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The ketone body 3-hydroxybutyrate (3-OHB) inhibits lipolysis in healthy individuals. The current study aimed to test whether this feedback suppression of lipolysis by 3-OHB is disrupted in individuals with type 1 diabetes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We used a single-blind, randomised, crossover design to study ten men diagnosed with type 1 diabetes and ten healthy control participants. Eligibility criteria were male sex, age \u226518 years, BMI of 19\u201326 kg\/m<jats:sup>2<\/jats:sup> and no severe comorbidities\/diseases. Following an overnight fast, each participant received two 3\u00a0h i.v. infusions: (i) sodium-<jats:sc>d\/l<\/jats:sc>-3-OHB and (ii) iso-osmolar saline (NaCl), separated by a 1\u00a0h washout period. The order of the two interventions was assigned by randomisation for each participant. Participants were blinded to the allocation throughout the study day, but investigators were aware of the assigned intervention order. We evaluated the lipolytic rate and glucose turnover using [9,10-<jats:sup>3<\/jats:sup>H]palmitate and [3-<jats:sup>3<\/jats:sup>H]glucose tracers. Additionally, adipose tissue signalling was quantified using western blotting techniques in subcutaneous abdominal adipose tissue biopsies. The primary endpoint measure was palmitate flux (lipolytic rate).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>During the infusion of 3-OHB, the <jats:sc>d\/l<\/jats:sc>-3-OHB blood concentrations increased to 3.3\u00a0\u00b1\u00a00.7 mmol\/l in participants with type 1 diabetes compared with 2.9\u00a0\u00b1\u00a00.5 mmol\/l in control participants (<jats:italic>p<\/jats:italic>=0.03). The infusion effectively suppressed the lipolytic rates by more than 50% (<jats:italic>p<\/jats:italic>&lt;0.001) and reduced circulating NEFA by approximately 0.5 mmol\/l (<jats:italic>p<\/jats:italic>&lt;0.001) compared with NaCl in both participants with type 1 diabetes and control participants. In adipose tissue, 3-OHB reduced protein kinase\u00a0A phosphorylation of perilipin (<jats:italic>p<\/jats:italic>&lt;0.001) and hormone-sensitive lipase phosphorylation at Ser660 (<jats:italic>p<\/jats:italic>&lt;0.001) and Ser563 (<jats:italic>p<\/jats:italic>&lt;0.01) similarly in participants with type 1 diabetes and control participants. Indices of glucose metabolism remained unaffected throughout in both groups.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>Our findings indicate that, in individuals with type 1 diabetes, the suppression of lipolysis, blood NEFA concentrations and adipose tissue signalling activity in response to 3-OHB remains intact compared with healthy control participants. These findings imply that derailment of receptor signalling by 3-OHB is unlikely to be involved in the development of diabetic ketoacidosis.<\/jats:p>\n            <jats:p>Trial registration: ClinicalTrials.gov NCT04656236<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Funding<\/jats:title>\n            <jats:p>Open access funding provided by Aarhus Universitet. This study was supported by the Novo Nordisk Foundation (NNF19OC0058872) and the Health Research Foundation of Central Denmark Region.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06423-5","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T19:25:07Z","timestamp":1744313107000},"page":"1390-1402","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metabolic effects of 3-hydroxybutyrate infusion in individuals with type 1 diabetes compared with healthy control participants: a randomised crossover trial showing intact feedback suppression of lipolysis"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-2854","authenticated-orcid":false,"given":"Maj","family":"Bangshaab","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9574-0612","authenticated-orcid":false,"given":"Mads V.","family":"Svart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9938-2181","authenticated-orcid":false,"given":"Nikolaj","family":"Rittig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3670-941X","authenticated-orcid":false,"given":"Mette G. 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Furthermore, we thank Lisa Buus, Elsebeth Hornemann and Eva Schriver (Medical\/Steno Aarhus Research Laboratory, Aarhus University, Denmark) for their skilled technical expertise during the study, and Helle Zibrandtsen (Medical\/Steno Aarhus Research Laboratory, Aarhus University, Denmark) for thorough training and assistance with laboratory procedures. Some of the data from the present study were presented as an abstract at the EASD Annual Meeting in 2022.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The corresponding author will make data available upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The study was financially supported by the Novo Nordisk Foundation (NNF19OC0058872) and the Health Research Foundation of Central Denmark Region. The study funders had no involvement in the study design, the collection, analysis and interpretation of data, or in the writing of the report, and did not impose any restrictions on publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no 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":"MB, MVS, NR and NM conceived and designed the study. MB, MGBP and JV conducted the study. MB analysed the data. MB, MVS, NR, NJ and NM contributed to the interpretation of results. MB drafted the manuscript. All authors reviewed and approved the final manuscript. NM and MB are the guarantors of the work, accept full responsibility for the work, have access to the data, and controlled the decision to publish.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}