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Extracellular vesicles (EVs) have emerged as important mediators of insulin sensitivity, although few studies on vascular function exist in humans. We determined the effect of insulin on EVs in relation to vascular function. Adults with MetS (<jats:italic>n<\/jats:italic>\u00a0=\u00a051, <jats:italic>n<\/jats:italic>\u00a0=\u00a09\u00a0M, 54.8\u2009\u00b1\u20091.0\u2009years, 36.4\u2009\u00b1\u20090.7\u00a0kg\/m<jats:sup>2<\/jats:sup>, ATPIII: 3.5\u2009\u00b1\u20090.1\u00a0a.u., VO<jats:sub>2<\/jats:sub>max: 22.1\u2009\u00b1\u20090.6\u00a0ml\/kg\/min) were enrolled in this cross\u2010sectional study. Peripheral insulin sensitivity (M\u2010value) was determined during a euglycemic clamp (40\u2009mU\/m<jats:sup>2<\/jats:sup>\/min, 90\u2009mg\/dl), and blood was collected for EVs (CD105+, CD45+, CD41+, TX+, and CD31+; spectral flow cytometry), inflammation, insulin, and substrates. Central hemodynamics (applanation tonometry) was determined at 0 and 120\u2009min via aortic waveforms. Pressure myography was used to assess insulin\u2010induced arterial vasodilation from mouse 3rd order mesenteric arteries (100\u2013200\u2009\u03bcm in diameter) at 0.2, 2 and 20\u2009nM of insulin with EVs from healthy and MetS adults. Adults with MetS had low peripheral insulin sensitivity (2.6\u2009\u00b1\u20090.2\u2009mg\/kg\/min) and high HOMA\u2010IR (4.7\u2009\u00b1\u20090.4\u2009a.u.) plus Adipose\u2010IR (13.0\u2009\u00b1\u20091.3\u2009a.u.). Insulin decreased total\/particle counts (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), CD45+ EVs (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.002), AIx75 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.005) and Pb (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.04), FFA (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), total adiponectin (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.006), ICAM (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.002), and VCAM (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.03). Higher M\u2010value related to lower fasted total EVs (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.40, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.004) while higher Adipose\u2010IR associated with higher fasted EVs (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.42, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.004) independent of VAT. Fasting CD105+ and CD45+ derived total EVs correlated with fasting AIx75 (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.29, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and Pb (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.30, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). EVs from MetS participants blunted insulin\u2010induced vasodilation in mesenteric arteries compared with increases from healthy controls across insulin doses (all <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005). These data highlight EVs as potentially novel mediators of vascular insulin sensitivity and disease risk.<\/jats:p>","DOI":"10.14814\/phy2.15530","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T04:59:05Z","timestamp":1672808345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Extracellular vesicles and insulin\u2010mediated vascular function in metabolic syndrome"],"prefix":"10.14814","volume":"11","author":[{"given":"Tristan J.","family":"Ragland","sequence":"first","affiliation":[{"name":"Department of Kinesiology &amp; Health Rutgers University  New Brunswick New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Heiston","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Pauley Heart Center Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Department of Kinesiology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ballantyne","sequence":"additional","affiliation":[{"name":"Department of Kinesiology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan R.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Kinesiology &amp; Health Rutgers University  New Brunswick New Jersey USA"},{"name":"Department of Kinesiology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"La Salvia","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Musante","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Luse","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center University of Virginia School of Medicine  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brant E.","family":"Isakson","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center University of Virginia School of Medicine  Charlottesville Virginia USA"},{"name":"Department of Molecular Physiology and Biophysics University of Virginia School of Medicine  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uta","family":"Erdbr\u00fcgger","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine University of Virginia  Charlottesville Virginia 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