{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:51:15Z","timestamp":1791899475015,"version":"4.3.4"},"reference-count":13,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF21SA0070428"],"award-info":[{"award-number":["NNF21SA0070428"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF23SA0084103"],"award-info":[{"award-number":["NNF23SA0084103"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001734","name":"Copenhagen University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001734","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>\n                      RUMTOR-derived peptides (RORDEPs) 1 and 2 are polypeptides synthesised by specific strains of the human gut commensal\n                      <jats:italic>Ruminococcus torques.<\/jats:italic>\n                      Preclinical studies have shown that RORDEPs lower blood glucose via an impact on plasma incretins and an improvement of hepatic insulin sensitivity. In a randomised, placebo-controlled, crossover trial, we here explore the safety and tolerability of, as well as any metabolic responses to, a duodenal infusion of recombinant RORDEP1 (r-RORDEP1) given to healthy men after oral intake of a liquid mixed meal.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seventeen healthy, normal-weight men between 18 and 35 years of age were randomised through block randomisation to receive either r-RORDEP1 or placebo as the initial intervention at Gentofte Hospital, Denmark. Exclusion criteria were use of any form of medication, use of antibiotics during the 3 months before intervention, lactose intolerance, smoking, alcohol or drug abuse, or the use of probiotics or creatine as dietary supplements during the study period. Blocks were created prior to trial initiation. Both participants and investigators were blinded to treatment. Following intake of a standardised liquid meal, r-RORDEP1 was given via a naso-duodenal tube as an initial bolus of 0.0108 mg\/kg body weight followed by a continuous infusion of 0.25 \u00b5g kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      min\n                      <jats:sup>\u22121<\/jats:sup>\n                      for 170 min. Primary outcomes were changes in plasma concentrations of incretins and peptide YY, while secondary endpoints were safety and tolerability, and changes in plasma insulin, C-peptide and glucose.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All 17 participants completed the trial. Duodenal infusion of r-RORDEP1 was well tolerated and without changes in biochemical measures of haematological, liver or renal functions. Compared with placebo, the bolus of r-RORDEP1 induced an early (at 15 or 30 min) rise in plasma glucagon-like peptide-1, insulin and C-peptide (\n                      <jats:italic>q<\/jats:italic>\n                      =0.001,\n                      <jats:italic>q<\/jats:italic>\n                      =0.001 and\n                      <jats:italic>q<\/jats:italic>\n                      =0.003, respectively) and a decline in plasma gastric inhibitory polypeptide and glucose (\n                      <jats:italic>q<\/jats:italic>\n                      =0.02 and\n                      <jats:italic>q<\/jats:italic>\n                      =0.006, respectively), while also increasing whole-body insulin sensitivity as measured with the Matsuda index of insulin sensitivity (\n                      <jats:italic>p<\/jats:italic>\n                      =0.049).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Short-term duodenal infusion of r-RORDEP1 is safe and well tolerated and elicits changes in plasma incretins, insulin and glucose, and a measure of whole-body insulin sensitivity, aligning with findings in rodents, supporting the hypothesis that RORDEPs hold a role in impacting host metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT06923839<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>EFSD\/Lilly European Diabetes Research Programme 2021, RUCILP F-19235-01-64 - NNF21SA0070428 grant and NNF23SA0084103 grant, the latter two from the Novo Nordisk Foundation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06751-0","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T16:37:06Z","timestamp":1779554226000},"page":"2338-2346","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A randomised clinical trial testing the safety of and metabolic responses to short-term duodenal infusion of recombinant RORDEP1 in healthy men"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5752-9241","authenticated-orcid":false,"given":"Joachim","family":"G\u00e6de","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-7017","authenticated-orcid":false,"given":"Yong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7387-8557","authenticated-orcid":false,"given":"Liwei","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7880-8515","authenticated-orcid":false,"given":"L\u00e6rke Smidt","family":"Gasbjerg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1531-4294","authenticated-orcid":false,"given":"Peter","family":"Rossing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-2036","authenticated-orcid":false,"given":"Bolette","family":"Hartmann","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\/0000-0003-1212-3764","authenticated-orcid":false,"given":"Asger B.","family":"Lund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-5034","authenticated-orcid":false,"given":"Filip K.","family":"Knop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3321-3972","authenticated-orcid":false,"given":"Oluf","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"issue":"8","key":"6751_CR1","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1136\/gutjnl-2020-323297","volume":"71","author":"A Koopen","year":"2022","unstructured":"Koopen A, Witjes J, Wortelboer K et al (2022) Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study. 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Mernild who assisted with the clinical part of the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data analysed in the current study are not publicly available due to data protection regulations but are available from the corresponding author upon reasonable request starting from the date of publication and for a minimum of 5 years. Data will be shared with qualified researchers addressing research questions meeting legal and ethical requirements. Data will be shared in anonymised form as Excel sheets.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The research was funded by EFSD\/Lilly European Diabetes Research Programme 2021, the RUCILP F-19235-01-64-NNF21SA0070428 grant and the NNF23SA0084103 grant from Novo Nordisk Foundation. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation (\n                      \n                      , grant no. NNF23SA0084103). The study sponsor\/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"ABL has received research support from Novo Nordisk and honoraria as a speaker for Boehringer Ingelheim, Novo Nordisk and AstraZeneca, and has served on the advisory board of Eli Lilly. FKK is currently employed by Novo Nordisk. YF and OP are founders of GutCRINE. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"OP, JG, YF and LSG designed the protocol for the clinical trial. OP supervised all phases of the study. ABL co-supervised the clinical part of the study. JG recruited and phenotyped the study participants and conducted the clinical part of the study. JG did the statistical analysis with supervision from YF. Plasma analyses of plasma incretins and PYY were done by BH and JJH. All authors contributed to the interpretation of the data. JG and OP drafted the manuscript with assistance from the other authors. All authors approved the manuscript. OP is guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}