A randomised clinical trial testing the safety of and metabolic responses to short-term duodenal infusion of recombinant RORDEP1 in healthy men.
Gæde Joachim J, Fan Yong Y, Lyu Liwei L, Gasbjerg Lærke Smidt LS et al.
RUMTOR-derived peptides (RORDEPs) 1 and 2 are polypeptides synthesised by specific strains of the human gut commensal Ruminococcus torques. 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. 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 µg kg-1 min-1 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. 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 (q=0.001, q=0.001 and q=0.003, respectively) and a decline in plasma gastric inhibitory polypeptide and glucose (q=0.02 and q=0.006, respectively), while also increasing whole-body insulin sensitivity as measured with the Matsuda index of insulin sensitivity (p=0.049). 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. ClinicalTrials.gov NCT06923839 FUNDING: 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.