Multi-omics atlas of ovarian cellular and molecular responses to diabetes.

Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including Cyp11a1, Fshr, and Lhcgr exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.