Single-cell atlas of reproductive endocrine organs reveals transcriptomic responses to type 1 diabetes mellitus in non-human primate

Type 1 diabetes mellitus characterized by insulin deficiency and hyperglycemia is associated with female subfertility. However, how hyperglycemia affects the hypothalamic-pituitary-ovarian-uterine axis remains poorly understood. In this study, we performed single-cell transcriptomic profiling of the hypothalamus, pituitary, ovary and uterus during the proliferative phase of the menstrual cycle in type 1 diabetic macaques to systematically characterize changes in tissue-specific cellular heterogeneity, gene expression, and intercellular communication networks under diabetic conditions. Our analysis revealed significant downregulation of the SPP1 signaling pathway across multiple tissues, concomitant with marked activation of inflammation-related pathways, including TNF signaling. Notably, we observed that diabetes impairs the recruitment of perifollicular CHIT1 ⁺ macrophages and leads to reduced FSHR expression during granulosa cell differentiation. This process is further exacerbated by upregulation of SFRP4 , a known antagonist of follicle-stimulating hormone signaling molecule, resulting in diminished granulosa cell responsiveness to follicle-stimulating hormone. Consequently, this dysregulation correlates with increased FSHB expression in pituitary gonadotropes, likely due to disrupted ovarian feedback signaling. Collectively, our findings provide a comprehensive landscape of cellular and molecular alterations in immune and endocrine compartments in female reproductive system in diabetic states, advancing our understanding of immune-endocrine crosstalk in the context of metabolic disease.