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).

Abstract

Introduction: 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).

Methods: 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.

Results: 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).

Discussion: 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.