Short-term modulation of human milk oligosaccharides in plasma and milk by glucose and insulin: insights into postpartum metabolic regulation

AIMS/HYPOTHESIS: Lactation is associated with reduced maternal risk of future diabetes mellitus and cardiovascular disease. 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. METHODS: At 5-7 weeks postpartum, 28 women (16 with prior gestational diabetes [GDM]; 18 who were breastfeeding) underwent both a 75 g oral glucose tolerance test (OGTT) and a hyperinsulinaemic-euglycaemic clamp. HMOs were quantified in plasma and milk using HPLC. RESULTS: 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'-sialyllactosamine (3'SLN) and 6'-sialyllactosamine (6'SLN) were only found in plasma. Lactation status had no significant impact on plasma HMO levels, except for a lower 6'SLN 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'-fucosyllactose (2'FL), lacto-N-fucopentaose 1 (LNFP1) and lacto-N-difucohexaose (LNDFH) significantly decreased, while that of 3'-sialyllactose (3'SL) increased; during the clamp, the levels of all fucosylated HMOs and 3'SL declined, whereas that of 3'SLN increased with rising insulin levels. In milk, only the levels of 2'FL 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. CONCLUSIONS/INTERPRETATION: 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.