Single-cell atlas of reproductive endocrine organs reveals transcriptomic responses to type 1 diabetes mellitus in nonhuman primates.

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 upregulation of the TNF signaling pathway across multiple tissues, concomitant with marked activation of inflammation-related pathways. Notably, the macrophage migration inhibitory factor signaling pathway exhibited a tissue-specific regulatory pattern, being significantly upregulated in the hypothalamus and pituitary but downregulated in the ovary and uterus, suggesting divergent inflammatory modulation along the reproductive endocrine axis in response to diabetes. Moreover, we observed that diabetes leads to reduced FSHR expression during granulosa cell differentiation, and this process is further exacerbated by the upregulated expression of SFRP4, a known antagonist of follicle-stimulating hormone signaling, resulting in diminished granulosa cell responsiveness to follicle-stimulating hormone. Consequently, this dysregulation is correlated 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 the female reproductive system in diabetic states, advancing our understanding of immune‒endocrine cell crosstalk in the context of metabolic disease.