期刊
DIABETES
卷 67, 期 11, 页码 2293-2304出版社
AMER DIABETES ASSOC
DOI: 10.2337/db17-1351
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK074966, R01-DK092616, R01-DK-093954, UC4-DK-104166, P30-DK-097512]
- Ball Brothers Foundation
- George and Frances Ball Foundation
- Diabetes and Obesity DeVault Fellowship at the Indiana University School of Medicine
- National Institutes of Health National Institute Allergy and Infectious Disease Training Grant [T32-AI-060519]
- JDRF Postdoctoral Research Award [3-PDF-2017-385-A-N]
Store-operated Ca2+ entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca2+ stores through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in beta-cell ER Ca2+ have been observed in diabetes. However, a role for impaired SOCE in this phenotype has not been tested. We measured the expression of SOCE molecular components in human and rodent models of diabetes and found a specific reduction in STIM1 mRNA and protein levels in human islets from donors with type 2 diabetes (T2D), islets from hyperglycemic streptozotocin-reated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca2+ oscillations and insulin secretion, and these effects were phenocopied by beta-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca2+ storage and increased ER stress, whereas STIM1 gain of function rescued beta-cell survival under proinflammatory conditions and improved insulin secretion in human islets from donors with T2D. Taken together, these data suggest that the loss of STIM1 and impaired SOCE contribute to ER Ca2+ dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca2+ transients may have the potential to improve beta-cell health and function.
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