Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus

Nature Reviews Endocrinology volume 17, pages 455–467 (2021)Cite this article

Subjects

Abstract

Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca2+ storage organelle, generating Ca2+ signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.

Key points

  • Physiological and chronic endoplasmic reticulum (ER) ‘stress’ exists in healthy β-cells.

  • Adaptive unfolded protein response signalling via chaperones maintains ER protein folding homeostasis in healthy β-cells.

  • Gene mutations in maturity-onset diabetes of the young exacerbate physiological ER stress, which causes β-cell loss.

  • Proinsulin is prone to misfolding and increased insulin production can exacerbate physiological ER stress on the path to type 2 diabetes mellitus.

  • The therapeutic inhibition of genes that promote ER stress in β-cells (for example, CHOP) might reduce the disease burden for patients with type 2 diabetes mellitus and is worthy of further exploration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ER stress and the UPR pathways in β-cells.
Fig. 2: Islet dysfunction during the development of T2DM.
Fig. 3: The association of β-cell ER stress with insulin hypersecretion, hepatic steatosis, adiposity and insulin resistance.
Fig. 4: Therapeutic intervention to correct vicious cycles in the metabolic syndrome.

Similar content being viewed by others

References

  1. Saeedi, P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edn. Diabetes Res. Clin. Pract. 157, 107843 (2019).

    PubMed  Google Scholar 

  2. Persaud, S. J. & Jones, P. M. A wake-up call for type 2 diabetes? N. Engl. J. Med. 375, 1090–1092 (2016).

    PubMed  Google Scholar 

  3. Weyer, C., Hanson, R. L., Tataranni, P. A., Bogardus, C. & Pratley, R. E. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 49, 2094–2101 (2000).

    CAS  PubMed  Google Scholar 

  4. Lyssenko, V. et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N. Engl. J. Med. 359, 2220–2232 (2008).

    CAS  PubMed  Google Scholar 

  5. Liu, M. et al. Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol. Metab. 21, 652–659 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. Delepine, M. et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat. Genet. 25, 406–409 (2000).

    CAS  PubMed  Google Scholar 

  7. Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  PubMed  Google Scholar 

  8. Wang, S. & Kaufman, R. J. The impact of the unfolded protein response on human disease. J. Cell Biol. 197, 857–867 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu, M. et al. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes Obes. Metab. 20 (Suppl 2), 28–50 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Back, S. H. & Kaufman, R. J. Endoplasmic reticulum stress and type 2 diabetes. Annu. Rev. Biochem. 81, 767–793 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Scheuner, D. & Kaufman, R. J. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr. Rev. 29, 317–333 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yong, J., Itkin-Ansari, P. & Kaufman, R. J. When less is better: ER stress and beta cell proliferation. Dev. Cell 36, 4–6 (2016).

    CAS  PubMed  Google Scholar 

  13. Wang, M. & Kaufman, R. J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335 (2016).

    CAS  PubMed  Google Scholar 

  14. Schroder, M. & Kaufman, R. J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789 (2005).

    PubMed  Google Scholar 

  15. Starling, S. β-cell dedifferentiation prior to insulitis prevents T1DM. Nat. Rev. Endocrinol. 16, 301 (2020).

    CAS  PubMed  Google Scholar 

  16. Lee, H. et al. Beta cell dedifferentiation induced by IRE1alpha deletion prevents type 1 diabetes. Cell Metab. 31, 822–836 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Eizirik, D. L., Pasquali, L. & Cnop, M. Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat. Rev. Endocrinol. 16, 349–362 (2020).

    CAS  PubMed  Google Scholar 

  18. Xin, Y. et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab. 24, 608–615 (2016).

    CAS  PubMed  Google Scholar 

  19. Szabat, M. et al. Reduced insulin production relieves endoplasmic reticulum stress and induces β cell proliferation. Cell Metab. 23, 179–193 (2016).

    CAS  PubMed  Google Scholar 

  20. Wang, S., Flibotte, S., Camunas-Soler, J., MacDonald, P. E. & Johnson, J. D. A new hypothesis for type 1 diabetes risk: the at-risk allele at rs3842753 associates with increased beta cell INS mRNA in a meta-analysis of single cell RNA sequencing data. Can. J. Diabetes https://doi.org/10.1016/j.jcjd.2021.03.007 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Han, J. & Kaufman, R. J. Physiological/pathological ramifications of transcription factors in the unfolded protein response. Genes Dev. 31, 1417–1438 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Amin-Wetzel, N. et al. A J-protein co-chaperone recruits BiP to monomerize IRE1 and repress the unfolded protein response. Cell 171, 1625–1637 e1613 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001).

    CAS  PubMed  Google Scholar 

  24. Casagrande, R. et al. Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol. Cell 5, 729–735 (2000).

    CAS  PubMed  Google Scholar 

  25. Shen, X., Ellis, R. E., Sakaki, K. & Kaufman, R. J. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet. 1, e37 (2005).

    PubMed  PubMed Central  Google Scholar 

  26. Hassler, J. R. et al. The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. PLoS Biol. 13, e1002277 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Prostko, C. R., Brostrom, M. A., Malara, E. M. & Brostrom, C. O. Phosphorylation of eukaryotic initiation factor (eIF) 2 alpha and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. J. Biol. Chem. 267, 16751–16754 (1992).

    CAS  PubMed  Google Scholar 

  28. Harding, H. P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999).

    CAS  PubMed  Google Scholar 

  29. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    CAS  PubMed  Google Scholar 

  30. Yong, J., Grankvist, N., Han, J. & Kaufman, R. J. Eukaryotic translation initiation factor 2 α phosphorylation as a therapeutic target in diabetes. Expert Rev. Endocrinol. Metab. 9, 345–356 (2014).

    CAS  PubMed  Google Scholar 

  31. Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).

    CAS  PubMed  Google Scholar 

  32. Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    CAS  PubMed  Google Scholar 

  35. Back, S. H. et al. Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 10, 13–26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Usui, M. et al. Atf6alpha-null mice are glucose intolerant due to pancreatic beta-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 61, 1118–1128 (2012).

    CAS  PubMed  Google Scholar 

  37. Gu, N. et al. Obesity has an interactive effect with genetic variation in the activating transcription factor 6 gene on the risk of pre-diabetes in individuals of Chinese Han descent. PLoS ONE 9, e109805 (2014).

    PubMed  PubMed Central  Google Scholar 

  38. Thameem, F., Farook, V. S., Bogardus, C. & Prochazka, M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55, 839–842 (2006).

    CAS  PubMed  Google Scholar 

  39. Lee, A. H., Heidtman, K., Hotamisligil, G. S. & Glimcher, L. H. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc. Natl Acad. Sci. USA 108, 8885–8890 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ittner, A. A. et al. The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo. Diabetologia 57, 1410–1419 (2014).

    CAS  PubMed  Google Scholar 

  41. Fritz, J. M. et al. Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects. Mol. Biol. Cell 25, 431–440 (2014).

    PubMed  PubMed Central  Google Scholar 

  42. Ladiges, W. C. et al. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54, 1074–1081 (2005).

    CAS  PubMed  Google Scholar 

  43. Han, J. et al. Antioxidants complement the requirement for protein chaperone function to maintain beta-cell function and glucose homeostasis. Diabetes 64, 2892–2904 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Synofzik, M. et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am. J. Hum. Genet. 95, 689–697 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Teodoro-Morrison, T., Schuiki, I., Zhang, L., Belsham, D. D. & Volchuk, A. GRP78 overproduction in pancreatic beta cells protects against high-fat-diet-induced diabetes in mice. Diabetologia 56, 1057–1067 (2013).

    CAS  PubMed  Google Scholar 

  46. Kulanuwat, S. et al. DNAJC3 mutation in Thai familial type 2 diabetes mellitus. Int. J. Mol. Med. 42, 1064–1073 (2018).

    CAS  PubMed  Google Scholar 

  47. Lindahl, M. et al. MANF is indispensable for the proliferation and survival of pancreatic β cells. Cell Rep. 7, 366–375 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shrestha, N., Reinert, R. B. & Qi, L. Endoplasmic reticulum protein quality control in β cells. Semin. Cell Dev. Biol. 103, 59–67 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ledermann, H. M. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet 345, 648 (1995).

    CAS  PubMed  Google Scholar 

  50. Sato, Y. et al. Anks4b, a novel target of HNF4alpha protein, interacts with GRP78 protein and regulates endoplasmic reticulum stress-induced apoptosis in pancreatic beta-cells. J. Biol. Chem. 287, 23236–23245 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Matschinsky, F. et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J. Clin. Invest. 92, 2092–2098 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Velho, G. et al. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 340, 444–448 (1992).

    CAS  PubMed  Google Scholar 

  53. van Buerck, L. et al. Enhanced oxidative stress and endocrine pancreas alterations are linked to a novel glucokinase missense mutation in ENU-derived Munich Gck(D217V) mutants. Mol. Cell Endocrinol. 362, 139–148 (2012).

    PubMed  Google Scholar 

  54. Shirakawa, J. et al. Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic beta-cells. Diabetes 62, 3448–3458 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996).

    CAS  PubMed  Google Scholar 

  56. Kirkpatrick, C. L. et al. Hepatic nuclear factor 1alpha (HNF1alpha) dysfunction down-regulates X-box-binding protein 1 (XBP1) and sensitizes beta-cells to endoplasmic reticulum stress. J. Biol. Chem. 286, 32300–32312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hagenfeldt-Johansson, K. A. et al. Beta-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1 alpha induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice. Endocrinology 142, 5311–5320 (2001).

    CAS  PubMed  Google Scholar 

  58. Stoffers, D. A., Ferrer, J., Clarke, W. L. & Habener, J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet. 17, 138–139 (1997).

    CAS  PubMed  Google Scholar 

  59. Johnson, J. D. et al. Increased islet apoptosis in Pdx1+/− mice. J. Clin. Invest. 111, 1147–1160 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Juliana, C. A. et al. A PDX1-ATF transcriptional complex governs beta cell survival during stress. Mol. Metab. 17, 39–48 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sachdeva, M. M. et al. Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc. Natl Acad. Sci. USA 106, 19090–19095 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnson, J. S. et al. Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet beta cell. J. Biol. Chem. 289, 32798–32810 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, M. et al. Saturated fatty acids entrap PDX1 in stress granules and impede islet beta cell function. Diabetologia 64, 1144–1157 (2021).

    CAS  PubMed  Google Scholar 

  64. Johnson, J. D. et al. Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome. Proc. Natl Acad. Sci. USA 103, 19575–19580 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Collombat, P. et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 17, 2591–2603 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Smith, S. B., Ee, H. C., Conners, J. R. & German, M. S. Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Mol. Cell Biol. 19, 8272–8280 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hu He, K. H. et al. In vivo conditional Pax4 overexpression in mature islet beta-cells prevents stress-induced hyperglycemia in mice. Diabetes 60, 1705–1715 (2011).

    PubMed  Google Scholar 

  68. Mellado-Gil, J. M. et al. PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus. Diabetologia 59, 755–765 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Haataja, L. et al. Disulfide mispairing during proinsulin folding in the endoplasmic reticulum. Diabetes 65, 1050–1060 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu, M. et al. Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport. PLoS One 5, e13333 (2010).

    PubMed  PubMed Central  Google Scholar 

  71. Rege, N. K. et al. Evolution of insulin at the edge of foldability and its medical implications. Proc. Natl Acad. Sci. USA 117, 29618–29628 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ma, S. et al. β cell replacement after gene editing of a neonatal diabetes-causing mutation at the insulin locus. Stem Cell Rep. 11, 1407–1415 (2018).

    CAS  Google Scholar 

  73. Modi, H. & Johnson, J. D. Folding mutations suppress early beta-cell proliferation. eLife 7, e43475 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    CAS  PubMed  Google Scholar 

  75. De Franco, E. et al. De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early-onset diabetes and transient hepatic dysfunction. Diabetes 69, 477–483 (2020).

    PubMed  Google Scholar 

  76. Inoue, H. et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat. Genet. 20, 143–148 (1998).

    CAS  PubMed  Google Scholar 

  77. Chaussenot, A. et al. Neurologic features and genotype-phenotype correlation in Wolfram syndrome. Ann. Neurol. 69, 501–508 (2011).

    CAS  PubMed  Google Scholar 

  78. Morikawa, S., Tajima, T., Nakamura, A., Ishizu, K. & Ariga, T. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatr. Diabetes 18, 934–941 (2017).

    CAS  PubMed  Google Scholar 

  79. Yurimoto, S. et al. Identification and characterization of wolframin, the product of the Wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein. Biochemistry 48, 3946–3955 (2009).

    CAS  PubMed  Google Scholar 

  80. Takei, D. et al. WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. FEBS Lett. 580, 5635–5640 (2006).

    CAS  PubMed  Google Scholar 

  81. Fonseca, S. G. et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J. Clin. Invest. 120, 744–755 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lu, S. et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc. Natl Acad. Sci. USA 111, E5292–E5301 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Abreu, D. et al. A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome. medRxiv https://doi.org/10.1101/2020.10.07.20208694 (2020).

  84. Scheuner, D. et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat. Med. 11, 757–764 (2005).

    CAS  PubMed  Google Scholar 

  85. Arunagiri, A. et al. Proinsulin misfolding is an early event in the progression to type 2 diabetes. eLife 8, e44532 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Harding, H. P. et al. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development. Proc. Natl Acad. Sci. USA 106, 1832–1837 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Song, B., Scheuner, D., Ron, D., Pennathur, S. & Kaufman, R. J. Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. 118, 3378–3389 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sharma, R. B. et al. Insulin demand regulates beta cell number via the unfolded protein response. J. Clin. Invest. 125, 3831–3846 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. Donath, M. Y. et al. Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Metab. Stress. Ther. 31 (Suppl. 2), S161–S164 (2008).

    CAS  Google Scholar 

  90. Johnson, A. R., Justin Milner, J. & Makowski, L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol. Rev. 249, 218–238 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745–758 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Maedler, K. et al. Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Boni-Schnetzler, M. et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).

    PubMed  PubMed Central  Google Scholar 

  94. Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007).

    CAS  PubMed  Google Scholar 

  95. Kahn, S. E., Andrikopoulos, S. & Verchere, C. B. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48, 241–253 (1999).

    CAS  PubMed  Google Scholar 

  96. Butler, A. E. et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  PubMed  Google Scholar 

  97. O’Neill, C. M. et al. Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male mice. Endocrinology 154, 3077–3088 (2013).

    PubMed  PubMed Central  Google Scholar 

  98. Ehses, J. A., Boni-Schnetzler, M., Faulenbach, M. & Donath, M. Y. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem. Soc. Trans. 36, 340–342 (2008).

    CAS  PubMed  Google Scholar 

  99. Westwell-Roper, C. Y., Ehses, J. A. & Verchere, C. B. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 63, 1698–1711 (2014).

    CAS  PubMed  Google Scholar 

  100. Boni-Schnetzler, M., Ehses, J. A., Faulenbach, M. & Donath, M. Y. Insulitis in type 2 diabetes. Diabetes Obes. Metab. 10(Suppl. 4), 201–204 (2008).

    CAS  PubMed  Google Scholar 

  101. Miani, M. et al. Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance. Cell Death Dis. 4, e701 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hasnain, S. Z. et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat. Med. 20, 1417–1426 (2014).

    CAS  PubMed  Google Scholar 

  103. Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

    CAS  PubMed  Google Scholar 

  104. Lerner, A. G. et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, J., Song, M.-Y., Lee, J. Y., Kwon, K. S. & Park, B.-H. The NLRP3 inflammasome is dispensable for ER stress-induced pancreatic β-cell damage in Akita mice. Biochem. Biophys. Res. Commun. 466, 300–305 (2015).

    CAS  PubMed  Google Scholar 

  107. Jang, I. et al. PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity. eLife 8, e44528 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu, M. et al. Normal and defective pathways in biogenesis and maintenance of the insulin storage pool. J. Clin. Invest. 131, e142240 (2021).

    CAS  PubMed Central  Google Scholar 

  109. Farack, L. et al. Transcriptional heterogeneity of beta cells in the intact pancreas. Dev. Cell 48, 115–125.e4 (2019).

    CAS  PubMed  Google Scholar 

  110. Fang, Z. et al. Single-cell heterogeneity analysis and crispr screen identify key β-cell-specific disease genes. Cell Rep. 26, 3132–3144.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Camunas-Soler, J. et al. Patch-seq links single-cell transcriptomes to human islet dysfunction in diabetes. Cell Metab. 31, 1017–1031.e4 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Robertson, R. P. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J. Biol. Chem. 279, 42351–42354 (2004).

    CAS  PubMed  Google Scholar 

  113. Kaneto, H., Kawamori, D., Matsuoka, T. A., Kajimoto, Y. & Yamasaki, Y. Oxidative stress and pancreatic beta-cell dysfunction. Am. J. Ther. 12, 529–533 (2005).

    PubMed  Google Scholar 

  114. Kaneto, H. et al. Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance. Int. J. Biochem. Cell Biol. 37, 1595–1608 (2005).

    CAS  PubMed  Google Scholar 

  115. Ravier, M. A. et al. Mechanisms of control of the free Ca2+ concentration in the endoplasmic reticulum of mouse pancreatic beta-cells: interplay with cell metabolism and [Ca2+]c and role of SERCA2b and SERCA3. Diabetes 60, 2533–2545 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Tong, X. et al. SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity. Diabetes 65, 3039–3052 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Michalak, M., Corbett, E. F., Mesaeli, N., Nakamura, K. & Opas, M. Calreticulin: one protein, one gene, many functions. Biochem. J. 344, 281–292 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Suzuki, C. K., Bonifacino, J. S., Lin, A. Y., Davis, M. M. & Klausner, R. D. Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca2+-dependent association with BiP. J. Cell Biol. 114, 189–205 (1991).

    CAS  PubMed  Google Scholar 

  119. Gelebart, P., Opas, M. & Michalak, M. Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum. Int. J. Biochem. Cell Biol. 37, 260–266 (2005).

    CAS  PubMed  Google Scholar 

  120. Guest, P. C., Bailyes, E. M. & Hutton, J. C. Endoplasmic reticulum Ca2+ is important for the proteolytic processing and intracellular transport of proinsulin in the pancreatic beta-cell. Biochem. J. 323, 445–450 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ling, Z. & Pipeleers, D. G. Prolonged exposure of human beta cells to elevated glucose levels results in sustained cellular activation leading to a loss of glucose regulation. J. Clin. Invest. 98, 2805–2812 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Ling, Z. et al. Effects of chronically elevated glucose levels on the functional properties of rat pancreatic beta-cells. Diabetes 45, 1774–1782 (1996).

    CAS  PubMed  Google Scholar 

  123. Schuit, F. C., In’t Veld, P. A. & Pipeleers, D. G. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. Proc. Natl Acad. Sci. USA 85, 3865–3869 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Yong, J. et al. Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+. eLife 8, e49682 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. Zhang, I. X., Ren, J., Vadrevu, S., Raghavan, M. & Satin, L. S. ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic β cells. J. Biol. Chem. 295, 5685–5700 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Templeman, N. M., Skovso, S., Page, M. M., Lim, G. E. & Johnson, J. D. A causal role for hyperinsulinemia in obesity. J. Endocrinol. 232, R173–R183 (2017).

    CAS  PubMed  Google Scholar 

  127. Thorpe, S. R. & Baynes, J. W. Maillard reaction products in tissue proteins: new products and new perspectives. Amino Acids 25, 275–281 (2003).

    CAS  PubMed  Google Scholar 

  128. Kooptiwut, S. et al. High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction. J. Mol. Endocrinol. 35, 39–48 (2005).

    CAS  PubMed  Google Scholar 

  129. Pascal, S. M. A., Veiga-da-Cunha, M., Gilon, P., Schaftingen, E. V. & Jonas, J. C. Effects of fructosamine-3-kinase deficiency on function and survival of mouse pancreatic islets after prolonged culture in high glucose or ribose concentrations. Am. J. Physiol. Endocrinol. Metab. 298, E586–E596 (2010).

    CAS  PubMed  Google Scholar 

  130. Piperi, C., Adamopoulos, C., Dalagiorgou, G., Diamanti-Kandarakis, E. & Papavassiliou, A. G. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. J. Clin. Endocrinol. Metab. 97, 2231–2242 (2012).

    CAS  PubMed  Google Scholar 

  131. Perl, S. et al. Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J. Clin. Endocrinol. Metab. 95, E234–E239 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Cohrs, C. M. et al. Dysfunction of persisting beta cells is a key feature of early type 2 diabetes pathogenesis. Cell Rep. 31, 107469 (2020).

    CAS  PubMed  Google Scholar 

  133. Mehran, A. E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).

    CAS  PubMed  Google Scholar 

  134. Templeman, N. M., Clee, S. M. & Johnson, J. D. Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity. Diabetologia 58, 2392–2402 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhang, A. M. Y. et al. Endogenous hyperinsulinemia contributes to pancreatic cancer development. Cell Metab. 30, 403–404 (2019).

    CAS  PubMed  Google Scholar 

  136. Page, M. M. et al. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain. FASEB J. 32, 1196–1206 (2018).

    CAS  PubMed  Google Scholar 

  137. Wiebe, N. et al. Temporal associations among body mass index, fasting insulin, and systemic inflammation: a systematic review and meta-analysis. JAMA Netw. Open 4, e211263 (2021).

    PubMed  PubMed Central  Google Scholar 

  138. Yong, J. et al. Chop/Ddit3 depletion in β-cells alleviates ER stress and corrects hepatic steatosis. bioRxiv https://doi.org/10.1101/2020.01.02.893271 (2020).

    Article  Google Scholar 

  139. Ammala, C. et al. Targeted delivery of antisense oligonucleotides to pancreatic beta-cells. Sci. Adv. 4, eaat3386 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Investigators, O. T. et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N. Engl. J. Med. 367, 319–328 (2012).

    Google Scholar 

  141. Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Smith, G. I. et al. Influence of adiposity, insulin resistance and intrahepatic triglyceride content on insulin kinetics. J. Clin. Invest. 130, 3305–3314 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Roumans, K. H. M. et al. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance. Nat. Commun. 11, 1891 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Vatner, D. F. et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc. Natl Acad. Sci. USA 112, 1143–1148 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang, T. et al. Association of insulin resistance and β-cell dysfunction with incident diabetes among adults in China: a nationwide, population-based, prospective cohort study. Lancet Diabetes Endocrinol. 8, 115–124 (2020).

    CAS  PubMed  Google Scholar 

  146. Wang, G. et al. Muscle-specific insulin receptor overexpression protects mice from diet-induced glucose intolerance but leads to postreceptor insulin resistance. Diabetes 69, 2294–2309 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Treadway, J. L., Whittaker, J. & Pessin, J. E. Regulation of the insulin receptor kinase by hyperinsulinism. J. Biol. Chem. 264, 15136–15143 (1989).

    CAS  PubMed  Google Scholar 

  148. Marshall, S. & Olefsky, J. M. Effects of insulin incubation on insulin binding, glucose transport, and insulin degradation by isolated rat adipocytes. Evidence for hormone-induced desensitization at the receptor and postreceptor level. J. Clin. Invest. 66, 763–772 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Cnop, M., Toivonen, S., Igoillo-Esteve, M. & Salpea, P. Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic beta cells. Mol. Metab. 6, 1024–1039 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Yamane, S. et al. GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated beta-cell damage in Akita mice. J. Diabetes Investig. 2, 104–110 (2011).

    CAS  PubMed  Google Scholar 

  151. Yusta, B. et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 4, 391–406 (2006).

    CAS  PubMed  Google Scholar 

  152. Wek, R. C. & Anthony, T. G. EXtENDINg beta cell survival by UPRegulating ATF4 translation. Cell Metab. 4, 333–334 (2006).

    CAS  PubMed  Google Scholar 

  153. Evans-Molina, C. et al. Peroxisome proliferator-activated receptor γ activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol. Cell Biol. 29, 2053–2067 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Luciani, D. S. et al. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes 58, 422–432 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Klein, M. C. et al. AXER is an ATP/ADP exchanger in the membrane of the endoplasmic reticulum. Nat. Commun. 9, 3489 (2018).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of NIH grants CA198103, DK113171, DK110973, DK103185 (R.J.K.) and DK48280 (P.A.), and the National Research Foundation of Korea NRF-2017M3A9G7072745, NRF-2019R1A5A8083404, NRF-2017M3A9C6033069, NRF-2019R1A2C1085284 (J.H.), and of the Diabetes Investigator Award from Diabetes Canada (J.D.J.).

Author information

Authors and Affiliations

  1. Degenerative Diseases Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA

    Jing Yong & Randal J. Kaufman

  2. Department of Cellular and Physiological Sciences & Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada

    James D. Johnson

  3. Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, MI, USA

    Peter Arvan

  4. Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Choongchungnam-do, Republic of Korea

    Jaeseok Han

Authors
  1. Jing Yong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James D. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Arvan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jaeseok Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Randal J. Kaufman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.J.K., J.Y., J.D.J. and J.H. researched data for the article. All authors contributed substantially to the discussion of the content. All authors wrote the article. R.J.K., J.Y., J.H., P.A. and J.D.J. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Jaeseok Han or Randal J. Kaufman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks H. Lickert and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yong, J., Johnson, J.D., Arvan, P. et al. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus. Nat Rev Endocrinol 17, 455–467 (2021). https://doi.org/10.1038/s41574-021-00510-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-021-00510-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing