The pivotal role of high glucose-induced overexpression of PKCβ in the appearance of glucagon-like peptide-1 resistance in endothelial cells.

PMID 26585565


Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21xa0days in normal glucose (5xa0mmol/L, NG) or high glucose (25xa0mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500xa0nM, respectively, alone or in combination, 1xa0h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCβ-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose-induced PKCβ overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCβ inhibitor. This study suggests that an increase in PKCβ, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway.