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

Abstract

Glucagon-like peptide 1 (GLP-1) improves angiogenesis, but the mechanism remains unclear. To address this question, we conducted a metabolomics analysis in bone marrow-derived endothelial progenitor cells (EPCs) isolated from T1DM mice treated with or without GLP-1(32-36) amide, an end-product of GLP-1. GLP-1(32-36) treatment recovered glycolysis. In addition, GLP-1(32-36) treatment rescued diabetic ischemic lower limbs and EPCs dysfunction by regulating PFKFB3-driven glycolytic flux capacity and mitochondrial dynamics. The effects of GLP-1(32-36) were abolished in mice lacking a functional GLP-1 receptor (Glp1r-/-), which could be partially rescued in EPCs transiently expressing GLP-1R. GLP-1(32-36) treatment activated the eNOS/cGMP/PKG pathway, increased glycolysis, and enhanced EPCs angiogenesis. Taken together, these findings suggest that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for DPAD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/543344v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@2559eorg.highwire.dtl.DTLVardef@1430faborg.highwire.dtl.DTLVardef@1b9b188org.highwire.dtl.DTLVardef@36809c_HPS_FORMAT_FIGEXP M_FIG C_FIG