Restoring Harmony in Renal Microcirculation Through Insulin and Liraglutide Amid Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a major risk factor for chronic kidney disease (CKD), contributing to its progression through microvascular complications that lead to end-stage renal disease. This study aims to elucidate the alterations in renal microcirculation associated with T2DM and evaluate the microcirculatory therapeutic efficacy of insulin and liraglutide. Utilizing a T2DM mouse model induced by a high-fat diet followed by streptozotocin injection, we implemented treatment phases with insulin and liraglutide. Renal microhemodynamics and oxygen was assessed through laser Doppler combined with wavelet transform analysis. Masson trichrome and hematoxylin-eosin staining for histological evaluation of fibrosis and renal microvasculature integrity. Additionally, renal microvascular endothelial cells were isolated to study cellular responses to hyperglycemic conditions in vitro, focusing on migration and angiogenic capacities. Complementarily, untargeted and targeted metabolomics were performed to unravel the metabolic impacts of T2DM and the modulatory effects of the treatments, linking metabolic alterations to microvascular and renal function changes. Our findings indicate that both insulin and liraglutide significantly mitigate renal structural and microvascular damage, enhance angiogenic and migratory responses, and restore metabolic disruptions of renal microvascular endothelial cells induced by T2DM. These effects were corroborated by improved histopathological profiles and normalized metabolic pathways critical in renal microvascular health. Our study highlights the detrimental impact of T2DM on renal microcirculation, thereby providing potential clinical strategies for managing CKD.