BACKGROUND:Restoring the capacity of endothelial progenitor cells (EPCs) to promote angiogenesis is the major therapeutic strategy of diabetic peripheral artery disease. The aim of this study was to investigate the effects of GLP-1 (glucagon-like peptide 1; 32–36)—an end product of GLP-1—on angiogenesis of EPCs and T1DM (type 1 diabetes) mice, as well as its interaction with the classical GLP-1R (GLP-1 receptor) pathway and its effect on mitochondrial metabolism.METHODS:In in vivo experiments, we conducted streptozocin-induced type 1 diabetic mice as a murine model of unilateral hind limb ischemia to examine the therapeutic potential of GLP-1(32–36) on angiogenesis. We also generated Glp1r^−/− mice to detect whether GLP-1R is required for angiogenic function of GLP-1(32–36). In in vitro experiments, EPCs isolated from the mouse bone marrow and human umbilical cord blood samples were used to detect GLP-1(32–36)–mediated angiogenic capability under high glucose treatment.RESULTS:We demonstrated that GLP-1(32–36) did not affect insulin secretion but could significantly rescue angiogenic function and blood perfusion in ischemic limb of streptozocin-induced T1DM mice, a function similar to its parental GLP-1. We also found that GLP-1(32–36) promotes angiogenesis in EPCs exposed to high glucose. Specifically, GLP-1(32–36) has a causal role in improving fragile mitochondrial function and metabolism via the GLP-1R–mediated pathway. We further demonstrated that GLP-1(32–36) rescued diabetic ischemic lower limbs by activating the GLP-1R–dependent eNOS (endothelial NO synthase)/cGMP/PKG (protein kinase G) pathway.CONCLUSIONS:Our study provides a novel mechanism with which GLP-1(32–36) acts in modulating metabolic reprogramming toward glycolytic flux in partnership with GLP-1R for improved angiogenesis in high glucose–exposed EPCs and T1DM murine models. We propose that GLP-1(32–36) could be used as a monotherapy or add-on therapy with existing treatments for peripheral artery disease.REGISTRATION:URL: www.ebi.ac.uk/metabolights/; Unique identifier: MTBLS9543.

中文翻译：

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GLP-1(32–36) 通过 GLP-1R 依赖性糖酵解拯救糖尿病下肢缺血的新血管生成作用

背景：恢复内皮祖细胞（EPC）促进血管生成的能力是糖尿病外周动脉疾病的主要治疗策略。本研究的目的是研究 GLP-1（胰高血糖素样肽 1；32-36）（GLP-1 的最终产物）对 EPC 和 T1DM（1 型糖尿病）小鼠以及方法：在体内实验中，我们采用链脲佐菌素诱导的1型糖尿病小鼠作为单侧后肢缺血的小鼠模型，以考察其与经典GLP-1R（GLP-1受体）途径的相互作用及其对线粒体代谢的影响。 GLP-1(32-36) 对血管生成的治疗潜力。我们还生成了Glp1r ^−/−小鼠来检测 GLP-1R 是否是 GLP-1 血管生成功能所必需的 (32–36)。在体外实验中，使用从小鼠骨髓和人脐带血样本中分离的EPC来检测高糖处理下GLP-1(32–36)介导的血管生成能力。 结果：我们证明GLP-1(32– 36)不影响胰岛素分泌，但可以显着挽救链佐星诱导的T1DM小鼠缺血肢体的血管生成功能和血液灌注，其功能与其亲本GLP-1相似。我们还发现 GLP-1(32-36) 促进暴露于高葡萄糖的 EPC 的血管生成。具体而言，GLP-1(32-36) 通过 GLP-1R 介导的途径在改善脆弱的线粒体功能和代谢方面具有因果作用。我们进一步证明GLP-1(32-36)通过激活GLP-1R依赖性eNOS（内皮NO合酶）/cGMP/PKG（蛋白激酶G）途径来挽救糖尿病下肢缺血。 结论：我们的研究提供了一种新的机制GLP-1(32-36) 与 GLP-1R 一起调节代谢重编程以实现糖酵解通量，从而改善高葡萄糖暴露的 EPC 和 T1DM 小鼠模型中的血管生成。我们建议 GLP-1(32–36) 可用作单一疗法或与现有外周动脉疾病治疗方法相结合的附加疗法。注册：URL：www.ebi.ac.uk/metabolights/；唯一标识符：MTBLS9543。