{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:21:53Z","timestamp":1787768513786,"version":"build-2784847793"},"reference-count":39,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"35","funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["20ZR1474400"],"award-info":[{"award-number":["20ZR1474400"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370796"],"award-info":[{"award-number":["32370796"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipal Science and Technology Major Project"},{"name":"Shanghai Key Laboratory of Aging Studies","award":["19DZ2260400"],"award-info":[{"award-number":["19DZ2260400"]}]},{"name":"Shanghai Basic Research Pioneer Project"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    Glucagon-like peptide-1 (GLP-1) is a key incretin hormone rapidly degraded by circulating proteases such as DPP-4. The metabolism of GLP-1 by other proteases, particularly tissue-resident proteases, remains largely unexplored. Here, we identify insulin-degrading enzyme (IDE) as a previously unknown GLP-1-degrading protease with two cleavage sites. We show that IDE-mediated degradation of GLP-1, but not insulin, represents a major mechanism regulating glucose control. To resist IDE, we engineered GLP-1 and Semaglutide with D-amino acid substitutions at these sites. These peptides exhibit enhanced stability in plasma, liver and intestinal secretomes, peritoneal fluid, and central nervous system (CNS). D-Ser\n                    <jats:sup>18<\/jats:sup>\n                    -Semaglutide shows prolonged plasma retention and sustained glucose-lowering effects in mice. Moreover, IDE knockdown and intracerebral injection of D-Ser\n                    <jats:sup>18<\/jats:sup>\n                    -Semaglutide confirm IDE\u2019s physiological role in GLP-1 degradation, particularly in the CNS. These findings reveal a previously unidentified regulatory mechanism of GLP-1 metabolism and provide a strategy for designing long-acting agonists with improved metabolic and CNS therapeutic potential.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh4670","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:59:39Z","timestamp":1787767179000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["IDE-mediated GLP-1 degradation as the basis for designing long-acting and CNS-stable GLP-1 receptor agonists"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1942-4538","authenticated-orcid":true,"given":"Lu","family":"Zhang","sequence":"first","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences; 386 Bibo Rd., Shanghai 201210, 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