{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:02:24Z","timestamp":1771459344419,"version":"3.50.1"},"reference-count":24,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Mitchell\u2013Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell\u2013Riley syndrome protracted diarrhea.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Two case report descriptions. in a tertiary pediatric hospital. \u201cOff-label\u201d treatment with liraglutide. We describe 2 children diagnosed with Mitchell\u2013Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell\u2013Riley syndrome protracted diarrhea.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\u201cOff-label\u201d liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Congenital GLP-1 deficiency was identified in patients with Mitchell\u2013Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa916","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T14:30:05Z","timestamp":1609425005000},"page":"e1084-e1090","source":"Crossref","is-referenced-by-count":8,"title":["Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell\u2013Riley Syndrome"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4437-1124","authenticated-orcid":false,"given":"Sara","family":"N\u00f3brega","sequence":"first","affiliation":[{"name":"Special Nutrition and Respiratory Care Unit, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"},{"name":"Gastroenterology and Hepatology Unit, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"},{"name":"Comprehensive Health Research Centre (CHRC), Medicine of Woman, Childhood and Adolescence, NOVA Medical School | Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, Lisbon, Portugal"}]},{"given":"Mariana P","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal"},{"name":"Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-6451","authenticated-orcid":false,"given":"Lu\u00eds","family":"Pereira-da-Silva","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC), Medicine of Woman, Childhood and Adolescence, NOVA Medical School | Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, Lisbon, Portugal"},{"name":"NICU, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"}]},{"given":"Sofia S","family":"Pereira","sequence":"additional","affiliation":[{"name":"Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal"},{"name":"Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (I3S), Universidade do Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-2036","authenticated-orcid":false,"given":"Bolette","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}]},{"given":"Jens J","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}]},{"given":"Raul","family":"Barbosa Silva","sequence":"additional","affiliation":[{"name":"Special Nutrition and Respiratory Care Unit, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"}]},{"given":"Gon\u00e7alo","family":"Cordeiro-Ferreira","sequence":"additional","affiliation":[{"name":"Special Nutrition and Respiratory Care Unit, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"},{"name":"Gastroenterology and Hepatology Unit, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"},{"name":"Comprehensive Health Research Centre (CHRC), Medicine of Woman, Childhood and Adolescence, NOVA Medical School | Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, Lisbon, Portugal"},{"name":"NICU, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central, Lisbon, Portugal"}]}],"member":"80","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"issue":"7282","key":"2021122205125358100_CIT0001","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/nature08748","article-title":"Rfx6 directs islet formation and insulin production in mice and humans","volume":"463","author":"Smith","year":"2010","journal-title":"Nature."},{"issue":"12","key":"2021122205125358100_CIT0002","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1007\/s00125-004-1576-3","article-title":"Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome","volume":"47","author":"Mitchell","year":"2004","journal-title":"Diabetologia."},{"issue":"2","key":"2021122205125358100_CIT0003","doi-asserted-by":"crossref","first-page":"87","DOI":"10.24911\/JBCGenetics\/183-1529491124","article-title":"Mitchell-riley syndrome report of novel mutation and review of the literature","volume":"1","author":"Alruqaie","year":"2018","journal-title":"J Biochem Clin Genet"},{"issue":"2","key":"2021122205125358100_CIT0004","doi-asserted-by":"crossref","first-page":"246","DOI":"10.4274\/jcrpe.2387","article-title":"A newly-discovered mutation in the RFX6 gene of the rare Mitchell-Riley syndrome","volume":"8","author":"Khan","year":"2016","journal-title":"J Clin Res Pediatr Endocrinol."},{"issue":"1","key":"2021122205125358100_CIT0005","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/pedi.12063","article-title":"Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6","volume":"15","author":"Concepcion","year":"2014","journal-title":"Pediatr Diabetes."},{"key":"2021122205125358100_CIT0006","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.molmet.2019.08.007","article-title":"Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production","volume":"29","author":"Piccand","year":"2019","journal-title":"Mol Metab."},{"issue":"7","key":"2021122205125358100_CIT0007","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1053\/j.gastro.2017.01.053","article-title":"The importance of the gastrointestinal tract in controlling food intake and regulating energy balance","volume":"152","author":"Monteiro","year":"2017","journal-title":"Gastroenterology."},{"key":"2021122205125358100_CIT0008","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.metabol.2019.04.014","article-title":"The incretin system in healthy humans: the role of GIP and GLP-1","volume":"96","author":"Holst","year":"2019","journal-title":"Metabolism."},{"issue":"3","key":"2021122205125358100_CIT0009","doi-asserted-by":"crossref","first-page":"715","DOI":"10.2337\/db14-1671","article-title":"Hepato-incretin function of GLP-1: novel concept and target in type 1 diabetes","volume":"64","author":"Ahr\u00e9n","year":"2015","journal-title":"Diabetes."},{"issue":"15","key":"2021122205125358100_CIT0010","doi-asserted-by":"crossref","first-page":"7911","DOI":"10.1073\/pnas.93.15.7911","article-title":"Induction of intestinal epithelial proliferation by glucagon-like peptide 2","volume":"93","author":"Drucker","year":"1996","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2021122205125358100_CIT0011","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3389\/fendo.2019.00260","article-title":"From the incretin concept and the discovery of GLP-1 to today\u2019s diabetes therapy","volume":"10","author":"Holst","year":"2019","journal-title":"Front Endocrinol (Lausanne)."},{"issue":"10","key":"2021122205125358100_CIT0012","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1089\/dia.2013.0366","article-title":"Liraglutide\u2019s safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial","volume":"16","author":"Klein","year":"2014","journal-title":"Diabetes Technol Ther."},{"issue":"5","key":"2021122205125358100_CIT0013","doi-asserted-by":"crossref","first-page":"e12495","DOI":"10.1111\/ijpo.12495","article-title":"Liraglutide effects in a paediatric (7-11 y) population with obesity: a randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics","volume":"14","author":"Mastrandrea","year":"2019","journal-title":"Pediatr Obes."},{"key":"2021122205125358100_CIT0014","first-page":"937201","article-title":"Mitchell-Riley syndrome: a novel mutation in RFX6 gene","volume":"2015","author":"Zegre Amorim","year":"2015","journal-title":"Case Rep Genet."},{"issue":"9","key":"2021122205125358100_CIT0015","doi-asserted-by":"crossref","first-page":"7506","DOI":"10.1002\/jcb.27062","article-title":"Differential GIP\/GLP-1 intestinal cell distribution in diabetics\u2019 yields distinctive rearrangements depending on Roux-en-Y biliopancreatic limb length","volume":"119","author":"Palha","year":"2018","journal-title":"J Cell Biochem."},{"issue":"8","key":"2021122205125358100_CIT0016","first-page":"2884","article-title":"In vivo and in vitro degradation of glucagon-like peptide-2 in humans","volume":"85","author":"Hartmann","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2021122205125358100_CIT0017","doi-asserted-by":"crossref","first-page":"1756284819842756","DOI":"10.1177\/1756284819842756","article-title":"Simultaneous analyses of carbohydrate-mediated serum GLP-1 and GLP-2 and duodenal receptor expression in children with and without celiac disease","volume":"12","author":"Rachmiel","year":"2019","journal-title":"Therap Adv Gastroenterol."},{"issue":"3","key":"2021122205125358100_CIT0018","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1210\/jc.2015-3885","article-title":"Altered plasma levels of glucagon, GLP-1 and glicentin during OGTT in adolescents with obesity and type 2 diabetes","volume":"101","author":"Manell","year":"2016","journal-title":"J Clin Endocrinol Metab."},{"issue":"10","key":"2021122205125358100_CIT0019","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1155\/2013\/460958","article-title":"A pilot study examining the relationship among Crohn disease activity, glucagon-like peptide-2 signalling and intestinal function in pediatric patients","volume":"27","author":"Sigalet","year":"2013","journal-title":"Can J Gastroenterol."},{"issue":"1","key":"2021122205125358100_CIT0020","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejmg.2009.10.004","article-title":"Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn","volume":"53","author":"Martinovici","year":"2010","journal-title":"Eur J Med Genet."},{"issue":"5","key":"2021122205125358100_CIT0021","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrgastro.2015.44","article-title":"Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies","volume":"12","author":"Canani","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol."},{"issue":"10","key":"2021122205125358100_CIT0022","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1097\/MCG.0b013e3182a89fc8","article-title":"From diarrhea to obesity in prohormone convertase 1\/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics","volume":"47","author":"Bandsma","year":"2013","journal-title":"J Clin Gastroenterol."},{"issue":"2","key":"2021122205125358100_CIT0023","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1053\/gast.2002.31068","article-title":"Biological actions and therapeutic potential of the glucagon-like peptides","volume":"122","author":"Drucker","year":"2002","journal-title":"Gastroenterology."},{"issue":"5","key":"2021122205125358100_CIT0024","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.3390\/ijms21051682","article-title":"Somatostatin analogs in clinical practice: a review","volume":"21","author":"Gomes-Porras","year":"2020","journal-title":"Int J Mol Sci"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgaa916\/35440232\/dgaa916.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/4\/e1084\/41847697\/dgaa916.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/4\/e1084\/41847697\/dgaa916.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T05:18:28Z","timestamp":1640150308000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/106\/4\/e1084\/6056479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":24,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,12,31]]},"published-print":{"date-parts":[[2021,3,25]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgaa916","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,4,1]]},"published":{"date-parts":[[2020,12,31]]}}}