Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats
Open accessAbstract
Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.
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Vasodilators can partially prevent or reverse diet-induced insulin resistance in rodents.
“vasodilators can partially prevent159, 160 or reverse161 diet-induced insulin resistance in rodents.”
From The Vasculature in Prediabetes (2018) · cites this paper as [160]
Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.
“Liraglutide treatment increases NO, decreases ET-1, normalizes endothelial function, and increases microvasculature blood flow and glucose disposal in obese rats.”
From The Vasculature in Prediabetes (2018) · cites this paper as [160]
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Zhao, J., Lv, S.-S., Qi, L., Cong, X., & Zhang, X. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s517101 · Cited by 2 · see citing works
Cellular Basis of Insulin Resistance: A Tale of the Microvasculature
Liu, Z. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819801-8.00015-6 · Cited by 2 · see citing works
Self-citationStructure and Function of the Musculoskeletal System
Gallagher, S., & Barbe, M. F. (2022) · doi:10.1002/9781119640172.ch3 · Cited by 2 · see citing works
Liu, J., Aylor, K. W., & Liu, Z. (2023) · doi:10.2337/figshare.22647826.v1 · Cited by 1 · see citing works
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- Authors
- Chai, W., Fu, Z., Aylor, K. W., Barrett, E. J., & Liu, Z.
- Affiliations
- University of Virginia Health System (US)
- Corresponding author
- Liu, Zhenqi
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2016-09-01
- Volume
- 311
- Issue
- 3
- Pages
- E640-E648
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC5142002
- OpenAlex
- W2489853663
- Cited by
- 51
- References
- 50
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 1
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK102359)
- HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (R01HL094722)
- American Diabetes Association (ADA) (1/15/CE-32)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- liraglutide, GLP-1 receptor agonists, insulin resistance, muscle microvasculature, high-fat diet, endothelial dysfunction, insulin-stimulated glucose disposal, AMPK, vascular endothelial growth factor, muscle oxygenation
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Animals, Capillaries, Endothelium, Vascular, Hypoglycemic Agents, Insulin, Insulin Resistance, Male, Regional Blood Flow, Vasodilation, Rats, Sprague-Dawley, Muscle, Skeletal, Rats, Glucagon-Like Peptide 1, Microvessels, Diet, High-Fat
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