1826-P: Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA2) Dysfunction Contributes to β-Cell Stress and the Development of Chemically Induced Type 1 Diabetes

by sugaradmin



Introduction and Objective: Increasing evidence suggests that stress pathways intrinsic to the β cell contribute to their destruction during type 1 diabetes (T1D) development. Our group has previously shown that loss of sarco-endoplasmic reticulum calcium (Ca2+) pump 2 (SERCA2) exacerbates high-fat diet-induced diabetes in murine models. Here, we assessed whether SERCA2 haploinsufficiency exacerbates loss of β cell function in a murine model of T1D.Methods: Multiple low-dose streptozotocin (STZ) injections were used to induce diabetes in mice haploinsufficient for SERCA2 (S2+/-) and in wild type (WT) C57BL/6J littermate controls. Next, to determine whether SERCA2 modulation could improve glycemia, STZ-WT mice were treated for 5 days with an allosteric SERCA activator or vehicle. Intraperitoneal glucose tolerance tests were performed, and proinsulin and insulin were measured by ELISA.Results: STZ treatment reduced endoplasmic reticulum Ca2+ levels in islets from both WT and S2+/- mice, with S2+/- islets showing a greater reduction. STZ-S2+/- mice also had worsened glucose tolerance as compared to STZ-WT mice. The non-fasting proinsulin to insulin ratio was increased in STZ-S2+/- mice, but not in STZ-WT mice, compared to untreated controls, indicating a potential defect in β cell protein processing. Importantly, SERCA activator-treatment in STZ-WT mice improved glucose tolerance compared to vehicle-treated mice.Conclusion: Taken together, these data indicate that SERCA2 dysregulation may be an important component of β cell stress during T1D development and that SERCA2 activation may improve glucose tolerance and insulin secretion.

Disclosure

R.N. Bone: Employee; Cardinal Health/Edgepark. C. Rostron: None. X. Tong: None. T. Kono: None. C. Evans-Molina: Advisory Panel; DiogenX. Research Support; Bristol-Myers Squibb Company, Lilly Diabetes. Advisory Panel; Isla Technologies, Neurodon. Research Support; Neurodon.

Funding

National Institutes of Health (R01DK127236-01A1); National Institutes of Health (R01 DK127308-01); National Institutes of Health (R01DK133881); National Institutes of Health (P30 DK097512); National Institutes of Health (3T32DK064466-22S1); U.S. Department of Veterans Affairs (5I01BX001733-11)



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