glucagon-like-peptide-1 and Vascular-Diseases

To test the effect of normoglycemia and glucagon-like peptide-1 (GLP-1), alone or in combination, on the possible normalization of endothelial function in type 1 diabetes.. Fifteen people with type 1 diabetes participated in three experiments: reaching and maintaining normoglycemia for 4h; reaching and maintaining hyperglycemia plus GLP-1 infusion for 4h; and reaching and maintaining normoglycemia for 4h with simultaneous infusion of GLP-1.. Both normoglycemia and GLP-1 infusion restored endothelial function and decreased and plasma 8-iso prostaglandin F2α levels. However, only the combination of normoglycemia and GLP-1 was able to normalize endothelial function.. This study confirms that long-lasting hyperglycemia in type 1 diabetes induces a permanent alteration which contributes to maintaining endothelial dysfunction even when glycemia is normalized, and that in the presence of normoglycemia, GLP-1 can contribute to normalizing endothelial function.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Dinoprost; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Infusions, Parenteral; Male; Oxidative Stress; Vascular Diseases; Young Adult

Glucagon-like peptide-1 (GLP-1) analogues have been found to exert protective effect on endothelial barrier dysfunction in vascular diseases. Moesin phosphorylation participates in the process of advanced glycation end products (AGEs) induced disruption of endothelial barrier integrity. Whether and how GLP-1 modulating moesin phosphorylation in endothelium under diabetic condition needs further clarification. Consistent with previous studies, our data showed that hyperglycemia and AGEs promoted moesin phosphorylation in ECs in vivo and vitro experiments. With or without AGEs incubation, overexpression of moesin and activated mutant moesin T558D increased ECs permeability, whereas knockdown of moesin decreased ECs permeability. Inhibition of Rho/ROCK, p38/MAPK and PKC β signal pathways also decreased moesin phosphorylation in ECs incubated with AGEs. Importantly, GLP-1 inhibited moesin phosphorylation in AGE-induced ECs in a dose-dependent manner. Intriguingly, the effects of GLP-1 elicited on moesin phosphorylation in ECs under diabetic condition were blunted by inhibition of cAMP/PKA and stimulation of Rho/ROCK, p38 and PKC β signaling pathways. Therefore, this study verified that the stabilizing effect of GLP-1 on the moesin phosphorylation mediated endothelial barrier function is mediated by GLP-1R/cAMP/PKA activation and subsequent down-regulation of Rho/ROCK, p38 and PKC β signaling pathways.

Topics: Cells, Cultured; Glucagon-Like Peptide 1; Glycation End Products, Advanced; Humans; Microfilament Proteins; Phosphorylation; Vascular Diseases

Chronic rejection induces the occurrence of orthotopic allograft transplantation (OAT) vasculopathy, which results in failure of the donor organ. Numerous studies have demonstrated that in addition to regulating blood sugar homeostasis, dipeptidyl peptidase-4 (DPP-4) inhibitors can also provide efficacious therapeutic and protective effects against cardiovascular diseases. However, their effects on OAT-induced vasculopathy remain unknown. Thus, the aim of this study was to investigate the direct effects of sitagliptin on OAT vasculopathy in vivo and in vitro.. The PVG/Seac rat thoracic aorta graft to ACI/NKyo rat abdominal aorta model was used to explore the effects of sitagliptin on vasculopathy. Human endothelial progenitor cells (EPCs) were used to investigate the possible underlying mechanisms.. We demonstrated that sitagliptin decreases vasculopathy in OAT ACI/NKyo rats. Treatment with sitagliptin decreased BNP and HMGB1 levels, increased GLP-1 activity and stromal cell-derived factor 1α (SDF-1α) expression, elevated the number of circulating EPCs, and improved the differentiation possibility of mononuclear cells to EPCs ex vivo. However, in vitro studies showed that recombinant B-type natriuretic peptide (BNP) and high mobility group box 1 (HMGB1) impaired EPC function, whereas these phenomena were reversed by glucagon-like peptide 1 (GLP-1) receptor agonist treatment.. We suggest that the mechanisms underlying sitagliptin-mediated inhibition of OAT vasculopathy probably occur through a direct increase in GLP-1 activity. In addition to the GLP-1-dependent pathway, sitagliptin may regulate SDF-1α levels and EPC function to reduce OAT-induced vascular injury. This study may provide new prevention and treatment strategies for DPP-4 inhibitors in chronic rejection-induced vasculopathy.

Topics: Animals; Aorta, Thoracic; Chemokine CXCL12; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Progenitor Cells; Glucagon-Like Peptide 1; HMGB1 Protein; Hypoglycemic Agents; Male; Natriuretic Peptide, Brain; Rats; Rats, Inbred ACI; Sitagliptin Phosphate; Transplantation, Homologous; Vascular Diseases