Metformin Has No Impact on Nitric Oxide Production in Patients With Pre-diabetes

Abstract Background: The effect of metformin on vascular system is still not fully understood and the studies performed on animals have suggested possible impact on the nitric oxide (NO) bioavailability. Aim: The evaluation of different doses of metformin impact on NO production in people with pre-diabetes. Methods: The metformin-naïve patients from one Diabetic Center with new-diagnosed pre-diabetes, without cardio-vascular diseases, were randomised (regarding to the identification number, individual for each inhabitant in the country) for treatment with different doses of metformin (group A 3 x 500 mg, group B 3 x 1000mg) for 15 weeks. The wide panel of L-arginine/NO pathway metabolites concentrations was assessed using the LC-MS/MS. Results: Between October 2017 and December 2018, 36 individuals were initially randomised to intervention groups, but 25 accomplished the study: 14 patients in group A, 11 in group B; also 11 healthy volunteers were recruited. There was no difference between participants with pre-diabetes and healthy volunteers as regards the baseline characteristics except for fasting glucose and fatty liver. The decrease of L-citrulline concentration only was reported for treatment groups during the intervention period, with no change for the other NO-production related substances. Conclusions: It was the first study on the in vivo release of NO in humans at different metformin doses, in patients with pre-diabetes. Metformin has no impact on NO production irrespective of the dose. The citrulline concentration change can indicate the drug impact on altered enterocytes’ condition. The small number of patients is a limitation of the study.Trial registration: ClinicalTrials; number: NCT03398356; retrospectively registered- date of registration:01 July 2018; https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007ODV&selectaction=Edit&uid=U0003WJC&ts=4&cx=1y9eeb