CoChat
Sign Up
Cited by 116Pancreatic function and diabetesEndoplasmic Reticulum Stress and DiseaseDiabetes and associated disorders

Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Open access
Chen, Chien-Wen, Guan, Bo-Jhih, Alzahrani, Mohammed R., Gao, Zhaofeng, Gao, Long, Bracey, Syrena, Wu, Jing, Mbow, Cheikh A. +14 more·2022·Nature Communications
DOI 10.1038/s41467-022-32425-7PMC PMC9360004

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-022-32425-7

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inflammatory cytokines, hypoxia, and hyperglycemia can all induce an ER stress response in β cells that leads to cell dysfunction and apoptosis.

    “Inflammatory cytokines, hypoxia, and hyperglycemia can all induce an ER stress response in β cells that leads to cell dysfunction and apoptosis.”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [128]

    The Introduction says inflammation can elicit severe ER stress in β-cells and that chronic, unresolved stress can produce a maladaptive response. The Discussion also identifies cytokines as a possible source of ER stress, but says the study did not mimic hyperglycemia or cytokine action; our copy does not identify hypoxia as a trigger or show that each named trigger leads to both dysfunction and apoptosis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 129 · Cited by 116

Research works printed but not linked: 84

  1. [1]Scheuner D Kaufman RJ The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes Endocr. Rev. 2008 29 317 333 10.1210/er.2007-0039 18436705 PMC2528859 · DOI
  2. [2]Eizirik DL Cnop M ER stress in pancreatic beta cells: the thin red line between adaptation and failure Sci. Signal. 2010 3 pe7 10.1126/scisignal.3110pe7 20179270 · DOI
  3. [4]Ron D Walter P Signal integration in the endoplasmic reticulum unfolded protein response Nat. Rev. Mol. cell Biol. 2007 8 519 529 10.1038/nrm2199 17565364 · DOI
  4. [5]Krokowski D A self-defeating anabolic program leads to beta-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux J. Biol. Chem. 2013 288 17202 17213 10.1074/jbc.M113.466920 23645676 PMC3682525 · DOI
  5. [6]Walter P Ron D The unfolded protein response: from stress pathway to homeostatic regulation Science 2011 334 1081 1086 10.1126/science.1209038 22116877 · DOI
  6. [7]Stamateris RE Sharma RB Hollern DA Alonso LC Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression. American journal of physiology Endocrinol. Metab. 2013 305 E149 E159 PMC3725565 23673159
  7. [8]Han D IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates Cell 2009 138 562 575 10.1016/j.cell.2009.07.017 19665977 PMC2762408 · DOI
  8. [9]Morita S Targeting ABL-IRE1alpha Signaling Spares ER-Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes Cell Metab. 2017 25 1207 10.1016/j.cmet.2017.04.026 28467938 · DOI
  9. [10]Arunagiri A Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes Ann. N. Y. Acad. Sci. 2018 1418 5 19 10.1111/nyas.13531 29377149 PMC5934315 · DOI
  10. [11]Arunagiri, A. et al. Proinsulin misfolding is an early event in the progression to type 2 diabetes. eLife8, 10.7554/eLife.44532 (2019). PMC6559786 31184302 · DOI
  11. [12]Back SH Kaufman RJ Endoplasmic reticulum stress and type 2 diabetes Annu. Rev. Biochem. 2012 81 767 793 10.1146/annurev-biochem-072909-095555 22443930 PMC3684428 · DOI
  12. [13]Eizirik DL Pasquali L Cnop M Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure Nat. Rev. Endocrinol. 2020 16 349 362 10.1038/s41574-020-0355-7 32398822 · DOI · Paper page
  13. [14]Engin F ER stress and development of type 1 diabetes J. investigative Med.: Off. Publ. Am. Federation Clin. Res. 2016 64 2 6 10.1097/JIM.0000000000000229 PMC7185224 26230493 · DOI
  14. [15]Engin F Nguyen T Yermalovich A Hotamisligil GS Aberrant islet unfolded protein response in type 2 diabetes Sci. Rep. 2014 4 4054 10.1038/srep04054 24514745 PMC3920274 · DOI
  15. [16]Lee H Beta Cell Dedifferentiation Induced by IRE1alpha Deletion Prevents Type 1 Diabetes Cell Metab. 2020 31 822 836 e825 10.1016/j.cmet.2020.03.002 32220307 PMC7346095 · DOI · Paper page
  16. [17]Ozcan U Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes Science 2004 306 457 461 10.1126/science.1103160 15486293 · DOI · Paper page
  17. [18]Sims EK Mirmira RG Evans-Molina C The role of beta-cell dysfunction in early type 1 diabetes Curr. Opin. Endocrinol., diabetes, Obes. 2020 27 215 224 10.1097/MED.0000000000000548 32618633 PMC7365587 · DOI
  18. [19]Harding HP Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival Mol. cell 2001 7 1153 1163 10.1016/S1097-2765(01)00264-7 11430819 · DOI
  19. [20]Sahin GS Lee H Engin F An accomplice more than a mere victim: The impact of beta-cell ER stress on type 1 diabetes pathogenesis Mol. Metab. 2021 54 101365 10.1016/j.molmet.2021.101365 34728341 PMC8606542 · DOI
  20. [21]Zhang K Kaufman RJ The unfolded protein response: a stress signaling pathway critical for health and disease Neurology 2006 66 S102 S109 10.1212/01.wnl.0000192306.98198.ec 16432136 · DOI
  21. [22]Guan BJ A Unique ISR Program Determines Cellular Responses to Chronic Stress Mol. cell 2017 68 885 900 e886 10.1016/j.molcel.2017.11.007 29220654 PMC5730339 · DOI
  22. [23]Abdullahi A Stanojcic M Parousis A Patsouris D Jeschke MG Modeling Acute ER Stress in Vivo and in Vitro Shock 2017 47 506 513 10.1097/SHK.0000000000000759 27755507 PMC5348263 · DOI
  23. [24]Gomez, J. A. & Rutkowski, D. T. Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression. eLife5, 10.7554/eLife.20390 (2016). PMC5179193 27938665 · DOI
  24. [25]Schneider K Protein Stability Buffers the Cost of Translation Attenuation following eIF2alpha Phosphorylation Cell Rep. 2020 32 108154 10.1016/j.celrep.2020.108154 32937139 PMC7495045 · DOI
  25. [26]Zhang X Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy Autophagy 2014 10 1801 1813 10.4161/auto.32136 25126734 PMC4198364 · DOI
  26. [27]Bommiasamy H Popko B Animal models in the study of the unfolded protein response Methods Enzymol. 2011 491 91 109 10.1016/B978-0-12-385928-0.00006-7 21329796 PMC6312104 · DOI
  27. [28]Yoshioka M Kayo T Ikeda T Koizumi A A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice Diabetes 1997 46 887 894 10.2337/diab.46.5.887 9133560 · DOI
  28. [29]You, K. et al. QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis. Science371, (2021). PMC8315080 33384352
  29. [30]Holm LJ Abnormal islet sphingolipid metabolism in type 1 diabetes Diabetologia 2018 61 1650 1661 10.1007/s00125-018-4614-2 29671030 PMC6445476 · DOI
  30. [31]Trembath, A. P. et al. NKG2D Signaling Within the Pancreatic Islets Reduces NOD Diabetes and Increases Protective Central Memory CD8(+) T-Cell Numbers. Diabetes69, 1749–1762 (2020). PMC7372071 32535552
  31. [32]Ishihara H Pancreatic beta cell line MIN6 exhibits characteristics of glucose metabolism and glucose-stimulated insulin secretion similar to those of normal islets Diabetologia 1993 36 1139 1145 10.1007/BF00401058 8270128 · DOI
  32. [33]Miyazaki J Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms Endocrinology 1990 127 126 132 10.1210/endo-127-1-126 2163307 · DOI
  33. [34]Moncoq K Trieber CA Young HS The molecular basis for cyclopiazonic acid inhibition of the sarcoplasmic reticulum calcium pump J. Biol. Chem. 2007 282 9748 9757 10.1074/jbc.M611653200 17259168 · DOI
  34. [35]Lytton J Westlin M Hanley MR Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps J. Biol. Chem. 1991 266 17067 17071 10.1016/S0021-9258(19)47340-7 1832668 · DOI
  35. [36]Novoa I Stress-induced gene expression requires programmed recovery from translational repression EMBO J. 2003 22 1180 1187 10.1093/emboj/cdg112 12606582 PMC150345 · DOI
  36. [37]Fumagalli F Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery Nat. cell Biol. 2016 18 1173 1184 10.1038/ncb3423 27749824 · DOI
  37. [38]Reid DW Chen Q Tay AS Shenolikar S Nicchitta CV The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum Cell 2014 158 1362 1374 10.1016/j.cell.2014.08.012 25215492 PMC4163055 · DOI
  38. [39]Haataja L Proinsulin intermolecular interactions during secretory trafficking in pancreatic beta cells J. Biol. Chem. 2013 288 1896 1906 10.1074/jbc.M112.420018 23223446 PMC3548498 · DOI
  39. [40]Sims EK Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes Diabetes care 2019 42 258 264 10.2337/dc17-2625 30530850 PMC6341288 · DOI
  40. [41]Liu M Biosynthesis, structure, and folding of the insulin precursor protein Diabetes, Obes. Metab. 2018 20 Suppl 2 28 50 10.1111/dom.13378 30230185 PMC6463291 · DOI
  41. [42]Reaven GM Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance J. Clin. Endocrinol. Metab. 1993 76 44 48 8421101
  42. [43]Rupprecht KR Development of a dot-blot assay for screening monoclonal antibodies to low-molecular-mass drugs Anal. Biochem. 2010 407 160 164 10.1016/j.ab.2010.08.003 20696124 · DOI
  43. [45]Ingolia NT Ghaemmaghami S Newman JR Weissman JS Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling Science 2009 324 218 223 10.1126/science.1168978 19213877 PMC2746483 · DOI · Paper page
  44. [46]Chen CW Tanaka M Genome-wide Translation Profiling by Ribosome-Bound tRNA Capture Cell Rep. 2018 23 608 621 10.1016/j.celrep.2018.03.035 29642016 · DOI
  45. [47]Fonseca SG WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells J. Biol. Chem. 2005 280 39609 39615 10.1074/jbc.M507426200 16195229 · DOI
  46. [49]Marchetti P Bugliani M De Tata V Suleiman M Marselli L Pancreatic Beta Cell Identity in Humans and the Role of Type 2 Diabetes Front. cell Dev. Biol. 2017 5 55 10.3389/fcell.2017.00055 28589121 PMC5440564 · DOI
  47. [50]Rutter GA Pullen TJ Hodson DJ Martinez-Sanchez A Pancreatic beta-cell identity, glucose sensing and the control of insulin secretion Biochemical J. 2015 466 203 218 10.1042/BJ20141384 25697093 · DOI
  48. [51]Nishimura W Takahashi S Yasuda K MafA is critical for maintenance of the mature beta cell phenotype in mice Diabetologia 2015 58 566 574 10.1007/s00125-014-3464-9 25500951 · DOI
  49. [52]Zhang C MafA is a key regulator of glucose-stimulated insulin secretion Mol. Cell. Biol. 2005 25 4969 4976 10.1128/MCB.25.12.4969-4976.2005 15923615 PMC1140590 · DOI
  50. [53]Guillam MT Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2 Nat. Genet. 1997 17 327 330 10.1038/ng1197-327 9354799 · DOI
  51. [54]Thorens B Guillam MT Beermann F Burcelin R Jaquet M Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion J. Biol. Chem. 2000 275 23751 23758 10.1074/jbc.M002908200 10823833 · DOI
  52. [56]Olbrot M Rud J Moss LG Sharma A Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA Proc. Natl Acad. Sci. USA 2002 99 6737 6742 10.1073/pnas.102168499 12011435 PMC124472 · DOI
  53. [57]Hoelen H Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97 PloS one 2015 10 e0128206 10.1371/journal.pone.0128206 26107514 PMC4479611 · DOI
  54. [58]Kultz D Evolution of the cellular stress proteome: from monophyletic origin to ubiquitous function J. Exp. Biol. 2003 206 3119 3124 10.1242/jeb.00549 12909693 · DOI
  55. [59]Mi H Muruganujan A Ebert D Huang X Thomas PD PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools Nucleic acids Res. 2019 47 D419 D426 10.1093/nar/gky1038 30407594 PMC6323939 · DOI
  56. [60]Eizirik DL Cardozo AK Cnop M The role for endoplasmic reticulum stress in diabetes mellitus Endocr. Rev. 2008 29 42 61 10.1210/er.2007-0015 18048764 · DOI · Paper page
  57. [61]Kaestner, K. H., Powers, A. C., Naji, A. & Atkinson, M. A. NIH Initiative to Improve Understanding of the Pancreas, Islet, and Autoimmunity in Type 1 Diabetes: The Human Pancreas Analysis Program (HPAP. Diabetes68, 1394–1402 (2019). PMC6609987 31127054
  58. [62]Campbell JE Newgard CB Mechanisms controlling pancreatic islet cell function in insulin secretion Nat. Rev. Mol. cell Biol. 2021 22 142 158 10.1038/s41580-020-00317-7 33398164 PMC8115730 · DOI
  59. [63]Katsarou A Type 1 diabetes mellitus Nat. Rev. Dis. Prim. 2017 3 17016 10.1038/nrdp.2017.16 28358037 · DOI · Paper page
  60. [66]Ji Z Ji H TSCAN: Pseudo-time reconstruction and evaluation in single-cell RNA-seq analysis Nucleic acids Res. 2016 44 e117 10.1093/nar/gkw430 27179027 PMC4994863 · DOI
  61. [67]Cao J The single-cell transcriptional landscape of mammalian organogenesis Nature 2019 566 496 502 10.1038/s41586-019-0969-x 30787437 PMC6434952 · DOI · Paper page
  62. [68]Nasteska D PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release Nat. Commun. 2021 12 674 10.1038/s41467-020-20632-z 33514698 PMC7846747 · DOI
  63. [69]Sharma RB Landa-Galvan HV Alonso LC Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic beta-Cells Diabetes 2021 70 2431 2443 10.2337/dbi20-0033 34711668 PMC8564401 · DOI
  64. [70]Gao XH Discovery of a Redox Thiol Switch: Implications for Cellular Energy Metabolism Mol. Cell. Proteom.: MCP 2020 19 852 870 10.1074/mcp.RA119.001910 PMC7196587 32132231 · DOI
  65. [71]Yadav V Hydrogen sulfide modulates eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation status in the integrated stress-response pathway J. Biol. Chem. 2017 292 13143 13153 10.1074/jbc.M117.778654 28637872 PMC5555178 · DOI
  66. [72]Xia F Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells Endocrinology 2008 149 5136 5145 10.1210/en.2008-0161 18599549 · DOI · Paper page
  67. [73]Rothman KJ Greenland S Causation and causal inference in epidemiology Am. J. public health 2005 95 Suppl 1 S144 S150 10.2105/AJPH.2004.059204 16030331 · DOI
  68. [74]Tersey SA Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model Diabetes 2012 61 818 827 10.2337/db11-1293 22442300 PMC3314371 · DOI · Paper page
  69. [75]Farack L Transcriptional Heterogeneity of Beta Cells in the Intact Pancreas Dev. Cell 2019 48 115 125 e114 10.1016/j.devcel.2018.11.001 30503750 · DOI · Paper page
  70. [76]Bennett DL Identification of the type 2 proinsulin processing endopeptidase as PC2, a member of the eukaryote subtilisin family J. Biol. Chem. 1992 267 15229 15236 10.1016/S0021-9258(18)42170-9 1634553 · DOI
  71. [77]Zhou Y RILP Restricts Insulin Secretion Through Mediating Lysosomal Degradation of Proinsulin Diabetes 2020 69 67 82 10.2337/db19-0086 31624142 · DOI
  72. [78]Tompkins LS Nullmeyer KD Murphy SM Weber CS Lynch RM Regulation of secretory granule pH in insulin-secreting cells Am. J. Physiol. Cell Physiol. 2002 283 C429 C437 10.1152/ajpcell.01066.2000 12107052 · DOI
  73. [79]Hussain SS Control of insulin granule formation and function by the ABC transporters ABCG1 and ABCA1 and by oxysterol binding protein OSBP Mol. Biol. Cell 2018 29 1238 1257 10.1091/mbc.E17-08-0519 29540530 PMC5935073 · DOI
  74. [80]Wijesekara N Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion Diabetologia 2010 53 1656 1668 10.1007/s00125-010-1733-9 20424817 PMC6101216 · DOI
  75. [81]Fehmann HC Habener JF Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells Endocrinology 1991 128 2880 2888 10.1210/endo-128-6-2880 1645253 · DOI
  76. [82]Koufakis T First Report of Diabetes Phenotype due to a Loss-of-Function ABCC8 Mutation Previously Known to Cause Congenital Hyperinsulinism Case Rep. Genet. 2019 2019 3654618 31110826 PMC6487141
  77. [83]Leon C The P2Y(1) receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice Purinergic Signal. 2005 1 145 151 10.1007/s11302-005-6209-x 18404499 PMC2096536 · DOI
  78. [84]Jiang L Potential of protein phosphatase inhibitor 1 as biomarker of pancreatic beta-cell injury in vitro and in vivo Diabetes 2013 62 2683 2688 10.2337/db12-1507 23557701 PMC3717856 · DOI
  79. [85]Sharma AK Secretagogin Regulates Insulin Signaling by Direct Insulin Binding iScience 2019 21 736 753 10.1016/j.isci.2019.10.066 31734536 PMC6864339 · DOI
  80. [86]Huang C Synaptotagmin 4 Regulates Pancreatic beta Cell Maturation by Modulating the Ca(2+) Sensitivity of Insulin Secretion Vesicles Dev. Cell 2018 45 347 361 e345 10.1016/j.devcel.2018.03.013 29656931 PMC5962294 · DOI
  81. [87]Pugliese A New insight on human type 1 diabetes biology: nPOD and nPOD-transplantation Curr. Diabetes Rep. 2014 14 530 10.1007/s11892-014-0530-0 PMC4174350 25142715 · DOI
  82. [89]Muraro MJ A Single-Cell Transcriptome Atlas of the Human Pancreas Cell Syst. 2016 3 385 394 e383 10.1016/j.cels.2016.09.002 27693023 PMC5092539 · DOI
  83. [91]Katanik J Measuring gluconeogenesis using a low dose of 2H2O: advantage of isotope fractionation during gas chromatography. American journal of physiology Endocrinol. Metab. 2003 284 E1043 E1048 12582010
  84. [92]Langmead B Salzberg SL Fast gapped-read alignment with Bowtie 2 Nat. Methods 2012 9 357 359 10.1038/nmeth.1923 22388286 PMC3322381 · DOI · Paper page

Authors
Chen, C.-W., Guan, B.-J., Alzahrani, M. R., Gao, Z., Gao, L., Bracey, S., Wu, J., Mbow, C. A., Jobava, R., Haataja, L., Zalavadia, A. H., Schaffer, A. E., Lee, H., LaFramboise, T., Bederman, I., Arvan, P., Mathews, C. E., Gerling, I. C., Kaestner, K. H., Tirosh, B., Engin, F., & Hatzoglou, M.
Affiliations
  • Case Western Reserve University (US)
  • University of Pennsylvania (US)
  • University of Michigan (US)
  • Cleveland Clinic (US)
  • University of Wisconsin–Madison (US)
  • University of Florida Health (US)
  • University of Tennessee Health Science Center (US)
  • Hebrew University of Jerusalem (IL)
Corresponding author
  • Chen, Chien-Wen
  • Engin, Feyza
  • Hatzoglou, Maria
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-08-08
Volume
13
Issue
1
Pages
4621-4621
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-32425-7
PMC
PMC9360004
OpenAlex
W4290653248
Cited by
116
References
129
Citations by year
2026: 32 · 2025: 36 · 2024: 25 · 2023: 18 · 2022: 2 · 2021: 2
FWCI
19.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Pennsylvania
  • Human Islet Research Network (U01-DK-123594, RRID: SCR_014393, UC4-DK-112217, SCR_014393, U01-DK-123716, UC4-DK-112232)
  • National Institutes of Health (1uc4dk112217-01, 1uc4dk104155-01)
  • National Cancer Institute (R01CA217992)
  • National Institute of General Medical Sciences (T32GM007250)
  • National Institute of Diabetes and Digestive and Kidney Diseases (UC4-DK-104155, UC4-DK-112217, U01DK127747, R56DK128136, U01DK123716, R01DK111174, R01DK053307, UC4DK112232, R37DK060596, R01DK048280, P30DK020572, U01DK123594, U01DK112217, R01DK130919, R01DK060596)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
endoplasmic reticulum stress, pancreatic beta cells, beta-cell identity, beta cell plasticity, type 1 diabetes, islets, beta-cell exhaustion, insulin secretion
MeSH terms
Cell Plasticity, Adaptation, Physiological, Endoplasmic Reticulum, Humans, Insulin, Insulin-Secreting Cells, Endoplasmic Reticulum Stress

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review