Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner
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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 A 1c (Hb A 1c ) 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.
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GLP-1RAs encourage initiating anti-inflammatory mechanisms such as the AMPK pathway, which helps suppress inflammation.
“Second, GLP-1RAs encourage initiating anti-inflammatory mechanisms such as the AMP-activated protein kinase (AMPK) pathway, which helps suppress inflammation.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [31]
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 [49]
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- Authors
- Wei, R., Ma, S., Wang, C., Ke, J., Yang, J., Li, W., Liu, Y., Hou, W., Feng, X., Wang, G., & Hong, T.
- Affiliations
- Department of Endocrinology and Metabolism and
- Peking University Third Hospital (CN)
- Corresponding author
- Hong, Tianpei
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2016-06-01
- Volume
- 310
- Issue
- 11
- Pages
- E947-E957
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2339053935
- Cited by
- 137
- References
- 41
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 16 · 2023: 8 · 2022: 14 · 2021: 17 · 2020: 8 · 2019: 13 · 2018: 14 · 2017: 11 · 2016: 2
- FWCI
- 13.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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, exendin-4, coronary endothelial function, type 2 diabetes, endothelial nitric oxide synthase, coronary flow velocity reserve, soluble adhesion molecules, cAMP signaling, exendin-9-39, reactive oxygen species
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Adult, Cardiotonic Agents, Diabetic Angiopathies, Dose-Response Relationship, Drug, Echocardiography, Endothelium, Vascular, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Multienzyme Complexes, Peptides, Venoms, Signal Transduction, Oncogene Protein v-akt, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases
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