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bioRxiv · 10.64898/2026.06.04.730181

Loss of Glucose Transporter 1 in Mouse Uterine Cells Disrupts Trophoblast Differentiation and Promotes Gestational Diabetes

Shukla, R.·Kannan, A.·Porter, K. W.·Summers, C. S.·Bhurke, A.·Bagchi, M. K.·BAGCHI, I. C.
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Abstract

A successful pregnancy hinges on a finely coordinated dialogue between the maternal endometrium and the implanting embryo. Following embryo attachment to the uterine epithelium, underlying stromal cells undergo a transformation into decidual cells that promote a vascularized maternal-fetal interface and direct trophoblast lineage decisions through paracrine cues. However, the metabolic adaptations that enable decidual cells to support these energetically demanding processes remain poorly understood. Here, using a uterine-specific knockout mouse model, we identify Glucose Transporter 1 (Glut1) as a critical metabolic regulator linking endometrial glucose uptake to reproductive success. We demonstrate that stromal Glut1, induced by hypoxia-inducible factor 2 (Hif2), sustains a Hif2-Rab27b feed-forward circuit that drives vesicular trafficking during pregnancy through the glucose-sensing transcription factor MAX-like protein X (Mlx). Mice lacking endometrial Glut1 are severely subfertile despite normal embryo attachment. Glut1-deficient uteri exhibit impaired stromal extracellular vesicle secretion, defective decidual angiogenesis, and marked dysregulation of trophoblast differentiation, including expansion of trophoblast progenitors, accumulation of glycogen trophoblast cells, and altered placental lactogen production. These placental defects culminate in mid-gestation fetal loss and maternal gestational diabetes mellitus (GDM). Collectively, our findings establish endometrial Glut1 as a metabolic gatekeeper of maternal glucose homeostasis and placentation and introduce a genetically tractable mouse model of spontaneously developing GDM, a disorder affecting nearly one in seven pregnancies worldwide. SIGNIFICANCEThis study uncovers endometrial Glut1 as a previously unrecognized metabolic regulator of placentation, demonstrating that maternal stromal glucose uptake dictates trophoblast fate and maternal glycemic control, and providing the field with its first genetically defined mouse model of spontaneously arising gestational diabetes.

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Shukla, R., Kannan, A., Porter, K. W., Summers, C. S., Bhurke, A., Bagchi, M. K., BAGCHI, I. C.. 2026-06-09. Loss of Glucose Transporter 1 in Mouse Uterine Cells Disrupts Trophoblast Differentiation and Promotes Gestational Diabetes. https://doi.org/10.64898/2026.06.04.730181

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