Female offspring exposed in utero to hyperglycaemia presented specific insulin sensitivity pathways at adulthood depending on breast milk metabotype received: evidence from a rodent model
Year: 2026
Type: conference-paper
Abstract: Background: Gestational Diabetes Mellitus (GDM) induces metabolic programming, increasing offspring-risk for insulin resistance (IR)-related diseases. Whether GDM-breast milk composition support offspring pancreatic β-cell maturation, and hepatic energy-homeostasis reducing IR-risk remains unclear. Methods: A rodent GDM-model was developed using a high-fat high-sucrose (HFHS) diet to induce impaired glucose tolerance (IGT) limited to gestation (4HFHS) or maintained until weaning (7HFHS), compared with a control-fed euglycemic group (CTL). Colostrum and mature milk lipidome were characterized. Cross-fostering at birth allowed to assess the impact of milk metabotype received during lactation from in utero exposure on GDM-offspring outcome. Offspring longitudinal metabolic trajectories were evaluated at birth, during lactation and at adulthood in response to a Western diet (WD)-challenge, using integrative blood, pancreas and liver phenotyping by mass spectrometry or gene expression analyses, and physiological tests (oral glucose tolerance test, euglycaemic-hyperinsulinaemic clamp).Results: Enrichment of insulino-trophic regulators, as very long-chain sphingolipids, was observed in colostrum from 4HFHS- and 7HFHS- vs. CTL-dams, and maintained in 7HFHS- vs. 4HFHS-mature milk. Islet gene expression suggested delayed β-cell maturation combined with lower insulinaemia, in GDM-pups nursed by 4HFHS-dams vs. those nursed by 7HFHS. Adult female GDM-offspring, which have been nursed by CTL-dams, exhibited reduced whole-body insulin-sensitivity in response to WD. This phenotype was combined with WD-adaptative responses as elevated expression of glucagon-like-peptide-1-receptor (GLP-1R) and prohormone convertase-2 (PCSK2) in islet, and fatty-acid-synthase (FASN) and the IR-biomarker FETUA in liver. These alterations support an increase in insulin secretory capacity and hepatic De novo lipogenesis. Conversely, adult female GDM-offspring, reared by 4HFHS-dams, maintained insulin sensitivity in response to WD, despite reduced islet expression of insulin, amylin and proglucagon. This phenotype was associated with increased hepatic gene expression in carnitine-palmitoyl-transferase-1 (CPT1), suggesting enhanced fatty acid oxidation. Conclusions: Breast milk metabotype influence whole-body insulin sensitivity and liver energy homeostasis in female GDM-offspring at adulthood.
Source: HAL
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212347077