incretins and exendin-3

The term incretin effect was used to describe the fact that oral glucose load produces a greater insulin response than that of an isoglycemic intravenous glucose infusion. This difference has been attributed to gastrointestinal peptides GLP-1 and GIP. Since incretin effect is reduced in subjects with type 2 diabetes, despite GLP-1 activity preservation, two forms of incretin-based treatment have emerged: GLP-1R agonists, administered subcutaneously and DPP-4 inhibitors, administered orally. There is a great interest whether incretin-based treatment will be associated with sustained long-term control and improvement in β-cell function. The observation that GLP-1R agonists improve myocardial function and survival of cardiomyocytes highlights the need for further studies. Incretin-based therapies offer a new option and show great promise for the treatment of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Peptides; Receptors, Glucagon; Venoms

Pulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear.. In the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-β1 (5 ng/ml) combining IL-1β (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-β1-IL-1β-induced phosphorylation of both Smad3 and ERK1/2.. Our data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Incretins; Liraglutide; Male; Peptides; Protective Agents; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate