Adaptive response of breastmilk metabotype and miRNAs patterns in a rat model of gestational diabetes and its...

Epidemiological evidence suggests fetal hyperglycemia predisposes the offspring of mothers with gestational diabetes (GDM) to insulin resistance. While breastfeeding is known to improve metabolic outcomes in offspring from GDM mothers, the breast-milk (BM) composition may be significantly altered. How the BM in GDM-induced changes influence insulin signaling and contribute to-or interfere with-these clinical benefits remains unknown. We hypothesized that impaired maternal glucose tolerance (IGT) during gestation alters BM-composition. Using a high-calorie nutritional rodent GDM-model, we investigated whether IGT and its resolution postpartum affect BM-composition, especially in emerging regulators of insulin-sensitivity (IS). Female rats were fed either a high-fat high-sucrose (HFHS) or control standard (CTL) diet during gestation. At delivery, IGT-dams (HFHS group) either switched to standard diet (4HFHS, resolved-IGT postpartum) or remained on HFHS (7HFHS, persistent-IGT) throughout lactation. BM-metabolome and lipidome were analyzed, combined with microRNAs profiles. Colostrum from IGT-dams displayed enrichments in specific lipids, including polyunsaturated-phospholipid-plasmalogens and medium-chain-acylglycerols, a readily useable source of energy for the newborn, as well as sphingolipids with very-long-chain fatty acids, associated with IS, with specificities depending on IGT status postpartum. 4HFHS milk retained elevated glutathione precursors, versus 7HFHS. Additionally, mature 4HFHS milk presented higher abundance of miRNAs linked to β-cell survival and insulin signaling (miR-200b-3p, miR-148a-3p). Resolution of maternal IGT postpartum restored mature milk metabotype, despite specificities in colostrum. Compared with persistent-IGT dams, milk of resolved-IGT dams was enriched in novel BM-candidate bioactive agents, including specific sphingolipids, plasmalogens, miRNAs, and glutathione precursors, that may impact neonatal glucose homeostasis and IS.