Novel Angiogenesis Role of GLP-1(32–36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R–Dependent Glycolysis in Mice

Abstract

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.