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Aims: Although diabetic retinopathy has long been considered a microvascular complication, retinal neurodegeneration and inflammation may precede its clinical manifestations. Despite all research efforts, the primary treatment options remain laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections, both aggressive and targeting the late stages of the disease. Medical treatments addressing the early phases of diabetic retinopathy are therefore needed. We aimed at verifying if thiamine and fenofibrate protect the cells of the inner blood-retinal barrier from the metabolic stress induced by diabetic-like conditions. Methods: Human microvascular endothelial cells (HMECs), retinal pericytes (HRPs) and Müller cells (MIO-M1) were cultured in intermittent high glucose (intHG) and/or hypoxia, with addition of fenofibrate or thiamine. Modulation of adhesion molecules and angiogenic factors was addressed. Results: Integrins β1/αVβ3 and ICAM1 were upregulated in HMECs/HRPs cultured in diabetic-like conditions, as well as metalloproteases MMP2/9 in HRP, with a reduction in their inhibitor TIMP1; MMP2 increased also in HMEC, and TIMP1 decreased in MIO-M1. VEGF and HIF-1α were strongly increased in HMEC in intHG + hypoxia, and VEGF also in HRP. Ang-1/2 augmented in HMEC/MIO-M1, and MCP-1 in HRP/MIO-M1 in intHG + hypoxia. Thiamine was able to normalize all such abnormal modulations, while fenofibrate had effects in few cases only. Conclusions: We suggest that endothelial cells and pericytes are more affected than Müller cells by diabetic-like conditions. Fenofibrate shows a controversial behavior, potentially positive on Müller cells and pericytes, but possibly detrimental to endothelium, while thiamine confirms once more to be an effective agent in reducing diabetes-induced retinal damage. [ABSTRACT FROM AUTHOR]