The β-cell Golgi, an important site of proinsulin maturation, is a significant store of intracellular Ca2+. However, the contribution of Golgi Ca2+ to diabetes pathophysiology is unknown. The Golgi primarily utilizes the Secretory Pathway Ca2+ ATPase (SPCA1) to maintain intra-Golgi Ca2+ stores. SPCA1 expression was measured in islets from Akita and db/db mice and cadaveric human islets from donors with T1D and T2D. In all cases, SPCA1 levels were significantly lower compared to nondiabetic controls. Proteomics and Reverse Phase Protein Array performed in INS-1 β-cells lacking SPCA1 (SPCA1KO) indicated dysregulated cell death, cell growth, and proliferation pathways compared to WT INS-1 cells. Consistent with this, SPCA1KO cells exhibited increased caspase-3/7 following tunicamycin treatment. SPCA1KO cells also had elevated basal cytosolic Ca2+ levels, decreased organelle Ca2+ reuptake following organelle Ca2+ store depletion, and accelerated Golgi collapse. Despite a significant reduction in GSIS, SPCA1KO cells exhibited a 12-fold insulin content increase. Autophagy has been reported as a key regulator in maintaining β-cell insulin homeostasis. Immunoblot revealed reduced expression of the autophagy marker LC3-II and the autophagosome Atg5/Atg12 complex in SPCA1KO cells, following autophagy induction with Torin. Islets from mice haploinsufficient for SPCA1 (SPCA1+/-) exhibited elevated cytosolic Ca2+ levels and impaired Ca2+ oscillations as reflected by increased phase 1 amplitude and period, compared to WT littermates. In islets, restoration of SPCA1 to normal levels rescued the oscillatory defect. Interestingly, islets from SPCA1+/- mice did not exhibit increased insulin content, however, SPCA1+/- islets had decreased insulin secretion and increased numbers of immature insulin granules. Taken together, we find that β-cell SPCA1 plays an important role in the maintenance of Golgi Ca2+ levels, while loss of SPCA1 led to dysregulated β-cell Ca2+ homeostasis.


R.N. Bone: None. T. Kono: None. C. Evans-Molina: None.

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