Endoplasmic Reticulum Stress and Pancreatic β-cell Death

Overview

Journal Trends Endocrinol Metab

Specialty Endocrinology

Date 2011 Apr 5

PMID 21458293

Citations 216

Authors

Sonya G Fonseca

Jesper Gromada

Fumihiko Urano

Affiliations

Soon will be listed here.

Abstract

In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment for insulin biosynthesis, which accounts for half of the total protein production in these cells. Protein flux through the ER must be carefully monitored to prevent dysregulation of ER homeostasis and stress. ER stress elicits a signaling cascade known as the unfolded protein response (UPR), which influences both life and death decisions in cells. β-cell loss is a pathological component of both type 1 and type 2 diabetes, and recent findings suggest that ER stress is involved. In this review, we address the transition from the physiological ER stress response to the pathological response, and explore the mechanisms of ER stress-mediated β-cell loss during the progression of diabetes.

Citing Articles

Molecular puzzle of insulin: structural assembly pathways and their role in diabetes.

Urbaniak E, Henry S, Lalowski M, Borowiak M Front Cell Dev Biol. 2025; 13:1502469.

PMID: 40052150 PMC: 11882602. DOI: 10.3389/fcell.2025.1502469.

Immune Evasion in Stem Cell-Based Diabetes Therapy-Current Strategies and Their Application in Clinical Trials.

Mu-U-Min R, Diane A, Allouch A, Al-Siddiqi H Biomedicines. 2025; 13(2).

PMID: 40002796 PMC: 11853723. DOI: 10.3390/biomedicines13020383.

Single-cell decoding of human islet cell type-specific alterations in type 2 diabetes reveals converging genetic- and state-driven -cell gene expression defects.

Bandesh K, Motakis E, Nargund S, Kursawe R, Selvam V, Bhuiyan R bioRxiv. 2025; .

PMID: 39896672 PMC: 11785113. DOI: 10.1101/2025.01.17.633590.

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.

Oguh A, Haemmerle M, Sen S, Rozo A, Shrestha S, Cartailler J Genes Dev. 2025; 39(3-4):261-279.

PMID: 39797759 PMC: 11789638. DOI: 10.1101/gad.352010.124.

Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.

Li G, Yang H, Zhang P, Guo Y, Yuan L, Xu S Front Mol Neurosci. 2025; 17:1443401.

PMID: 39744539 PMC: 11688397. DOI: 10.3389/fnmol.2024.1443401.

References

Lipson K, Ghosh R, Urano F . The role of IRE1alpha in the degradation of insulin mRNA in pancreatic beta-cells. PLoS One. 2008; 3(2):e1648. PMC: 2241665. DOI: 10.1371/journal.pone.0001648. View

Sparso T, Andersen G, Albrechtsen A, Jorgensen T, Borch-Johnsen K, Sandbaek A . Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation. Diabetologia. 2008; 51(9):1646-52. DOI: 10.1007/s00125-008-1064-2. View

Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T . Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem. 2001; 276(17):13935-40. DOI: 10.1074/jbc.M010677200. View

Galehdar Z, Swan P, Fuerth B, Callaghan S, Park D, Cregan S . Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci. 2010; 30(50):16938-48. PMC: 6634926. DOI: 10.1523/JNEUROSCI.1598-10.2010. View

Lipson K, Fonseca S, Ishigaki S, Nguyen L, Foss E, Bortell R . Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 2006; 4(3):245-54. DOI: 10.1016/j.cmet.2006.07.007. View

Ritzel R, Meier J, Lin C, Veldhuis J, Butler P . Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes. 2006; 56(1):65-71. DOI: 10.2337/db06-0734. View

Liew C, Bochenski J, Kawamori D, Hu J, Leech C, Wanic K . The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells. J Clin Invest. 2010; 120(8):2876-88. PMC: 2912176. DOI: 10.1172/JCI36849. View

Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K . ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002; 16(11):1345-55. PMC: 186318. DOI: 10.1101/gad.992302. View

Mattsson G, Jansson L, Carlsson P . Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes. 2002; 51(5):1362-6. DOI: 10.2337/diabetes.51.5.1362. View

10.

Marselli L, Thorne J, Dahiya S, Sgroi D, Sharma A, Bonner-Weir S . Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010; 5(7):e11499. PMC: 2903480. DOI: 10.1371/journal.pone.0011499. View

11.

Hollien J, Lin J, Li H, Stevens N, Walter P, Weissman J . Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009; 186(3):323-31. PMC: 2728407. DOI: 10.1083/jcb.200903014. View

12.

Han D, Lerner A, Vande Walle L, Upton J, Xu W, Hagen A . IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 2009; 138(3):562-75. PMC: 2762408. DOI: 10.1016/j.cell.2009.07.017. View

13.

Carlsson P, Palm F, Mattsson G . Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab. 2002; 87(12):5418-23. DOI: 10.1210/jc.2002-020728. View

14.

Seo H, Kim Y, Lee K, Min A, Kim M, Kim H . Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology. 2008; 149(8):3832-41. PMC: 2488228. DOI: 10.1210/en.2008-0015. View

15.

Hollien J, Weissman J . Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006; 313(5783):104-7. DOI: 10.1126/science.1129631. View

16.

Oslowski C, Urano F . A switch from life to death in endoplasmic reticulum stressed β-cells. Diabetes Obes Metab. 2010; 12 Suppl 2:58-65. PMC: 3713507. DOI: 10.1111/j.1463-1326.2010.01277.x. View

17.

Laybutt D, Preston A, Akerfeldt M, Kench J, BUSCH A, Biankin A . Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 2007; 50(4):752-63. DOI: 10.1007/s00125-006-0590-z. View

18.

Kharroubi I, Ladriere L, Cardozo A, Dogusan Z, Cnop M, Eizirik D . Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004; 145(11):5087-96. DOI: 10.1210/en.2004-0478. View

19.

Jonas J, Bensellam M, Duprez J, Elouil H, Guiot Y, Pascal S . Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes Obes Metab. 2009; 11 Suppl 4:65-81. DOI: 10.1111/j.1463-1326.2009.01112.x. View

20.

Schafer S, Mussig K, Staiger H, Machicao F, Stefan N, Gallwitz B . A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia. 2009; 52(6):1075-82. DOI: 10.1007/s00125-009-1344-5. View