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CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of\n                      <jats:italic>CD36<\/jats:italic>\n                      coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Our multi-disciplinary approach included hyperinsulinaemic\u2013euglycaemic clamps in\n                      <jats:italic>Cd36<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with\/without CD36 depletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Insulin clamps showed that\n                      <jats:italic>Cd36<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>CD36 deficiency was previously shown to reduce muscle\/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle\/heart metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Clinicaltrials.gov NCT03012386<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>\n                      The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/geo\/\" ext-link-type=\"uri\">www.ncbi.nlm.nih.gov\/geo\/<\/jats:ext-link>\n                      ) under accession code GSE235988 (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE235988\" ext-link-type=\"uri\">https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE235988<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-024-06292-4","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T02:06:26Z","timestamp":1730858786000},"page":"662-675","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency"],"prefix":"10.1007","volume":"68","author":[{"given":"Cyndya A.","family":"Shibao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek S.","family":"Peche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri A.","family":"Pietka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri","family":"Samovski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naji N.","family":"Abumrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Gamazon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Wasserman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada A.","family":"Abumrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"issue":"1","key":"6292_CR1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/5013","volume":"21","author":"TJ Aitman","year":"1999","unstructured":"Aitman TJ, Glazier AM, Wallace CA et al (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. 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Mecham (Washington University) with measurements of vessel compliance in\n                      Cd36\n                      \u2212\/\u2212\n                      mice and the help of S. C. Beeman (Arizona State University) with ASL MRI of microvascular perfusion in the kidney.Dr. David Wasserman died on 20 June 2024 from health issues. David was the Annie Mary Lyle Professor of Molecular Physiology and Biophysics at Vanderbilt University, he contributed groundbreaking research to our understanding of the factors that regulate glucose metabolism by various organs. He also founded and directed the Mouse Metabolic Phenotyping Center, which became an international resource for studying mouse metabolism. This manuscript is dedicated to his memory as a wonderful scientist,\u00a0collaborator and friend.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (\n                      \n                      ) under accession code GSE235988 (\n                      \n                      ). Microarray data are available as ESM Table\n                      \n                      . All other data analysed for this study are available from the corresponding author upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"We acknowledge support from the National Institute of Health (RO1DK111175 [NAA, CAS, NNA]); NHLBI R01HL157584 [CAS]; NHLBI R01 HL045095 [IJG, NAA]), Clinical Translational Science Award (CAS) and assistance from Vanderbilt Institute for Clinical and Translational Sciences (5UL1TR002243-03) and Washington University Nutrition and Obesity Center (NORC, P30 DK056341).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"CAS and NNA designed the human studies. CAS recruited participants, performed the insulin clamps and CAS and NNA analysed the data. VSP designed, performed and analysed all cell studies. DHW and IMW designed, performed and analysed the mice insulin clamps and insulin flux experiments. DS designed, performed and analysed the mice metabolic studies. TP performed the human genotyping, the vessel compliance assays, the immunohistochemistry and gene expression studies, and analysed the RNAseq and microarray data. CAS, VSP, TP, DS, IMW and DHW reviewed and edited the manuscript. NNA and IJG contributed to study design and to data interpretation and critically reviewed the manuscript. ERG designed the PrediXcan approach to query the Vanderbilt BioVu patient biobank, collected and analysed the PrediXcan data and edited the manuscript. All authors approved the final manuscript version. NAA conceived and designed the study, analysed the data, wrote the manuscript and is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}