Treffer: Effect of maternal hyperglycemia and milk composition on hepatic and pancreatic metabolic programming in offspring: an experimental study in rats.

Background: Gestational diabetes (GDM) is a major risk factor for metabolic programming in offspring, increasing their vulnerability to type 2 diabetes (T2D) and metabolic dysfunction-associated fatty liver disease (MASLD). While the benefits of breastfeeding are well established, their modulation in the context of GDM remains poorly studied. Objectives: To evaluate the impact of breast milk composition associated with maternal hyperglycemia on pancreatic β-cell maturation and hepatic homeostasis in offspring according to their sex. Methods: In accordance with Directive 2010/63/EU and the 3Rs, a mouse model of GDM was developed by exposure to a high-fat, high-sugar (HFHS) diet, either restricted to gestation (4HFHS) or extended to lactation (7HFHS), compared to a euglycemic control group (CTL). Cross-fostering at birth allowed the effects of gestation to be dissociated from those of lactation. Milk was characterized at LD1 and LD14 (metabolome and lipidome). The impact on offspring was assessed at different ages (birth, PD8, PND14, PND220 in response to a Western diet) using metabolic tests (oral glucose tolerance test (OGTT), euglycemic-hyperinsulinemic clamp, body composition), gene expression analyses (pancreas, liver), and plasma metabolome. Results: Colostrum from GDM mothers, particularly 7HFHS, was enriched in long-chain sphingolipids. At birth, GDM offspring had β-cell hyperplasia. At PND14, those breastfed by 7HFHS mothers showed overexpression of pancreatic genes (NeuroD1, GLUT2, insulin) and fasting hyperglycemia. In adulthood, GDM offspring breastfed by CTL mothers showed impaired glucose tolerance (males) and reduced insulin sensitivity (females), associated with hepatic dysregulation (incomplete fatty acid oxidation (FAO), increased FETUA). Conversely, nursing by 4HFHS mothers improved certain metabolic markers, particularly in females (complete FAO, reduced gluconeogenesis and lipogenesis, decreased FETUA). Conclusions: Maternal glucose tolerance during the perinatal period influences milk composition and the metabolic trajectory of offspring. These effects, with gender-specific characteristics, highlight breastfeeding as a key period for modulating the postnatal risk of MASLD and T2D, opening up avenues for targeted nutritional intervention.