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Several gut hormones were tested for metabolic actions with disappointing results until the discovery of the proglucagon derivative, glucagon\u2010like peptide\u20101 (GLP\u20101). This peptide from the distal intestine has preserved activity on insulin secretion in people with type 2 diabetes and turned out to regulate both secretion and motility in the gastrointestinal tract and importantly, appetite and food intake, thus functioning as an efficient \u2018ileal brake\u2019 hormone. However, the natural hormone acts predominantly via sensory afferent systems and is extremely rapidly removed from the circulation by enzymatic degradation and renal elimination, and increasing the doses merely results in nausea and vomiting. Lipidation of analogs turned out to provide both stability and limit renal elimination, and very slow up\u2010titration of dosing improves tolerance. Indeed, the most recent agonists may near\u2010normalize glycaemic control in type 2 diabetes, may cause weight losses of up to 25% of body weight, and significantly reduce cardiovascular risk, effects that resemble those of bariatric surgery. Thus, a solution to one of the most serious health problems of modern civilization, the increased morbidity and mortality of the metabolic syndrome, may be addressed by mobilization of one of the body's own regulatory mechanisms.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16401-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp287461","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T17:39:19Z","timestamp":1731173959000},"page":"6613-6629","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens Juul","family":"Holst","sequence":"first","affiliation":[{"name":"The NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, The Faculty of Health Sciences University of Copenhagen, The Panum Institute  Copenhagen N Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.03.011"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.24945"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61375-1"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(82)80708-4"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/304368a0"},{"key":"e_1_2_2_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/302716a0"},{"key":"e_1_2_2_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-1272"},{"key":"e_1_2_2_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2006.00602.x"},{"key":"e_1_2_2_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00344-4"},{"key":"e_1_2_2_11_1","first-page":"III","article-title":"Gastric inhibitory polypeptide","volume":"24","author":"Brown J. 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