{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:33:32Z","timestamp":1772559212397,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,28]]},"group-title":"Molecular Biology","reference-count":97,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["K99 DK135915"],"award-info":[{"award-number":["K99 DK135915"]}]},{"name":"NIH","award":["R01 AG021961"],"award-info":[{"award-number":["R01 AG021961"]}]},{"name":"NIH","award":["R01 DK120322"],"award-info":[{"award-number":["R01 DK120322"]}]},{"name":"NIH","award":["DK 94244"],"award-info":[{"award-number":["DK 94244"]}]},{"name":"Boston Family Endowment Funds","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,28]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Skeletal muscle (SkM) insulin resistance is a central defect in T2D, yet cell specific molecular determinants remain incompletely understood. Here, we integrate full-length single-nucleus transcriptomics with gold-standard stable isotope-labeled hyperinsulinemic-euglycemic clamps to generate a nucleus-resolved transcriptomic atlas of SkM insulin resistance. We identify previously unrecognized myonuclear populations whose proportions associate with insulin sensitivity across independent cohorts, revealing MYH7B+ myonuclei are metabolically favorable over EGF+ myonuclei. Modeling transcriptional variation against tracer-derived glucose disposal uncovers highly nucleus-specific molecular programs that are obscured when using surrogate fasting indices. Mechanistically, we identify zinc transporter ZIP14 as a positive regulator of insulin-stimulated glucose uptake and implicate EGF signaling in impaired branched-chain amino acid catabolism and inflammatory cross-talk within the SkM niche. Together, these findings redefine SkM insulin resistance as a multicellular, nucleus-resolved process and highlight new cell type specific targets for metabolic intervention.<\/jats:p>","DOI":"10.64898\/2026.02.26.708250","type":"posted-content","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T15:15:11Z","timestamp":1772291711000},"source":"Crossref","is-referenced-by-count":0,"title":["A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-9452","authenticated-orcid":false,"given":"Katie L","family":"Whytock","sequence":"first","affiliation":[{"name":"Translational Research Institute, AdventHealth, Orlando, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1310-2092","authenticated-orcid":false,"given":"Adeline","family":"Divoux","sequence":"additional","affiliation":[{"name":"Translational Research 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