ORIGINAL RESEARCH article
Front. Ophthalmol.
Sec. Retina
Volume 5 - 2025 | doi: 10.3389/fopht.2025.1570232
This article is part of the Research TopicIschemic retinopathy: underlying pathologic mechanisms and identifying therapeutic molecular targetsView all 3 articles
Effects of Regular, Glulisine, and Aspart Insulin on Vascular Endothelial Growth Factor and Angiotensinogen Expression in Hyperglycemic Retinal Pigment Epithelial (RPE) and Human Retinal Endothelial Cells (HRECs)
Provisionally accepted
- Shiraz University of Medical Sciences, Shiraz, Iran
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Diabetic retinopathy (DR) is a leading cause of vision loss and is primarily driven by chronic hyperglycemia, which induces retinal vascular damage through mechanisms involving vascular endothelial growth factor (VEGF) and the renin-angiotensin system (RAS). This study investigated the effects of hyperglycemia and different insulin formulations—regular, glulisine, and aspart—on VEGF-A and angiotensinogen (AGT) gene expression in two human retinal cell types: retinal pigment epithelial (RPE) cells and human retinal microvascular endothelial cells (HRECs). Cells were cultured from donor tissue and exposed to physiologic and hyperglycemic glucose concentrations, with or without insulin treatment. Gene expression levels were quantified using real-time PCR. Hyperglycemia significantly upregulated VEGF-A and AGT in both RPE and HREC cells (e.g., VEGF-A in RPE: 2.62-fold, P = 0.001; AGT in RPE: 3.32-fold, P = 0.093), supporting a role for both osmotic and glucose-specific pathways. Among insulin treatments, regular insulin significantly reduced VEGF-A expression in both RPE (0.72-fold, P = 0.033) and HRECs (0.57-fold, P = 0.009). In contrast, aspart and glulisine had modest effects on VEGF-A in HRECs (0.82-fold each; P = 0.035 and P = 0.060, respectively) and no significant impact in RPE cells. Regarding AGT, aspart insulin showed the most consistent suppressive effect, reducing expression in both RPE (0.15-fold, P < 0.001) and HRECs (0.22-fold, P = 0.004). Glulisine significantly increased AGT in RPE (1.56-fold, P = 0.009) but reduced it in HRECs (0.58-fold, P = 0.074). Regular insulin showed no effect on AGT in RPE (P = 0.680) and a non-significant increase in HRECs (1.36-fold, P = 0.097). These findings highlight the differential biological effects of insulin analogues and suggest that aspart insulin, in particular, may offer therapeutic benefits beyond glycemic control by modulating both VEGF-A and RAS-related pathways. Tailored insulin therapies could represent innovative strategies for managing or slowing the progression of diabetic retinopathy.
Keywords: Angiotensinogen, Aspart, Diabetic Retinopathy, Glulisine, Human retinal endothelial cells, Insulin, Retinal Pigment Epithelium, Vascular Endothelial Growth Factor
Received: 28 Feb 2025; Accepted: 30 Apr 2025.
Copyright: © 2025 Sanie-Jahromi, Khosravi, Hadianfard and Nowroozzadeh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mohammad Hosein Nowroozzadeh, Shiraz University of Medical Sciences, Shiraz, Iran
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