288-OR: Role of Endoplasmic Reticulum (ER) Calcium in ß-Cell Senescence and Type 1 Diabetes Pathophysiology

Abstract

Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic β cells. Recent data suggest that activation of senescence and acquisition of a senescence-associated secretory phenotype (SASP) by β cells may contribute to T1D pathogenesis; however, the molecular mechanisms responsible for this phenotype are not well understood. Our previous work has linked loss of β cell ER Ca2+ with diabetes pathophysiology and demonstrated accelerated onset of hyperglycemia in non-obese diabetic (NOD) mice with haploinsufficiency of the SERCA2 pump (NOD-S2+/-). Therefore, we hypothesized that loss of ER Ca2+ via reduced SERCA2 activity may drive β cell senescence, SASP, mitochondrial dysfunction and T1D development. To test this hypothesis, SERCA2 KO INS-1 β cells (S2KO) and islets from NOD-S2+/- mice were assessed for senescence associated β-galactosidase staining (SA-β-gal), mRNA expression of senescence markers cdkn1a and cdkn2a, mitochondrial membrane potential and function (TMRM, Seahorse) as well as mitochondrial DNA copy number. S2KO β cells displayed increased SA-β-gal staining as well as increased mitochondrial coupling efficiency and baseline mitochondrial copy number compared to WT β cells, suggesting a senescence phenotype, and altered mitochondrial function. Pancreatic islets isolated from NOD-S2+/- mice show increased mRNA expression of the senescence marker cdkn2a at 12wks compared to age matched control mice (p<0.05), whereas cdkn1a remained unchanged across all timepoints tested. Our results suggest that loss of SERCA2 and reduced ER Ca2+ alters β cell mitochondrial function and is associated with features of senescence. Future studies will test whether SERCA2 activation and/or senolytic/senomorphic drugs are able to prevent or delay diabetes onset in NOD-S2+/- mice. This study has the potential to inform new paradigms of T1D prevention and therapy with the overall goal of improving β cell health during autoimmunity. Disclosure S. A. Weaver: None. T. Kono: None. F. Syed: None. R. N. Bone: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. Funding Indiana Clinical and Translational Sciences Institute (UL1TR002529)