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Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure

Nature Reviews Endocrinology volume 16, pages 349–362 (2020)Cite this article

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Abstract

Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.

Key points

  • Pancreatic β-cell dysfunction and cell death are key processes in the development of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).

  • The pathogenesis of T1DM and T2DM is fundamentally distinct, differentially impacting early β-cell dysfunction (immune mediated versus metabolic in T1DM and T2DM, respectively) and cell fate (massive versus mild-to-moderate β-cell loss).

  • Pancreatic islet cells have unexpected plasticity; however, the magnitude and clinical relevance of this phenomenon in humans remains to be determined.

  • A substantial fraction of T1DM-associated genetic variants act at the β-cell level but only become manifest upon immune-mediated islet cell perturbations, whereas T2DM genetic signals largely regulate β-cell development and function.

  • In T1DM (and potentially in other autoimmune diseases), enhancers pre-bound by tissue-specific transcription factors seemingly facilitate cell type-specific responses to ubiquitous pro-inflammatory signals, which could explain the tissue selectivity in autoimmune attack.

  • Endoplasmic reticulum stress affects β-cells in both T1DM and T2DM; however, the signalling differs, with predominantly IRE1-mediated β-cell damage in T1DM and PERK–eIF2α-mediated β-cell damage in T2DM.

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Fig. 1: Transcriptomes of human islets exposed to pro-inflammatory cytokines versus β-cells from donors with T1DM or T2DM.
Fig. 2: T1DM and T2DM risk variants affect pancreatic islet cis-regulatory elements.
Fig. 3: ER stress signalling in β-cells in T1DM and T2DM.

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References

  1. Cnop, M. et al. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54 (Suppl. 2), 97–107 (2005).

    Article  Google Scholar 

  2. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes — 2019. Diabetes Care 42 (Suppl. 1), 13–28 (2019).

    Article  Google Scholar 

  3. Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018). This study attempted, for the first time, to subtype adult diabetes mellitus using clinical variables, identifying five subgroups with differing disease progression and risk of chronic complications.

    Article  PubMed  Google Scholar 

  4. Pearson, E. R. Type 2 diabetes: a multifaceted disease. Diabetologia 62, 1107–1112 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nat. Rev. Endocrinol. 5, 219–226 (2009). This article presented, for the first time and in a comprehensive way, the role for inflammation at the different stages of autoimmunity progression in T1DM.

    Article  CAS  PubMed  Google Scholar 

  6. Gonzalez-Duque, S. et al. Conventional and neo-antigenic peptides presented by β cells are targeted by circulating naive CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab. 28, 946–960.e6 (2018). A detailed genomics and peptidomics analysis, identifying several potential neoantigens in human β-cells, including splice variants.

    Article  CAS  PubMed  Google Scholar 

  7. Thomaidou, S., Zaldumbide, A. & Roep, B. O. Islet stress, degradation and autoimmunity. Diabetes Obes. Metab. 20 (Suppl. 2), 88–94 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. DiMeglio, L. A., Evans-Molina, C. & Oram, R. A. Type 1 diabetes. Lancet 391, 2449–2462 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Op de Beeck, A. & Eizirik, D. L. Viral infections in type 1 diabetes mellitus - why the β cells? Nat. Rev. Endocrinol. 12, 263–273 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 15, 635–650 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Todd, J. A. Etiology of type 1 diabetes. Immunity 32, 457–467 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Colli, M. L. et al. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and -γ via IRF1 induction. EBioMedicine 36, 367–375 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Martinov, T. & Fife, B. T. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. Ann. NY Acad. Sci. 1461, 73–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Sims, E. K. & DiMeglio, L. A. Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes. Mol. Metab. 27S, S129–S138 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Pociot, F. & Lernmark, A. Genetic risk factors for type 1 diabetes. Lancet 387, 2331–2339 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Patterson, C. C. et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia 62, 408–417 (2019).

    Article  PubMed  Google Scholar 

  17. Livingstone, S. J. et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 313, 37–44 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huo, L., Harding, J. L., Peeters, A., Shaw, J. E. & Magliano, D. J. Life expectancy of type 1 diabetic patients during 1997-2010: a national Australian registry-based cohort study. Diabetologia 59, 1177–1185 (2016).

    Article  PubMed  Google Scholar 

  19. Insel, R. A. et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the endocrine society, and the American Diabetes Association. Diabetes Care 38, 1964–1974 (2015). This article provides a novel approach to classify the different stages of T1DM, indicating new windows for therapeutic intervention.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Greenbaum, C. J. et al. Strength in numbers: opportunities for enhancing the development of effective treatments for type 1 diabetes-the TrialNet experience. Diabetes 67, 1216–1225 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Herold, K. C. et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 381, 603–613 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weyer, C., Bogardus, C., Mott, D. M. & Pratley, R. E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J. Clin. Invest. 104, 787–794 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lyssenko, V. et al. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 54, 166–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Cnop, M. et al. Progressive loss of β-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 30, 677–682 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Zaharia, O. P. et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol. 7, 684–694 (2019).

    Article  PubMed  Google Scholar 

  26. Zheng, Y., Ley, S. H. & Hu, F. B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 14, 88–98 (2018).

    Article  PubMed  Google Scholar 

  27. NCD Risk Factor Collaboration. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387, 1513–1530 (2016).

    Article  Google Scholar 

  28. Sattar, N. et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation 139, 2228–2237 (2019).

    Article  PubMed  Google Scholar 

  29. RISE Consortium. Lack of durable improvements in β-cell function following withdrawal of pharmacological interventions in adults with impaired glucose tolerance or recently diagnosed type 2 diabetes. Diabetes Care 42, 1742–1751 (2019).

    Article  CAS  Google Scholar 

  30. Tripathy, D. et al. Diabetes incidence and glucose tolerance after termination of pioglitazone therapy: results from ACT NOW. J. Clin. Endocrinol. Metab. 101, 2056–2062 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Velloso, L. A., Eizirik, D. L. & Cnop, M. Type 2 diabetes mellitus-an autoimmune disease? Nat. Rev. Endocrinol. 9, 750–755 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Mandrup-Poulsen, T. Type 2 diabetes mellitus: a metabolic autoinflammatory disease. Dermatol. Clin. 31, 495–506 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Lytrivi, M., Igoillo-Esteve, M. & Cnop, M. Inflammatory stress in islet β-cells: therapeutic implications for type 2 diabetes? Curr. Opin. Pharmacol. 43, 40–45 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J. Am. Coll. Cardiol. 71, 2392–2401 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Pugliese, A. et al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr. Diabetes 15, 1–9 (2014).

    Article  PubMed  Google Scholar 

  36. Rodriguez-Calvo, T., Richardson, S. J. & Pugliese, A. Pancreas pathology during the natural history of type 1 diabetes. Curr. Diab. Rep. 18, 124 (2018).

    Article  PubMed  Google Scholar 

  37. Krogvold, L. et al. Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia 57, 841–843 (2014).

    Article  PubMed  Google Scholar 

  38. Kaestner, K. H., Powers, A. C., Naji, A., HPAP Consortium & Atkinson, M. A. NIH initiative to improve understanding of the pancreas, islet, and autoimmunity in type 1 diabetes: the Human Pancreas Analysis Program (HPAP). Diabetes 68, 1394–1402 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Morgan, N. G. & Richardson, S. J. Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made. Diabetologia 61, 2499–2506 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Marhfour, I. et al. Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia 55, 2417–2420 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Westermark, G. T., Krogvold, L., Dahl-Jorgensen, K. & Ludvigsson, J. Islet amyloid in recent-onset type 1 diabetes-the DiViD study. Ups. J. Med. Sci. 122, 201–203 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Beery, M. L., Jacobsen, L. M., Atkinson, M. A., Butler, A. E. & Campbell-Thompson, M. Islet amyloidosis in a child with type 1 diabetes. Islets 11, 44–49 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gotthardt, M., Eizirik, D. L., Cnop, M. & Brom, M. Beta cell imaging - a key tool in optimized diabetes prevention and treatment. Trends Endocrinol. Metab. 25, 375–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Oram, R. A., Sims, E. K. & Evans-Molina, C. Beta cells in type 1 diabetes: mass and function; sleeping or dead? Diabetologia 62, 567–577 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Thompson, P. J. et al. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  46. Damond, N. et al. A map of human type 1 diabetes progression by imaging mass cytometry. Cell Metab. 29, 755–768.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Strandell, E., Eizirik, D. L. & Sandler, S. Reversal of beta-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J. Clin. Invest. 85, 1944–1950 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krogvold, L. et al. Function of isolated pancreatic islets from patients at onset of type 1 diabetes: insulin secretion can be restored after some days in a nondiabetogenic environment in vitro: results from the DiViD study. Diabetes 64, 2506–2512 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Marchetti, P. et al. Function of pancreatic islets isolated from a type 1 diabetic patient. Diabetes Care 23, 701–703 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Brissova, M. et al. α cell function and gene expression are compromised in type 1 diabetes. Cell Rep. 22, 2667–2676 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mastracci, T. L. et al. Distinct gene expression pathways in islets from individuals with short- and long-duration type 1 diabetes. Diabetes Obes. Metab. 20, 1859–1867 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. Marroqui, L. et al. Pancreatic α cells are resistant to metabolic stress-induced apoptosis in type 2 diabetes. EBioMedicine 2, 378–385 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Marroqui, L. et al. Differential cell autonomous responses determine the outcome of coxsackievirus infections in murine pancreatic α and β cells. eLife 4, e06990 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oram, R. A. et al. Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors. Diabetes Care 38, 323–328 (2015). This study provides one of the first solid pieces of evidence that some pancreatic β-cells may survive and secrete insulin many years after onset of T1DM.

    Article  CAS  PubMed  Google Scholar 

  55. Sims, E. K. et al. Proinsulin secretion is a persistent feature of type 1 diabetes. Diabetes Care 42, 258–264 (2019). Relevant evidence that surviving β-cells in T1DM may be able to synthesize proinsulin but fail to process it into mature insulin.

    Article  CAS  PubMed  Google Scholar 

  56. Lam, C. J., Chatterjee, A., Shen, E., Cox, A. R. & Kushner, J. A. Low-level insulin content within abundant non-β islet endocrine cells in long-standing type 1 diabetes. Diabetes 68, 598–608 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Thorel, F. et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Courtney, M. et al. The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS Genet. 9, e1003934 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Eizirik, D. L. & Gurzov, E. N. Can GABA turn pancreatic α-cells into β-cells? Nat. Rev. Endocrinol. 14, 629–630 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Ortis, F. et al. Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells. Diabetes 59, 358–374 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Eizirik, D. L. et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 8, e1002552 (2012). This study provided the first RNA sequencing study of cytokine-stressed human β-cells and showed that >50% of the candidate genes for T1DM are expressed in human islets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Marroqui, L. et al. Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes. Diabetologia 60, 656–667 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Osum, K. C. et al. Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes. Sci. Rep. 8, 8295 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wyatt, R. C., Lanzoni, G., Russell, M. A., Gerling, I. & Richardson, S. J. What the HLA-I! Classical and non-classical HLA class I and their potential roles in type 1 diabetes. Curr. Diab. Rep. 19, 159 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Akturk, H. K. et al. Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis. Diabet. Med. 36, 1075–1081 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moore, F. et al. STAT1 is a master regulator of pancreatic β-cell apoptosis and islet inflammation. J. Biol. Chem. 286, 929–941 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Lundberg, M., Krogvold, L., Kuric, E., Dahl-Jorgensen, K. & Skog, O. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes 65, 3104–3110 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Ramos-Rodriguez, M. et al. The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat. Genet. 51, 1588–1595 (2019). This study identifies, for the first time, β-cell stimulus-responsive regulatory elements and finds that they are implicated in the genetic risk of T1DM, possibly playing a role in the early stages of the disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Russell, M. A. et al. HLA class II antigen processing and presentation pathway components demonstrated by transcriptome and protein analyses of islet β-cells from donors with type 1 diabetes. Diabetes 68, 988–1001 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10 (Suppl. 4), 32–42 (2008).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  73. Sakuraba, H. et al. Reduced β-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia 45, 85–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Hanley, S. C. et al. β-cell mass dynamics and islet cell plasticity in human type 2 diabetes. Endocrinology 151, 1462–1472 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Yoon, K. H. et al. Selective β-cell loss and α-cell expansion in patients with type 2 diabetes mellitus in Korea. J. Clin. Endocrinol. Metab. 88, 2300–2308 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Del Guerra, S. et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727–735 (2005).

    Article  PubMed  Google Scholar 

  77. Raleigh, D., Zhang, X., Hastoy, B. & Clark, A. The β-cell assassin: IAPP cytotoxicity. J. Mol. Endocrinol. 59, R121–R140 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. Islet-associated macrophages in type 2 diabetes. Diabetologia 52, 1686–1688 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Henquin, J. C. & Rahier, J. Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720–1725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Utzschneider, K. M. et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 32, 335–341 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Green, D. R., Oguin, T. H. & Martinez, J. The clearance of dying cells: table for two. Cell Death Differ. 23, 915–926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cnop, M. et al. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 53, 321–330 (2010). This study modelled lipofuscin accumulation in human β-cells with age; together with the complementary methods used in reference 84, this shows that, past age 20–30 years, little or no new β-cells are formed and β-cells age with the body.

    Article  CAS  PubMed  Google Scholar 

  83. Cnop, M. et al. Longevity of human islet α- and β-cells. Diabetes Obes. Metab. 13 (Suppl. 1), 39–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Perl, S. et al. Significant human β-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). This study used radiocarbon dating of human to assess their ‘birthdate’; together with the complementary methods used in reference 83, this shows that, past age 20–30 years, little or no new β-cells are formed and β-cells age with the body.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gregg, B. E. et al. Formation of a human β-cell population within pancreatic islets is set early in life. J. Clin. Endocrinol. Metab. 97, 3197–3206 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Butler, A. E. et al. β-cell deficit in obese type 2 diabetes, a minor role of β-cell dedifferentiation and degranulation. J. Clin. Endocrinol. Metab. 101, 523–532 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Md Moin, A. S. et al. Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 3628–3636 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Cinti, F. et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Sun, J. et al. -cell dedifferentiation in patients with T2D with adequate glucose control and nondiabetic chronic pancreatitis. J. Clin. Endocrinol. Metab. 104, 83–94 (2019).

    PubMed  Google Scholar 

  90. Spijker, H. S. et al. Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes 64, 2928–2938 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Butler, A. E. et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 62, 2595–2604 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Masini, M. et al. Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes. PLoS One 12, e0179398 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tamura, Y. et al. Telomere attrition in beta and alpha cells with age. Age 38, 61 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tamura, Y. et al. β-cell telomere attrition in diabetes: inverse correlation between HbA1c and telomere length. J. Clin. Endocrinol. Metab. 99, 2771–2777 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Gunton, J. E. et al. Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122, 337–349 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Solimena, M. et al. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. Diabetologia 61, 641–657 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Fadista, J. et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc. Natl Acad. Sci. USA 111, 13924–13929 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Marselli, L. et al. Gene expression profiles of beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One 5, e11499 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, Y. J. & Kaestner, K. H. Single-cell RNA-seq of the pancreatic islets-a promise not yet fulfilled? Cell Metab. 29, 539–544 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Carrano, A. C., Mulas, F., Zeng, C. & Sander, M. Interrogating islets in health and disease with single-cell technologies. Mol. Metab. 6, 991–1001 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bosco, D. & Meda, P. Actively synthesizing β-cells secrete preferentially after glucose stimulation. Endocrinology 129, 3157–3166 (1991).

    Article  CAS  PubMed  Google Scholar 

  103. Pipeleers, D. G. Heterogeneity in pancreatic β-cell population. Diabetes 41, 777–781 (1992).

    Article  CAS  PubMed  Google Scholar 

  104. Salomon, D. & Meda, P. Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells. Exp. Cell Res. 162, 507–520 (1986).

    Article  CAS  PubMed  Google Scholar 

  105. Ling, Z. et al. Intercellular differences in interleukin 1β-induced suppression of insulin synthesis and stimulation of noninsulin protein synthesis by rat pancreatic β-cells. Endocrinology 139, 1540–1545 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Mawla, A. M. & Huising, M. O. Navigating the depths and avoiding the shallows of pancreatic islet cell transcriptomes. Diabetes 68, 1380–1393 (2019). An excellent analysis of heterogeneity and caveats of single islet cell RNA sequencing.

    Article  CAS  PubMed  Google Scholar 

  107. Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Onengut-Gumuscu, S. et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cudworth, A. G. & Woodrow, J. C. Letter: HL-A antigens and diabetes mellitus. Lancet 2, 1153 (1974).

    Article  CAS  PubMed  Google Scholar 

  110. Polychronakos, C. & Li, Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat. Rev. Genet. 12, 781–792 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Floyel, T. et al. CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc. Natl Acad. Sci. USA 111, 10305–10310 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Koskinen, M. K. et al. Longitudinal pattern of first-phase insulin response is associated with genetic variants outside the class II HLA region in children with multiple autoantibodies. Diabetes 69, 12–19 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Minton, J. A. et al. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations. Diabetes 51, 1287–1290 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Sandhu, M. S. et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat. Genet. 39, 951–953 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cheurfa, N. et al. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study. Diabetologia 54, 554–562 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Pennacchio, L. A. & Visel, A. Limits of sequence and functional conservation. Nat. Genet. 42, 557–558 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Article  CAS  Google Scholar 

  120. Bernstein, B. E. et al. The NIH roadmap epigenomics mapping consortium. Nat. Biotechnol. 28, 1045–1048 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pasquali, L. et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014). This study unravelled that DNA variation at islet enhancers plays a role in the genetic predisposition to T2DM and provides a reference cis-regulatory map for ongoing efforts to dissect the transcriptional program of pancreatic β-cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Parker, S. C. et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl Acad. Sci. USA 110, 17921–17926 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Gaulton, K. J. et al. A map of open chromatin in human pancreatic islets. Nat. Genet. 42, 255–259 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bhandare, R. et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 20, 428–433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fogarty, M. P., Panhuis, T. M., Vadlamudi, S., Buchkovich, M. L. & Mohlke, K. L. Allele-specific transcriptional activity at type 2 diabetes-associated single nucleotide polymorphisms in regions of pancreatic islet open chromatin at the JAZF1 locus. Diabetes 62, 1756–1762 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Fogarty, M. P., Cannon, M. E., Vadlamudi, S., Gaulton, K. J. & Mohlke, K. L. Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus. PLoS Genet. 10, e1004633 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kulzer, J. R. et al. A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am. J. Hum. Genet. 94, 186–197 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Horikoshi, M. et al. Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms. Hum. Mol. Genet. 25, 2070–2081 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Greenwald, W. W. et al. Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk. Nat. Commun. 10, 2078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Miguel-Escalada, I. et al. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nat. Genet. 51, 1137–1148 (2019). This study resolved 3D chromatin contact maps in human islet cells allowing the identification of promoter targets of distal regulatory elements at T2DM and fasting glucose GWAS loci.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S. & Orban, T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 359, 2849–2850 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Aly, T. A. et al. Extreme genetic risk for type 1A diabetes. Proc. Natl Acad. Sci. USA 103, 14074–14079 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Winkler, C. et al. Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes. Diabetologia 57, 2521–2529 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Oram, R. A. et al. A type 1 diabetes genetic risk score can aid discrimination between type 1 and type 2 diabetes in young adults. Diabetes Care 39, 337–344 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Bonifacio, E. et al. Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: a prospective study in children. PLoS Med. 15, e1002548 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Sharp, S. A. et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care 42, 200–207 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Le Stunff, C., Fallin, D., Schork, N. J. & Bougneres, P. The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat. Genet. 26, 444–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15, 289–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Farh, K. K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Alasoo, K. et al. Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response. Nat. Genet. 50, 424–431 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chun, S. et al. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat. Genet. 49, 600–605 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Eizirik, D. L., Cardozo, A. K. & Cnop, M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Pirot, P. et al. Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs. Diabetologia 50, 1006–1014 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Tersey, S. A. et al. Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 61, 818–827 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Engin, F. et al. Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes. Sci. Transl Med. 5, 211ra156 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Brozzi, F. & Eizirik, D. L. ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Ups. J. Med. Sci. 121, 133–139 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Eizirik, D. L., Miani, M. & Cardozo, A. K. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56, 234–241 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Morita, S. et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab. 25, 883–897 e888 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ghosh, R. et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158, 534–548 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Brozzi, F. et al. A combined “omics” approach identifies N-myc interactor as a novel cytokine-induced regulator of IRE1α protein and c-Jun N-terminal kinase in pancreatic β cells. J. Biol. Chem. 289, 20677–20693 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Brozzi, F. et al. Ubiquitin D regulates IRE1α/c-Jun N-terminal kinase (JNK) protein-dependent apoptosis in pancreatic beta cells. J. Biol. Chem. 291, 12040–12056 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hagerkvist, R., Sandler, S., Mokhtari, D. & Welsh, N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of β-cell NF-κB activation and anti-apoptotic preconditioning. FASEB J. 21, 618–628 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01781975 (2013).

  156. Marre, M. L., James, E. A. & Piganelli, J. D. β cell ER stress and the implications for immunogenicity in type 1 diabetes. Front. Cell Dev. Biol. 3, 67 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Kracht, M. J. et al. Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat. Med. 23, 501–507 (2017). Relevant evidence that β-cell stress modifies ribosomal processing of human insulin mRNA-generating neoantigens.

    Article  CAS  PubMed  Google Scholar 

  158. Vomund, A. N. et al. Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc. Natl Acad. Sci. USA 112, E5496–E5502 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Laybutt, D. R. et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50, 752–763 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Huang, C. J. et al. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated β-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56, 2016–2027 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Hartman, M. G. et al. Role for activating transcription factor 3 in stress-induced β-cell apoptosis. Mol. Cell Biol. 24, 5721–5732 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hull, R. L. et al. Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress. Diabetologia 52, 1102–1111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Engin, F., Nguyen, T., Yermalovich, A. & Hotamisligil, G. S. Aberrant islet unfolded protein response in type 2 diabetes. Sci. Rep. 4, 4054 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Marchetti, P. et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 50, 2486–2494 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Chan, J. Y., Luzuriaga, J., Bensellam, M., Biden, T. J. & Laybutt, D. R. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes. Diabetes 62, 1557–1568 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Biden, T. J., Boslem, E., Chu, K. Y. & Sue, N. Lipotoxic endoplasmic reticulum stress, β cell failure, and type 2 diabetes mellitus. Trends Endocrinol. Metab. 25, 389–398 (2014).

    Article  CAS  PubMed  Google Scholar 

  167. Elouil, H. et al. Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets. Diabetologia 50, 1442–1452 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Lipson, K. L. et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4, 245–254 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Cunha, D. A. et al. Initiation and execution of lipotoxic ER stress in pancreatic β-cells. J. Cell Sci. 121, 2308–2318 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Cunha, D. A. et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes 61, 2763–2775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cnop, M. et al. Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis. J. Biol. Chem. 282, 3989–3997 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Ladrière, L. et al. Enhanced signaling downstream of ribonucleic acid-activated protein kinase-like endoplasmic reticulum kinase potentiates lipotoxic endoplasmic reticulum stress in human islets. J. Clin. Endocrinol. Metab. 95, 1442–1449 (2010).

    Article  CAS  PubMed  Google Scholar 

  173. Abdulkarim, B. et al. Guanabenz sensitizes pancreatic β cells to lipotoxic endoplasmic reticulum stress and apoptosis. Endocrinology 158, 1659–1670 (2017).

    Article  CAS  PubMed  Google Scholar 

  174. Abdulkarim, B. et al. A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Diabetes 64, 3951–3962 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  176. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Skopkova, M. et al. EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum. Mutat. 38, 409–425 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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).

    Article  CAS  PubMed  Google Scholar 

  180. Valero, R., Bannwarth, S., Roman, S., Paquis-Flucklinger, V. & Vialettes, B. Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene. Diabet. Med. 25, 657–661 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Bonnycastle, L. L. et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes 62, 3943–3950 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Bensellam, M., Jonas, J. C. & Laybutt, D. R. Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions. J. Endocrinol. 236, R109–R143 (2018).

    Article  PubMed  Google Scholar 

  183. Brozzi, F. et al. Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia 58, 2307–2316 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02218619 (2014).

  185. Xiao, C., Giacca, A. & Lewis, G. F. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and β-cell dysfunction in humans. Diabetes 60, 918–924 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Plaisier, S. B., Taschereau, R., Wong, J. A. & Graeber, T. G. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 38, e169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Colli, ULB Center for Diabetes Research, for preparing Fig. 1 and M. Ramos-Rodríguez, IGTP, for preparing part of Fig. 2. D.L.E. acknowledges the support of a grant from the Welbio-FNRS (Fonds National de la Recherche Scientifique), Belgium, the Dutch Diabetes Fonds (DDFR), Holland, and start up-funds from the Indiana Biosciences Research Institute (IBRI), Indianapolis, Indiana, USA. D.L.E. and M.C. acknowledge the support of joint grants from the European Union’s Horizon 2020 research and innovation programme, project T2DSystems, under grant agreement No 667191; Brussels Capital Region-Innoviris project Diatype; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA), supported by the European Union’s Horizon 2020 research and innovation programme, and EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust; and the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No. 115881, supported by the European Union’s Horizon 2020 Research and Innovation Programme, EFPIA and the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 16.0097. M.C. acknowledges the support of the FNRS, Belgium. L.P. acknowledges the support of grants from the Spanish Ministry of Economy and Competitiveness (SAF2017-86242-R), Marató TV3 (201624.10), EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research and the further support of ISCIII (PIE16/00011).

Review criteria

Relevant publications were identified by searching the PubMed database (Jan 1, 2005 to October 30, 2019) using combinations of the following terms: “pancreatic beta cells”, “pancreatic islets”, “insulin release”, “insulin secretion”, “diabetes”, “type 1 diabetes”, “type 2 diabetes”, “pathogenesis”, “histology”, “transcriptome”, “genetics”, “candidate genes”, “islet gene regulation”, “islet epigenomics”, “endoplasmic reticulum stress” and “apoptosis”. We preferentially selected publications in the past 5 years, plus earlier key publications for citation. A manual search of some references cited in these papers or in relevant articles related to the role of pancreatic β-cells in the pathogenesis of diabetes was also done. All selected papers were English-language, full-text articles. Review articles are often cited to provide the readers with additional references. Many of the references identified could not be included owing to space restrictions.

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Authors and Affiliations

  1. ULB Center for Diabetes Research, Welbio Investigator, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

    Décio L. Eizirik

  2. Indiana Biosciences Research Institute (IBRI), Indianapolis, IN, USA

    Décio L. Eizirik

  3. Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, Barcelona, Spain

    Lorenzo Pasquali

  4. Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain

    Lorenzo Pasquali

  5. Josep Carreras Leukaemia Research Institute, Barcelona, Spain

    Lorenzo Pasquali

  6. ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium

    Miriam Cnop

  7. Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium

    Miriam Cnop

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  1. Décio L. Eizirik
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  2. Lorenzo Pasquali
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  3. Miriam Cnop
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The authors contributed equally to all aspects of the article.

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Correspondence to Décio L. Eizirik, Lorenzo Pasquali or Miriam Cnop.

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Nature Reviews Endocrinology thanks F. Urano, A. Zaldumbide and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

INNODIA: https://www.innodia.eu/

Rhapsody: https://imi-rhapsody.eu/

TIGER (the Translational Human Pancreatic Islet Genotype Tissue-Expression Resource): http://tiger.bsc.es/

Glossary

Neoantigens

Antigens that have not been previously presented or recognized by the immune system. They can be formed as a result in changes in transcription, translation or post-translational events.

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Eizirik, D.L., Pasquali, L. & Cnop, M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16, 349–362 (2020). https://doi.org/10.1038/s41574-020-0355-7

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