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Most venom components disrupt nervous, locomotor, and cardiovascular systems or cause tissue damage. The discovery that certain fish-hunting cone snails use weaponized insulins to induce hypoglycemic shock in prey highlights a unique example of toxins targeting glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, <jats:italic>Conus geographus<\/jats:italic>, uses a selective somatostatin receptor 2 (SSTR<jats:sub>2<\/jats:sub>) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms with a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin\u2019s N-terminal tail closely mimics a glycosylated somatostatin from fish pancreas and is crucial for activating the fish SSTR<jats:sub>2<\/jats:sub>. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.<\/jats:p>","DOI":"10.1038\/s41467-024-50470-2","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T10:02:39Z","timestamp":1724148159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Fish-hunting cone snail disrupts prey\u2019s glucose homeostasis with weaponized mimetics of somatostatin and insulin"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3087-238X","authenticated-orcid":false,"given":"Ho Yan","family":"Yeung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3971-3107","authenticated-orcid":false,"given":"Iris Bea L.","family":"Ramiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Lund","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1019-9239","authenticated-orcid":false,"given":"Walden E.","family":"Bj\u00f8rn-Yoshimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Espino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0418-5765","authenticated-orcid":false,"given":"Sergey Y.","family":"Vakhrushev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasper B.","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-6750","authenticated-orcid":false,"given":"Noortje","family":"de Haan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1689-0442","authenticated-orcid":false,"given":"Agnes L.","family":"Hipgrave Ederveen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baldomero M.","family":"Olivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7237-8457","authenticated-orcid":false,"given":"Jakob G.","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-7388","authenticated-orcid":false,"given":"Hans","family":"Br\u00e4uner-Osborne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8592-6763","authenticated-orcid":false,"given":"Katrine T.","family":"Schjoldager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens Juul","family":"Holst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1984-2721","authenticated-orcid":false,"given":"Helena","family":"Safavi-Hemami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"50470_CR1","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.3389\/fphar.2020.01132","volume":"11","author":"KCF Bordon","year":"2020","unstructured":"Bordon, K. 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