Genome-wide cell type-specific and sex-specific transcriptional dysregulation in the islet of Langerhans underlies islet dysfunction in Down syndrome-related diabetes.

Individuals with Down syndrome (trisomy of human chromosome 21) are at a significantly higher risk of developing type 2 diabetes (T2D) than the general population. Systemic metabolic defects in Down syndrome have been linked to gene expression dysregulation in peripheral tissues like the liver, muscle, brain, and adipose. However, the contribution of gene expression dysregulation in the islets of Langerhans to the increased risk of T2D in Down syndrome has not been explored. Here we show that trisomic Ts65Dn mice, a common Down syndrome mouse model, are glucose intolerant and display reduced β-to-α cell ratio compared to disomic controls. Using single cell RNA sequencing on islets from Ts65Dn mice we found genome-wide, cell type-specific, and sex-specific transcriptional dysregulation in trisomic islets compared to controls. The Down syndrome-associated transcriptional signature revealed important islet defects, both at the cell autonomous level and at the whole-islet level, increasing T2D susceptibility. Our results put forth innate islet defects as a central underlying cause of Down syndrome-related T2D, warranting additional studies.