Introduction and Objective: GLP-1(32-36), a major end-product of glucagon-like peptide 1 (GLP-1), improves diabetic limb ischemia in mice independent of its insulinotropic effect. However, the mechanisms underlying this effect and its relevance in human ischemic lesions remain unclear.Methods: We used single-cell transcriptomics on the plantar muscles of diabetic foot patients and healthy controls to investigate changes in lipid metabolism genes and pathways. We also applied cellular and spatial metabolomics to evaluate the impact of GLP-1(32-36) on lipid metabolism and lipid accumulation in the gastrocnemius microvasculature in diabetic mice. Adenovirus and lentivirus were used for gene silencing in vivo and in vitro, respectively. Cross orthogonal coupling was employed for drug modification of GLP-1(32-36).Results: High glucose induces lipid metabolism dysregulation in endothelial cells (ECs) and in diabetic mice with limb ischemia. GLP-1(32-36) binds atrial natriuretic peptide receptor A (NPRA) to regulate cholesterol transport via oxysterol-binding protein (OSBP), promoting blood flow in ischemic limbs. NPRA knockdown inhibited GLP-1(32-36)’s pro-angiogenic effects, independent of the GLP-1 receptor (GLP-1R). Single-cell RNA sequencing (scRNA seq) revealed lipid metabolism dysregulation in capillary ECs of diabetic foot patients. To prolong GLP-1(32-36)’s half-life, we synthesized the ROS-responsive prodrug tEC-cRGD-(32-36) for EC-specific delivery, enhancing blood flow recovery and reducing lipid droplet formation.Conclusion: Our findings demonstrate that GLP-1(32-36) regulates lipid metabolism via the NPRA-OSBP axis to alleviate endothelial dysfunction and promote diabetic ischemic recovery, supporting the development of EC-targeting GLP-1(32-36) for treating diabetic ischemia.
Y. Zhang: None. S. Wang: None. Q. Zhou: None. C. Zheng: None.
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