GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery

ArticleinThe American journal of physiology 265(4 Pt 1):L374-81 · November 1993with9 Reads
Impact Factor: 3.28 · Source: PubMed

Recent data revealed the existence of specific receptors for glucagon-like peptide-1(7-36)amide (GLP-1) on rat lung membranes. Utilizing slide-mount autoradiography of fresh frozen lung tissue sections, we have localized binding sites for GLP-1 on mucous glands in the trachea and on vascular smooth muscle of the pulmonary artery. When tracheas were incubated in a modified Ussing chamber, the addition of GLP-1 to the submucosal side increased 35S-sulfate-labeled macromolecule secretion (191 +/- 12% above basal, P < 0.005). The optimal secretory response elicited by GLP-1 was approximately 23% of the maximal secretory response after a maximal acetylcholine stimulation. Other proglucagon-derived peptides such as glucagon, oxyntomodulin, and GLP-2 had no effect. In isolated rings of arteries, GLP-1 (10(-8) to 10(-5) M) induced a dose-dependent and time-reversible relaxation of preconstricted arteries. In a preparation with denuded epithelium, GLP-1 lost its effect. In conclusion, GLP-1 might represent another neuropeptide that acts as neurotransmitter of the peptidergic, nonadrenergic-noncholinergic nervous system that innervates the airways.

    • "It has been reported that GLP-1 receptors are expressed in vascular endothelial cells [22] and it has been reported to directly increase NO production and inhibit the expressions of endothelial cell adhesion factors [23]. GLP-1 increases NO production to improve the vasodilatory response [8]. In addition, GLP-1 is reported to inhibit overexpression of hyperglycemiainduced vascular cell adhesion molecule-1 in vascular endothelial cells [9] . "
    [Show abstract] [Hide abstract] ABSTRACT: Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to their indirect effects on postprandial glucose and lipid metabolism. GLP-1 analogs are also reported to inhibit postprandial vascular endothelial dysfunction. This study examined whether the GLP-1 analog exenatide inhibits postprandial vascular endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). Seventeen patients with T2DM underwent a meal tolerance test to examine changes in postprandial vascular endothelial function and in glucose and lipid metabolism, both without exenatide (baseline) and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was determined using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide tests. The natural logarithmically-scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. The use of exenatide resulted in a significant decrease in triglycerides (TG) area under the curve and coefficient of variation (CV). The change in L_RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L_RHI, contributing to 41% of the observed change. Exenatide inhibited postprandial vascular endothelial dysfunction after the meal loading test, suggesting that exenatide has a multiphasic anti-atherogenic action involving not only glucose but also lipid metabolism. UMIN000015699 .
    Full-text · Article · Dec 2015 · Cardiovascular Diabetology
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    • "At present, GLP-1 analogs and DPP-4 inhibitors have been widely used in type-2 diabetes mellitus (T2DM) treatment [9,30]. Meanwhile, several studies has identified the expression of GLP-1R in the lung, including airway epithelial cells, type-II alveolar cells and vascular smooth muscle of the pulmonary artery, both in rodents and humans1011121314151617. Then, Viby et al. [18] showed the protective role of GLP-1R agonists in a mouse model of obstructive lung disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Asthma is a common chronic pulmonary inflammatory disease, featured with mucus hyper-secretion in the airway. Recent studies found that glucagon like peptide-1 (GLP-1) analogs, including liraglutide and exenatide, possessed a potent anti-inflammatory property through a protein kinase A (PKA)-dependent signaling pathway. Therefore, the aim of current study was to investigate the value of GLP-1 analog therapy liraglutide in airway inflammation and mucus secretion in a murine model of ovalbumin (OVA)-induced asthma, and its underlying molecular mechanism. In our study, BALB/c mice were sensitized and challenged by OVA to induce chronic asthma. Pathological alterations, the number of cells and the content of inflammatory mediators in bronchoalveolar lavage fluid (BALF), and mucus secretion were observed and measured. In addition, the mRNA and protein expression of E-selectin and MUC5AC were analyzed by qPCR and Western blotting. Then, the phosphorylation of PKA and nuclear factor-κB (NF-κB) p65 were also measured by Western blotting. Further, NF-κB p65 DNA binding activity was detected by ELISA. OVA-induced airway inflammation, airway mucus hyper-secretion, the up-regulation of E-selectin and MUC5AC were remarkably inhibited by GLP-1 in mice (all p < 0.01). Then, we also found that OVA-reduced phosphorylation of PKA, and OVA-enhanced NF-κB p65 activation and NF-κB p65 DNA binding activity were markedly improved by GLP-1 (all p < 0.01). Furthermore, our data also figured out that these effects of GLP-1 were largely abrogated by the PKA inhibitor H-89 (all p < 0.01). Taken together, our results suggest that OVA-induced asthma were potently ameliorated by GLP-1 possibly through a PKA-dependent inactivation of NF-κB in mice, indicating that GLP-1 analogs may be considered an effective and safe drug for the potential treatment of asthma in the future.
    Full-text · Article · Sep 2015 · International Journal of Molecular Sciences
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    • "This effect was suggested by the authors to involve reduced foam cell formation, because oxidized low-density lipoprotein-induced cholesteryl ester accumulation was significantly decreased in macrophages harvested from GLP-1-treated animals [58]. In contrast, others have reported that the GLP-1R agonist taspoglutide had no effect on the aortic plaque area in apoE À/À mice on a high-fat diet, with a streptozotocin-induced hyperglycaemia to simulate T2DM [32]. Thus, the effect of GLP-1 on atherosclerosis development is still unclear, and more data on atherosclerosisassociated outcomes, especially in diabetic human beings, after long-term treatment with incretin-based therapy, are much needed [59]. "
    [Show abstract] [Hide abstract] ABSTRACT: Diabetes is rapidly increasing worldwide, and the number of patients suffering from diabetes is projected to rise by 50 % over the next 25 years, then affecting almost 600 million adults. Type 2 diabetes comprises 90-95% of all people with diabetes, and they constitute a patient group that carries a high burden of cardiovascular disease. The relationship between hyperglycaemia and macrovascular complications is still uncertain, at least in terms of the possibility of reducing cardiovascular events solely by improving glycaemic control. This MiniReview has thus focused on the effect of common antidiabetic agents, with emphasis on glucagon like peptide-1, on the endothelial cells of the vasculature. Patients with type 2 diabetes suffer a 2-4 times higher risk of myocardial infarction and stroke than healthy persons. In addition to this, diabetic patients have an increased atherosclerotic burden. Endothelial dysfunction is thought to be an early and important predictor of atherosclerosis and cardiovascular disease, and in people with type 2 diabetes endothelial dysfunction is a common finding. It is therefore of importance to consider whether drugs used within the clinical management of T2DM exert direct and positive effects on the vasculature independent of their glucose-lowering ability. This might serve to limit the adverse consequences of the macrovascular complications of T2DM, as dysfunction of endothelial cells is believed to contribute to a premature development of atherosclerosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2015 · Basic & Clinical Pharmacology & Toxicology
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