Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans
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GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist–mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.
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In vitro/ex vivo studies on endothelial cells showed that GLP-1RAs such as exenatide and liraglutide stimulate endothelial nitric oxide production and eNOS activation, eliciting vasodilatation through GLP-1 receptor-dependent AMPK/Akt/eNOS signaling.
“In vitro/ex vivo studies conducted on endothelial cells showed that GLP-1RAs such as exenatide and liraglutide stimulate endothelial NO production and endothelial nitric oxide synthase (eNOS) activation, eliciting vasodilatation through activation of the GLP-1 receptor-dependent AMP-activated protein kinase (AMPK)/protein kinase B (Akt)/eNOS signaling pathway [48–50].”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [48]
Human studies provide conflicting information about the effect of GLP-1 or stable analogues on endothelial function.
“Human studies provide conflicting information about the effect of GLP-1 or stable analogues on endothelial function.212-217”
From The Vasculature in Prediabetes (2018) · cites this paper as [213]
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Self-citation
- Authors
- Koska, J., Sands, M., Burciu, C., D’Souza, K. M., Raravikar, K., Liu, J., Truran, S., Franco, D. A., Schwartz, E. A., Schwenke, D. C., D’Alessio, D., Migrino, R. Q., & Reaven, P. D.
- Affiliations
- Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ
- Phoenix VA Health Care System (US)
- Duke University (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2015-02-26
- Volume
- 64
- Issue
- 7
- Pages
- 2624-2635
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4477348
- OpenAlex
- W2130583827
- Cited by
- 174
- References
- 52
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 20 · 2023: 11 · 2022: 20 · 2021: 14 · 2020: 6 · 2019: 13 · 2018: 14 · 2017: 16 · 2016: 12 · 2015: 4
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R21HL-092344-01)
- U.S. Department of Veterans Affairs (1I01CX000598, BLRD I01BX007080)
- American Diabetes Association (1-10-CT-31)
- Amyloidosis Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- exenatide, GLP-1 receptor agonists, endothelial dysfunction, vasodilation, type 2 diabetes, impaired glucose tolerance, AMPK, endothelial nitric oxide synthase, nitric oxide, high glucose, hypertriglyceridemia, endothelial cells
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Humans, Male, Peptides, Triglycerides, Vasodilation, Venoms, Receptors, Glucagon, Cross-Over Studies, Endothelial Cells, AMP-Activated Protein Kinases
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