Title: Beyond Gene Dosage: Multidimensional Islet Dysfunction in Down Syndrome-Related Type 2 Diabetes
Abstract: Individuals with Down syndrome are four times more likely to develop type 2 diabetes (T2D) than the general population, with onset occurring at younger ages and less correlation with obesity. Recent work has attributed systemic metabolic defects in Down syndrome to gene expression dysregulation in peripheral tissues such as liver, muscle, and adipose. Yet the contribution of the islets of Langerhans- the tissue whose dysfunction defines T2D- has not been explored. Here, we use the Ts65Dn mouse model of Down syndrome to test the hypothesis that trisomy-driven transcriptional alterations in the islets contribute directly to T2D susceptibility. We show that young trisomic mice are glucose intolerant despite normal insulin sensitivity, and display a reduced β-to-α cell ratio with preserved total β cell area, suggesting compensatory hypertrophy. Single-cell RNA sequencing of islets reveals genome-wide, cell type-specific, and sex-specific transcriptional dysregulation extending far beyond the triplicated region. Trisomic islets show overexpression of triplicated genes implicated in β cell proliferation, mitochondrial dysfunction, and oxidative stress, alongside broad downregulation of immediate early genes, disruption of ER stress response coordination, impaired incretin receptor expression, and aberrant Notch signaling- collectively indicating defects at both the cell-autonomous and intra-islet communication levels. Our results put forth innate islet defects as a central underlying cause of Down syndrome-related T2D, providing a comprehensive transcriptomic resource and warranting studies that target the islet directly.
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