Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

Abstract

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

Fucoidan ameliorates pancreatic β‐cell death and impaired insulin synthesis in streptozotocin‐treated β cells and mice via a Sirt‐1‐dependent manner

“…GLP‐1 has an advantage to stimulate glucose‐dependent insulin secretion, therefore avoiding the side effects such as hypoglycemia that traditional diabetic drugs may cause, suggesting that GLP‐1R‐activating reagents are potential agents for alleviating T2DM and its associated complications . Activation of ERK1/2 and PI3K/Akt, and AMPK/Sirt‐1 signaling has been considered as major mechanisms accounting for the beneficial effects of GLP‐1R . Accordingly, induction of GLP‐1R can enhance the transcription of PDX‐1 through activation of these signaling pathways.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Similarly, it is questionable whether the required micromolar concentrations of P-site inhibitors can be obtained in the intact organism without off-target effects (Seifert, 2016). Overall, NKY80, SQ22,536, and vidarabine, which are very widely used as "selective mAC inhibitors" (or even more problematic as "selective AC5 inhibitors") (e.g., Rangel-Barajas et al, 2011; Bravo et al, 2016;Liu and Steketee, 2016;Wada et al, 2016;Wei et al, 2016), should be used with great caution as pharmacological tools, and any observed effects should be carefully checked for off-target actions (Seifert, 2014(Seifert, , 2016. It is particularly important to confirm that the AC inhibitor used actually prevents a GPCR-or FSKmediated cAMP increase (Brunskole Hummel et al, 2013).…”

Madagascine Induces Vasodilatation via Activation of AMPK

“…These results suggest that AMPK/eNOS signaling pathway is involved in madagascine-induced vasodilatation ( Figure 4 ). Both AMPK/eNOS and AMPK/AKT/eNOS are known to be related to increase the production of NO (Bradley et al, 2010; Wei et al, 2016). As shown in Figure 5 , madagascine-induced vasodilatation in the presence of SC66 was more transient than that in the absence of SC66.…”