retinal neovascularization [81]; increase in TNF-α, IL-1, IL-6, and VEGF expression [82]; functional abnormalities by ERG [80] | Low cost, readily available, easy to administer | Lack of ischemic phenotype; variation in phenotypes, in part due to disagreement over ideal protocol [88,89,90,91]; spontaneous β-cell regeneration may cause instability; significant amount of time required to reach moderate to severe phenotypes; mice present less severe retinal lesions compared to rats [125] |
Alloxan | Type 1 | Within 4–5 days of injection | Retinal pericyte ghosts and acellular capillaries [104]; functional abnormalities by ERG [174] | Low cost, readily available, easy to administer | Several notable inconsistencies and abnormal findings [102,103]; no consistent evidence of retinal vascular abnormalities [104,105,106] |
Akita (Ins2Akita) | Type 1 | Within 8 weeks | Increased retinal vascular permeability [110]; retinal thinning [110]; alteration in astrocytes and microglia [110]; RGC reduction [111]; functional abnormalities by ERG [109] | Commercially available with a variety of mouse genetic backgrounds, relatively consistent and predictable onset of phenotype | Does not allow for study of autoimmune process of DM [98]; β-cell regeneration is unlike human condition and can complicate study results [113] |
Akimba (Ins2Akita/VEGF+/−) | Type 1 | Within 8 weeks | Rod photoreceptor degeneration [115]; neovascularization [114]; capillary nonperfusion [114]; fibrosis [114]; edema [114]; increased pro-inflammatory and pro-angiogenic markers [119] | Higher blood glucose from earlier age [114]; consistent and predictable onset of phenotype; capable of replicating many phenotypical changes in DR | Vascular changes are not due to hyperglycemia but due to the transgene hVEGF165 [114] |
Non-obese diabetic (NOD) | Type 1 | 12–30 weeks old (variation based on gender) [175] | Increase in VEGF [176]; increase in ganglion cell and endothelial cell apoptosis [176]; microaneurysms [124]; increase in retinal thickness [124]; vasculopathy and retinal edema [124] | Many similarities to human DR phenotype, polygenic model resulting in disease phenotype similar to human DM [177] | Requires specific pathogen-free environment due to propensity to immunomodulation [77]; varying incidence rate depending on gender [77,120]; more severe perinsulitis than humans [120,122] |
Db/db | Type 2 | 4–8 weeks | Reduced retinal ganglion cells [125,126]; thinning of inner limiting membrane [126]; increased MMP-2 [123], MMP-2 [123], CD31 [126], VEGF [126], and HIF-1α [126]; reduced ERG amplitudes and ganglion cell loss [125,130] | Exhibits many features of neurodegenerative process seen in human eyes; hyperglycemia is main cause of neurodegenerative changes [125] | Neurodegenerative changes occur before any noted vascular changes are seen [130] |
Goto–Kakizaki (GK) | Type 2 | 4–6 weeks | Retinal angiogenesis [132]; increase in VEGF, PDGF, MMP-2, MMP-9, and IGF-1 [132]; increased endothelial/pericyte ratio [133], alterations to photoreceptor outer segments and vacuolization of RPE cells [134] | Relatively consistent findings, commercially available, fasting glucose remains mild and stable throughout lifetime [77] | Early β cell destruction does not truly represent human type 2 diabetes [77]; phenotypes take significant time to develop |
Pancreatectomy | Type 1 | Varies depending on species | In cats: capillary basement membrane thickening [135]; microaneurysms [136]; capillary nonperfusion [136]; neovascularization [136] In monkeys: no consistent DR findings In dogs: no consistent DR findings | Useful for studying systemic Type 1 diabetic changes; confident and consistent induction of DM | Takes significant time to develop DR phenotype, with some species never developing DR phenotype; generally only performed on larger animals due to technical complexity |
STZ + UCCAO | Type 1 | Within 1 week of STZ injection | Increase in retinal inflammatory cells [155]; decrease in capillary vessel diameter [155]; increase in retinal mRNA expression of Ccl2, Ccl12, Bnip3, Pdk1, Hsp25, and Vegfa [155] | Includes ischemic phenotype in DM model; accelerates inflammatory and ischemic DR phenotype findings compared to STZ-only models | Requires some technical precision to perform UCCAO |
In Vitro Models | |||||
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Cell monocultures |
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Cell co-cultures |
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3D cell models and organoids |
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Gettinger, K.; Lee, D.; Tomita, Y.; Negishi, K.; Kurihara, T. Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models. Int. J. Mol. Sci. 2025, 26, 9882. https://doi.org/10.3390/ijms26209882
Gettinger K, Lee D, Tomita Y, Negishi K, Kurihara T. Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models. International Journal of Molecular Sciences. 2025; 26(20):9882. https://doi.org/10.3390/ijms26209882
Chicago/Turabian StyleGettinger, Kate, Deokho Lee, Yohei Tomita, Kazuno Negishi, and Toshihide Kurihara. 2025. "Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models" International Journal of Molecular Sciences 26, no. 20: 9882. https://doi.org/10.3390/ijms26209882
APA StyleGettinger, K., Lee, D., Tomita, Y., Negishi, K., & Kurihara, T. (2025). Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models. International Journal of Molecular Sciences, 26(20), 9882. https://doi.org/10.3390/ijms26209882