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However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia. <\/jats:p>","DOI":"10.1152\/ajpregu.00006.2022","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T12:01:56Z","timestamp":1650974516000},"page":"R43-R58","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity"],"prefix":"10.1152","volume":"323","author":[{"given":"Ryan J.","family":"Pettit-Mee","sequence":"first","affiliation":[{"name":"Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Power","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Cabral-Amador","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4920-383X","authenticated-orcid":true,"given":"Francisco I.","family":"Ramirez-Perez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9877-683X","authenticated-orcid":true,"given":"Rogerio N.","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neekun","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9710-6666","authenticated-orcid":true,"given":"Demetra D.","family":"Christou","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Kanaley","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-5717","authenticated-orcid":true,"given":"Luis A.","family":"Martinez-Lemus","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, Missouri"},{"name":"Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri"},{"name":"Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-404X","authenticated-orcid":true,"given":"Camila","family":"Manrique-Acevedo","sequence":"additional","affiliation":[{"name":"Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri"},{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri"},{"name":"Research Services, Harry S. 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