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A common G\u2010allele in the <jats:italic>MTNR1B<\/jats:italic> locus has been associated with an increased risk of type 2 diabetes (T2DM). We aimed to examine acute effects of high doses of melatonin on glucose metabolism with attention to MTNR1B genotype. Twenty men were examined in a double\u2010blinded, randomized crossover study on two nonconsecutive days with four doses of 10\u00a0mg oral melatonin or placebo. Insulin sensitivity and insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and a hyperinsulinaemic\u2010euglycaemic clamp (HEC). Blood samples were drawn to determine the metabolic profile and MTNR1B rs10830963 genotype. Indirect calorimetry and blood pressure measurements were also performed. Insulin sensitivity index was significantly reduced on the melatonin day (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.028) in the whole group and in homozygous carriers of the rs10830963 C\u2010allele (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.041). Glucose during the IVGTT was unaffected, but there was a tendency towards lower insulin and C\u2010peptide levels in the first minutes after glucose administration in G\u2010allele carriers. Systolic blood pressure decreased and lipid oxidation increased significantly on the melatonin day in rs10830963 G\u2010allele carriers. Overall, our study reports that acute administration of melatonin in supra\u2010physiological doses may have a negative impact on insulin sensitivity.<\/jats:p><jats:p><jats:bold>Clinical trial registration number<\/jats:bold> (clinicaltrial.gov): NCT03204877.<\/jats:p>","DOI":"10.1111\/jpi.12706","type":"journal-article","created":{"date-parts":[[2020,11,21]],"date-time":"2020-11-21T20:15:43Z","timestamp":1605989743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Acute metabolic effects of melatonin\u2014A randomized crossover study in healthy young men"],"prefix":"10.1111","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2234-7780","authenticated-orcid":false,"given":"Ulla","family":"Kampmann","sequence":"first","affiliation":[{"name":"Steno Diabetes Center Aarhus Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esben 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