{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:30:32Z","timestamp":1789684232675,"version":"4.0.1"},"reference-count":49,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1143224"],"award-info":[{"award-number":["APP1143224"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1162511"],"award-info":[{"award-number":["APP1162511"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2011540"],"award-info":[{"award-number":["APP2011540"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000971","name":"Diabetes Australia","doi-asserted-by":"publisher","award":["Y21G-MONM"],"award-info":[{"award-number":["Y21G-MONM"]}],"id":[{"id":"10.13039\/501100000971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) and impaired glycemic control are closely linked; however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycemic defects. We identify hexosaminidase A (HEXA) as an NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides\u2014sphingolipids that are primarily localized to cell-surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated virus vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA\u2019s enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing IGF-1 signaling and GLUT4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. In this study, we identify a pathway for intertissue communication between liver and skeletal muscle in the regulation of systemic glycemic control.<\/jats:p>","DOI":"10.2337\/db22-0590","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T18:40:22Z","timestamp":1672339222000},"page":"715-727","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":20,"title":["Liver-Secreted Hexosaminidase A Regulates Insulin-Like Growth Factor Signaling and Glucose Transport in Skeletal Muscle"],"prefix":"10.2337","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2551-4174","authenticated-orcid":false,"given":"Magdalene K.","family":"Montgomery","sequence":"first","affiliation":[{"name":"1Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Williamson","sequence":"additional","affiliation":[{"name":"2Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine J.","family":"Ooi","sequence":"additional","affiliation":[{"name":"3Centre for Obesity Research and Education, Department of Surgery, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy A.","family":"Brown","sequence":"additional","affiliation":[{"name":"3Centre for Obesity Research and Education, Department of Surgery, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Burton","sequence":"additional","affiliation":[{"name":"3Centre for Obesity Research and Education, Department of Surgery, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Gregorevic","sequence":"additional","affiliation":[{"name":"1Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia"},{"name":"4Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig A.","family":"Goodman","sequence":"additional","affiliation":[{"name":"1Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia"},{"name":"4Centre for Muscle Research, The 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