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It is thought that the marked body weight\u2010lowering effects of bariatric surgery involve stimulated secretion of appetite\u2010regulating gut hormones, including glucagon\u2010like peptide 1. We here report that intestinal expression of secretin is markedly upregulated in a rat model of Roux\u2010en\u2010Y gastric bypass, suggesting an additional role of secretin in the beneficial metabolic effects of Roux\u2010en\u2010Y gastric bypass. We therefore developed novel secretin\u2010based peptide co\u2010agonists and identified a lead compound, GUB06\u2010046, that exhibited potent agonism of both the secretin receptor and glucagon\u2010like peptide 1 receptor. Semi\u2010acute administration of GUB06\u2010046 to lean mice significantly decreased cumulative food intake and improved glucose tolerance. Chronic administration of GUB06\u2010046 to diabetic db\/db mice for 8\u00a0weeks improved glycemic control, as indicated by a 39% decrease in fasting blood glucose and 1.6% reduction of plasma HbA1c levels. Stereological analysis of db\/db mice pancreata revealed a 78% increase in beta\u2010cell mass after GUB06\u2010046 treatment, with no impact on exocrine pancreas mass or pancreatic duct epithelial mass. The data demonstrate beneficial effects of GUB06\u2010046 on appetite regulation, glucose homeostasis, and beta\u2010cell mass in db\/db mice, without proliferative effects on the exocrine pancreas and the pancreatic duct epithelium. Copyright \u00a9 2017 European Peptide Society and John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/psc.3048","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T14:03:05Z","timestamp":1508767385000},"page":"845-854","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["GUB06\u2010046, a novel secretin\/glucagon\u2010like peptide 1 co\u2010agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice"],"prefix":"10.1002","volume":"23","author":[{"given":"S\u00f8ren B.","family":"van Witteloostuijn","sequence":"first","affiliation":[{"name":"Gubra ApS  H\u00f8rsholm Kongevej 11B 2970 H\u00f8rsholm Denmark"},{"name":"Department of Chemistry, Faculty of Science University of Copenhagen  Thorvaldsensvej 40 1871 Frederiksberg C 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