Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic β-Cell

Abstract

Store-operated Ca entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca stores through reversible gating of plasma membrane Ca channels by the ER Ca sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in β-cell ER Ca 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 oscillations and insulin secretion, and these effects were phenocopied by β-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca storage and increased ER stress, whereas STIM1 gain of function rescued β-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 dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca transients may have the potential to improve β-cell health and function.

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

“…STIM1 gates TRPC1 by intermolecular electrostatic interaction between the positively charged poly-lysine domain in the C-terminus of STIM1 with the negatively charged aspartates in the TRPC1 [15]. SOCE is impaired in the β-cells obtained from patients with type 2 diabetes (T2D) [16]. The human TRPC1 gene is located on the chromosome 3q23;the band 3q is associated with T2D [17,18].…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…103 Insulin resistance associated with overnutrition pressures ER to meet increased demand for insulin production. 109 As ER maintains higher calcium concentration compared with cytosol to support protein folding and to regulate [Ca 2+ ] i , [Ca 2+ ] ER depletion results in ER stress and dysregulates insulin secretion. 109 As ER maintains higher calcium concentration compared with cytosol to support protein folding and to regulate [Ca 2+ ] i , [Ca 2+ ] ER depletion results in ER stress and dysregulates insulin secretion.…”

“…104 High concentrations of FA have been shown to deplete [Ca 2+ ] ER in beta cells 105,106 by reducing expression of pumps that regulate [Ca 2+ ] ER homeostasis, such as sarco/ER Ca 2+ -ATPase 2B (SERCA2B), 107 sorcin, 108 and stromal interaction molecule 1 (STIM1). 109 As ER maintains higher calcium concentration compared with cytosol to support protein folding and to regulate [Ca 2+ ] i , [Ca 2+ ] ER depletion results in ER stress and dysregulates insulin secretion. Overload of FA, especially that of saturated FA, is reported to alter the composition of membrane PLs and contribute to ER stress, mitochondrial dysfunction, and production of proinflammatory metabolites such as AA.…”

Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress

“…A significant proportion (40%; 86/220) of sequences containing T2D-associated index or linked SNPs exhibiting allelic skew under control conditions had significantly higher MPRA activity under ER stress, suggesting – i) MIN6 cells cultured under standard, high glucose (25 mM) conditions are already under a basal level of ER stress, and ii) many T2D-associated SNPs overlap CREs relevant for β cells to respond to ER stress. Uncompensated ER stress was found to lead to the inactivation of β cell-specific TFs causing the downregulation of insulin transcription and secretion 50–54 . ER folding and trafficking capacity may therefore be a major factor determining how much insulin can be released by β cells under elevated blood glucose levels, before stress ensues.…”