Our initial experiments revealed that GLP-1(32-36), an end-product of GLP-1, did not affect insulin secretion, but could significantly rescue angiogenic function and blood perfusion in ischemic limb of STZ-induced type 1 diabetes mellitus (T1DM) mice, a function similar to its parental GLP-1. We hypothesized that GLP-1(32-36) might exert its angiogenetic effects by an unknown mechanism independent of the insulinotropic activity. We demonstrate that GLP-1(32-36) ameliorated high glucose (HG)-induced excessive mitochondrial fission by resorting to aerobic glycolysis. GLP-1(32-36)-mediated angiogenesis in T1DM mice after hindlimb ischemia (HLI) were dependent on GLP-1R expression. GLP-1R, though not involved in GLP-1(32-36) entry into the cells, was required for GLP-1(32-36)-mediated pro-angiogenetic activities, including mitochondrial homeostasis, activation of the eNOS/cGMP/PKG pathway, and enhanced glycolysis via PFKFB3. Thus, our study provides a novel mechanism with which GLP-1(32-36) acts in modulating metabolic reprogramming towards glycolytic flux in partnership with GLP-1R for improved angiogenesis in HG-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 arterial disease.
Y. Zhang: None. S. Wang: None. Q. Zhou: None. Y. Xie: None. C. Zheng: None.
National Natural Science Foundation of China(82100862, 82070833)
