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Our team has recently identified hexosaminidase\u00a0A (HEXA) as an endocrine factor secreted by the liver that regulates sphingolipid metabolism in skeletal muscle. Specifically, HEXA converts GM2 to GM3 gangliosides within cell-surface lipid rafts. Remodelling of ganglioside composition by HEXA enhances IGF1 signalling in skeletal muscle, increasing muscle glucose uptake and improving blood glucose control.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We produced a long-acting HEXA-FC fusion protein (murine HEXA and the fragment crystallisable [FC] region from IgG1) and evaluated the effects of chronic bi-weekly HEXA-FC administration (1 mg\/kg body weight) on glycaemic control in C57BL\/6 mice with diet-induced obesity and insulin resistance and the <jats:italic>db<\/jats:italic>\/<jats:italic>db<\/jats:italic> mouse model of severe type 2 diabetes. Outcome measures included glucose and insulin tolerance, including a stable isotope-labelled GTT and assessment of tissue-specific glucose disposal, as well as proteomics analysis to define changes in skeletal muscle metabolism.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Chronic administration of a long-acting recombinant HEXA-FC fusion protein led to improvements in random blood glucose, fasting blood glucose and glucose tolerance, driven by increased glucose disposal into skeletal muscle, effects that were associated with enhancement of IGF1 signalling in muscle.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>Given that skeletal muscle is a primary site of insulin resistance in individuals with type 2 diabetes, HEXA-FC protein therapy may open new avenues for therapeutic advancement in type 2 diabetes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06413-7","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T14:51:27Z","timestamp":1743432687000},"page":"1530-1543","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["HEXA-FC protein therapy increases skeletal muscle glucose uptake and improves glycaemic control in mice with insulin resistance and in a mouse model of type 2 diabetes"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2551-4174","authenticated-orcid":false,"given":"Magdalene K.","family":"Montgomery","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-670X","authenticated-orcid":false,"given":"Chieh-Hsin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1085-9591","authenticated-orcid":false,"given":"Krishneel","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi Li","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7324-3551","authenticated-orcid":false,"given":"Jacqueline","family":"Bayliss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8981-0701","authenticated-orcid":false,"given":"Michael G.","family":"Leeming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2173-3452","authenticated-orcid":false,"given":"Nicholas A.","family":"Williamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-1926","authenticated-orcid":false,"given":"Kim","family":"Loh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Watt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"key":"6413_CR1","unstructured":"International Diabetes Federation (2021) IDF Diabetes Atlas, 10th edn.\u00a0IDF,\u00a0Brussels, Belgium. 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All other data, including the MS raw files, are available on request from the corresponding author.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open Access funding enabled and organized by CAUL and its Member Institutions. These studies were supported by funding from the National Health and Medical Research Foundation of Australia (APP2011540 to MKM, APP1098972 to MJW, and APP1162511 to MJW).","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":"All authors listed in this manuscript fulfil the following criteria: (1) substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data; (2) drafting the article or reviewing it critically for important intellectual content; and (3) final approval of the version to be published. MKM is responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}