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Human milk oligosaccharides (HMOs), bioactive glycans produced in the mammary gland and already detectable in the maternal circulation during pregnancy, are hypothesised to exert endocrine and metabolic effects. We investigated circulating HMOs in the postpartum period, and assessed their short-term modulation by glucose and insulin, and the relationship between plasma and milk HMO profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>At 5\u20137 weeks postpartum, 28 women (16 with prior gestational diabetes [GDM]; 18 who were breastfeeding) underwent both a 75\u00a0g oral glucose tolerance test (OGTT) and a hyperinsulinaemic\u2013euglycaemic clamp. HMOs were quantified in plasma and milk using HPLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Seventeen HMOs were detected in milk, of which six were also detected in plasma at concentrations that were approximately 10,000-fold lower but were highly correlated across the two compartments. The lactosamine-based glycans 3\u2032-sialyllactosamine (3\u2032SLN) and 6\u2032-sialyllactosamine (6\u2032SLN) were only found in plasma. Lactation status had no significant impact on plasma HMO levels, except for a lower 6\u2032SLN level in breastfeeding women. Women with prior GDM showed lower HMO concentrations in milk when fasting. Plasma HMOs exhibited short-term changes during both tests: during the OGTT, the levels of the fucosylated HMOs 2\u2032-fucosyllactose (2\u2032FL), lacto-\n                      <jats:italic>N<\/jats:italic>\n                      -fucopentaose\u00a01 (LNFP1) and lacto-\n                      <jats:italic>N<\/jats:italic>\n                      -difucohexaose (LNDFH) significantly decreased, while that of 3\u2032-sialyllactose (3\u2032SL) increased; during the clamp, the levels of all fucosylated HMOs and 3\u2032SL declined, whereas that of 3\u2032SLN increased with rising insulin levels. In milk, only the levels of 2\u2032FL and lactodifucotetraose (LDFT) decreased significantly during the clamp. During the clamp, the area under the curve (AUC) of plasma oligosaccharides partly correlated with BMI and metabolic clearance rate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Circulating HMOs persist during lactation and are acutely regulated by glucose and insulin. The differential response of fucosylated and sialylated species suggests metabolic regulation of HMO biosynthesis, secretion or clearance. These findings support the concept of HMOs as candidate signal molecules in maternal metabolism, linking lactation with postpartum metabolic adaptation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06729-y","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:19:51Z","timestamp":1776424791000},"page":"2029-2043","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Short-term modulation of human milk oligosaccharides in plasma and milk by glucose and insulin: insights into postpartum metabolic regulation"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3066-9683","authenticated-orcid":false,"given":"Lukas","family":"Sch\u00f6nbacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Walzl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Stern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald C.","family":"K\u00f6feler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Sourij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Fluhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3568-891X","authenticated-orcid":false,"given":"Evelyn","family":"Jantscher-Krenn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7090-162X","authenticated-orcid":false,"given":"Maria A.","family":"Ramos-Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"issue":"9","key":"6729_CR1","doi-asserted-by":"publisher","first-page":"5334","DOI":"10.1021\/jf9044205","volume":"58","author":"A Marcobal","year":"2010","unstructured":"Marcobal A, Barboza M, Froehlich JW et al (2010) Consumption of human milk oligosaccharides by gut-related microbes. 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This study was partly supported by grants from the American Diabetes Association (1-14-TS-33) and the National Institutes of Health (R03-DK-097463) (to MRR). This research was funded in part by the Austrian Science Fund (FWF) (grant DOI 10.55776\/KLI784).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The data that support the findings of this study are not openly available for reasons of sensitivity but are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"MRR, EJK and LS were responsible for the conception and design of this study. MRR, EJK, LS, AMW and HCK were responsible for data acquisition and analysis. MRR, EJK, LS, CS, HF and HS contributed to interpretation of the results. LS took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript. All authors approved the final manuscript. EJK is responsible for the integrity of the work as a whole.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}