296-LB: Loss of SERCA2 Induces Mitochondrial Dysfunction, Increases ß-Cell Senescence, and Accelerates Type 1 Diabetes Development

Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic β-cells. Senescence and activation of a senescence-associated secretory phenotype (SASP) in β-cells may contribute to T1D pathogenesis; however, the mechanisms responsible for this phenotype are not well understood. We hypothesized that loss of endoplasmic reticulum (ER) Ca2+ induces mitochondrial dysfunction and drives the development of β-cell senescence during T1D. To test this hypothesis, we generated sarco/ER Ca2+-ATPase 2 (SERCA2) haploinsufficient mice on the NOD background (NOD-S2+/-). NOD-S2+/- mice displayed accelerated T1D onset compared to NOD-WT mice (14 wks vs 18 wks; p≤ 0.0001 female and 21 wks vs 24.5 wks male; p