title: Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats.
abstract: 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Weidong
authors.initials: W
authors.lastname: Chai
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Aylor
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Barrett
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia zl3e@virginia.edu.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D055806:Microvessels / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: endothelial function; glucagon-like peptide-1; insulin resistance; microvascular recruitment; vasodilation