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We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fifty\u2010eight sedentary adults (37\u2009\u00b1\u200912\u2009years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow\/Ob), or (3) T2D. Body composition, aerobic capacity, and insulin sensitivity were assessed during a 3\u2010day inpatient stay. A fasted skeletal muscle biopsy was obtained to assess mitochondrial functions. C2C12 myoblasts were transfected with FLAG\u2010HA\u2010USP15 and FLAG\u2010HA\u2010USP30 and harvested to assess mitochondrial dynamics and cellular insulin action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Insulin sensitivity and aerobic capacity were lower in Ow\/Ob (132% and 28%, respectively) and T2D (1024% and 83%, respectively) relative to HW. Patients with T2D presented with elevated skeletal muscle mitochondrial fission (3.2 fold relative to HW and Ow\/Ob), decreased fusion, and impairments in quality control. Mitochondrial content was lower in Ow\/Ob (26%) and T2D (56%). USP13 (84%), USP15 (96%) and USP30 (53%) expression were increased with decreased Parkin and Ub activation in T2D alone. USP15 (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090.55,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and USP30 (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090.40,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 (3.6 and 3.7 fold, respectively) while inhibiting AKT (96% and 81%, respectively) and AS160 (2.1 and 3.5 fold, respectively) phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Mitochondrial fragmentation bypasses defects in mitophagy to sustain skeletal muscle quality control in patients with T2D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13763","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T08:55:47Z","timestamp":1741078547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes"],"prefix":"10.1002","volume":"16","author":[{"given":"Wagner\u00a0S.","family":"Dantas","sequence":"first","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"},{"name":"Lerner Research Institute Cleveland Clinic Foundation  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth\u00a0C.","family":"Heintz","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth\u00a0R.\u00a0M.","family":"Zunica","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob\u00a0T.","family":"Mey","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"},{"name":"Lerner Research Institute Cleveland Clinic Foundation  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa\u00a0L.","family":"Erickson","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"},{"name":"Lerner Research Institute Cleveland Clinic Foundation  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn\u00a0P.","family":"Belmont","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Analisa\u00a0L.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangarao","family":"Davuluri","sequence":"additional","affiliation":[{"name":"Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Cryo\u2010Electron Microscopy Core Case Western Reserve University  Cleveland OH USA"},{"name":"School of Medicine Case Western Reserve University  Cleveland Ohio 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