Obesity-Associated Gestational Diabetes Promotes Cellular Heterogeneity and Dysfunction in Neonatal Offspring-Islets

<b>Background/Objectives</b>: Given the lack of clarity regarding how maternal overnutrition during pregnancy regulates offspring metabolic health, our study intends to explore the specific influences of maternal Western diet (WD) exposure on neonatal islet cell development and heterogeneity. <b>Methods</b>: Using a WD-induced gestational diabetes mellitus (GDM) rat model, we assessed glucose homeostasis via blood glucose and serum insulin levels. Target protein expression and islet function were evaluated using immunofluorescence and insulin secretion assays, respectively. To delineate alterations in cellular heterogeneity, we subsequently performed single-cell RNA sequencing (scRNA-seq) on isolated islet cells. <b>Results</b>: Maternal WD exposure induced significant glucose intolerance and insulin resistance, confirming GDM establishment. Their neonatal offspring consequently displayed disrupted glucose homeostasis, characterized by concurrent hypoglycemia, hyperinsulinemia, and enhanced insulin secretion. ScRNA-seq analysis further identified the enhanced endocrine cells in GDM-offspring islets, with imbalanced α/β-cell subsets-specifically, reduced immature α1/β1 subsets and expanded mature α2/β2/β3/β4 subsets, alongside upregulated expression of insulin- and glucagon-related genes (Ins1, Ins2, Gcg). Notably, β cells in GDM offspring displayed metabolic hyperactivity (enriched ribosomal and glycolytic pathways) with multiple organelle dysfunction, including mitochondrial swelling, cristae reduction, decreased membrane potential, and severe endoplasmic reticulum stress. <b>Conclusions</b>: The metabolic dysregulation of WD-induced GDM in maternal rats is transmitted to offspring, leading to disrupted neonatal α/β-cell subset balance and accelerated islet maturation. However, such excessive development comes at the cost of organelle damage in β cells. Our findings provide a molecular basis for mitigating the intergenerational transmission of diabetes through early nutritional interventions.