Integrating Spatial and Single‐Nucleus Transcriptomic Data to Assess the Effects of Intrauterine Hyperglycemia on Fetal Pancreatic Development

Abstract Maternal pregestational diabetes mellitus (PGDM) can lead to adverse fetal outcomes, including lasting impacts on pancreatic development. However, the specific impacts of maternal PGDM on cellular functions and intercellular communication within the fetal pancreas remain poorly understood. Here, single‐nucleus RNA sequencing and spatial transcriptomics (ST) are employed to investigate cellular responses and spatial changes in the fetal pancreas (E16.5 and E18.5) under maternal PGDM conditions. The findings reveal significant cellular heterogeneity among acinar and beta cells, along with pronounced metabolic stress responses. More importantly, decreased insulin secretion is observed and accompanied by the compensatory increase of Pdx1, Nkx6.2, and Mafa, and substantial alterations in cell‐cell communication across multiple cell types. ST analysis further highlights enhanced spatial enrichment in cellular niches exposed to maternal PGDM. These findings provide valuable insights into the molecular mechanisms underlying fetal pancreatic response to maternal PGDM and offer a detailed spatiotemporal perspective on these processes.