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Extracellular vesicles (EVs) have been increasingly noticed as one critical paracrine communicator inducing insulin resistance and metabolic disorders in T2D, but clinically available pharmaceuticals for controlling pathological EV release is lacking. Here, we discover that the natural monosaccharide D\u2010mannose exists with an altered level in the db\/db mouse T2D model. Intriguingly, oral administration of D\u2010mannose with the drinking water safely ameliorates diabetic symptoms in db\/db mice. D\u2010mannose administration does not critically regulate the gut microbiome and circulatory T lymphocytes in treating T2D, while administrated D\u2010mannose rapidly accumulates in the liver, alleviates hepatic steatosis and rescues insulin resistance. Regarding the mechanism, the T2D pathological EVs released by macrophages are targeted and reduced by D\u2010mannose, which metabolically inhibits CD36 expression and restores function of hepatocytes. Importantly, by regulating macrophage EV release, D\u2010mannose administration reveals extra\u2010hepatic benefits and retards diabetic bone loss. Taken together, our findings unveil D\u2010mannose as a candidate T2D therapeutic and highlight sugars governing intercellular EV crosstalk, paving an avenue for pharmaceutical T2D approaches with amelioration of multi\u2010organ deteriorations.<\/jats:p>","DOI":"10.1002\/exp.20240133","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T09:48:03Z","timestamp":1756115283000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["D\u2010Mannose Alleviates Type 2 Diabetes and Rescues Multi\u2010Organ Deteriorations by Controlling Release of Pathological Extracellular Vesicles"],"prefix":"10.1002","volume":"5","author":[{"given":"Sha","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Fourth Military Medical University  Xi'an China"},{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University  Xi'an China"},{"name":"College of Basic Medicine Shaanxi University of Chinese Medicine  Xianyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; 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Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Yuan","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang\u2010Xiang","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University  Xi'an China"},{"name":"The First Clinical Medical College Shaanxi University of Chinese Medicine  Xianyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gong","sequence":"additional","affiliation":[{"name":"Military Medical Innovation Center The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhao","sequence":"additional","affiliation":[{"name":"Xi'an Key Laboratory of Stem Cell and Regenerative Medicine Institute of Medical Research Northwestern Polytechnical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Ma","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Tian","sequence":"additional","affiliation":[{"name":"College of Basic Medicine Shaanxi University of Chinese Medicine  Xianyang China"},{"name":"Department of Diabetes School of Translational Medicine Monash University  Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Experiment Center Shaanxi University of Chinese Medicine  Xianyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Li","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College Shaanxi University of Chinese Medicine  Xianyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Chang","family":"Di\u2010Wu","sequence":"additional","affiliation":[{"name":"College of Basic Medicine Shaanxi University of Chinese Medicine  Xianyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Han","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Stomatology the First Medical Center Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery School of Stomatology The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1152","authenticated-orcid":false,"given":"Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; 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