| First Author | Kono T | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 11 | Pages | 2293-2304 |
| PubMed ID | 30131394 | Mgi Jnum | J:265945 |
| Mgi Id | MGI:6206853 | Doi | 10.2337/db17-1351 |
| Citation | Kono T, et al. (2018) Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic beta-Cell. Diabetes 67(11):2293-2304 |
| abstractText | Store-operated Ca(2+) entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca(2+) stores through reversible gating of plasma membrane Ca(2+) channels by the ER Ca(2+) sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in beta-cell ER Ca(2+) 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-treated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca(2+) oscillations and insulin secretion, and these effects were phenocopied by beta-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca(2+) 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 Ca(2+) dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca(2+) transients may have the potential to improve beta-cell health and function. |
