Advertisement

Current Diabetes Reports

, 18:124 | Cite as

Pancreas Pathology During the Natural History of Type 1 Diabetes

  • Teresa Rodriguez-Calvo
  • Sarah J. Richardson
  • Alberto Pugliese
Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of Type 1 Diabetes

Abstract

Purpose of review

We provide an overview of pancreas pathology in type 1 diabetes (T1D) in the context of its clinical stages.

Recent findings

Recent studies of pancreata from organ donors with T1D and non-diabetic donors expressing T1D-associated autoantibodies reveal pathological changes/disease mechanisms beyond the well-known loss of β cells and lymphocytic infiltrates of the islets (insulitis), including β-cell stress, dysfunction, and viral infections. Pancreas pathology evolves through disease stages, is asynchronous, and demonstrates a chronic disease that remains active years after diagnosis. Critically, β-cell loss is not complete at onset, although young age is associated with increased severity.

Summary

The recognition of multiple pathogenic alterations and the chronic nature of disease mechanisms during and after the development of T1D inform improved clinical trial design and reveal additional targets for therapeutic manipulation, in the context of an expanded time window for intervention.

Keywords

Type 1 diabetes Insulitis β cell Pancreas Islet autoimmunity 

Abbreviations

AAb+

Autoantibody positive

EADB

Exeter Archival Diabetes Biobank

ER

Endoplasmic reticulum

DiViD

Diabetes Virus Detection Study

GAD

Glutamic acid decarboxylase

HA

Hyaluronan

HLAI

Human leukocyte antigen class I

IA-2

Islet antigen-2

ICI

Insulin-containing islet

IDI

Insulin-deficient islet

MODY

Maturity onset diabetes of the young

NOD

Non-obese diabetic mouse

nPOD

Network for Pancreatic Organ Donors with Diabetes

T2D

Type 2 diabetes

Notes

Acknowledgments

We would like to acknowledge Dr. Pia Leete (University of Exeter, UK) for providing immunofluorescence images. We are pleased to acknowledge financial support from the European Union’s Seventh Framework Programme PEVNET (FP7/2007–2013) under grant agreement number 261441. The participants of the PEVNET consortium are described at http://www.uta.fi/med/pevnet/publications.html. Additional support was from a Diabetes Research Wellness Foundation Non-Clinical Research Fellowship and, since 2014, a JDRF Career Development Award (5-CDA-2014-221-A-N) to S.J.R., a JDRF research grant awarded to the nPOD-V consortium (JDRF 25-2012-516), which also supports T.R.-C. and A.P. Research reviewed here involves patients from the EADB, DiViD, and nPOD collections; nPOD, The Network for Pancreatic Organ Donors with Diabetes, a collaborative type 1 diabetes research project. nPOD and A.P. are supported by grants from JDRF (5-SRA-2018-557-Q-R) and The Leona M. and Barry B. Helmsley Charitable Trust (2015PG-T1D052 and 2018PG-T1D060). Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php.

Compliance with Ethical Standards

Conflict of Interest

T.R.-C., S.J.R., and A.P. declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Studies reviewed in this article involved organ donors or deceased patients (not considered human subjects from the regulatory point of view), and living patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed in the animal studies reviewed in this article.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT. Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK biobank. Lancet Diabetes Endocrinol. 2018;6(2):122–9.CrossRefGoogle Scholar
  2. 2.
    Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am. 2010;39(3):481–97.CrossRefGoogle Scholar
  3. 3.
    Pugliese A. Autoreactive T cells in type 1 diabetes. J Clin Invest. 2017;127(8):2881–91.CrossRefGoogle Scholar
  4. 4.
    Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965;14(10):619–33.CrossRefGoogle Scholar
  5. 5.
    Gepts W, De Mey J. Islet cell survival determined by morphology. An immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus. Diabetes. 1978;27(Supplement 1):251–61.CrossRefGoogle Scholar
  6. 6.
    Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia. 1986;29(5):267–74.CrossRefGoogle Scholar
  7. 7.
    Hanafusa T, Miyazaki A, Miyagawa J, Tamura S, Inada M, Yamada K, et al. Examination of islets in the pancreas biopsy specimens from newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990;33(2):105–11.CrossRefGoogle Scholar
  8. 8.
    Itoh N, Hanafusa T, Miyazaki A, Miyagawa J, Yamagata K, Yamamoto K, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest. 1993;92(5):2313–22.CrossRefGoogle Scholar
  9. 9.
    Krogvold L, Edwin B, Buanes T, Ludvigsson J, Korsgren O, Hyoty H, 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. 2014;57(4):841–3.CrossRefGoogle Scholar
  10. 10.
    Atkinson MA. Pancreatic biopsies in type 1 diabetes: revisiting the myth of Pandora’s box. Diabetologia. 2014;57(4):656–9.CrossRefGoogle Scholar
  11. 11.
    Pugliese A, Yang M, Kusmarteva I, Heiple T, Vendrame F, Wasserfall C, et al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr Diabetes. 2014;15(1):1–9.CrossRefGoogle Scholar
  12. 12.
    • Krogvold L, Wiberg A, Edwin B, Buanes T, Jahnsen FL, Hanssen KF, et al. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia. 2016;59(3):492–501. This article reports obtaining pancreas tail biopsies from living patients with new onset T1D in the DiViD study. CrossRefGoogle Scholar
  13. 13.
    Lecompte PM. Insulitis in early juvenile diabetes. AMA Arch Pathol. 1958;66(4):450–7.PubMedGoogle Scholar
  14. 14.
    Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2(7892):1279–83.CrossRefGoogle Scholar
  15. 15.
    Foulis AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987;30(5):333–43.CrossRefGoogle Scholar
  16. 16.
    Pujol-Borrell R, Todd I, Londei M, Foulis A, Feldmann M, Bottazzo GF. Inappropriate major histocompatibility complex class II expression by thyroid follicular cells in thyroid autoimmune disease and by pancreatic beta cells in type I diabetes. Mol Biol Med. 1986;3(2):159–65.PubMedGoogle Scholar
  17. 17.
    Bottazzo GF, Dean BM, McNally JM, Mackay EH, Swift PGF, Gamble DR. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. New Engl J Med. 1985;313:353–60.CrossRefGoogle Scholar
  18. 18.
    In't Veld P. Insulitis in human type 1 diabetes: the quest for an elusive lesion. Islets. 2011;3(4):131–8.CrossRefGoogle Scholar
  19. 19.
    Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. ClinexpImmunol. 2009;155(2):173–81.Google Scholar
  20. 20.
    • Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et al. Insulitis and beta-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–31. The study reports the characterization of insulitis and β-cell mass in nPOD donors across a spectrum of ages and disease duration. CrossRefGoogle Scholar
  21. 21.
    Campbell-Thompson ML, Atkinson MA, Butler AE, Chapman NM, Frisk G, Gianani R, et al. The diagnosis of insulitis in human type 1 diabetes. Diabetologia. 2013;56(11):2541–3.CrossRefGoogle Scholar
  22. 22.
    •• Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012;209(1):51–60. This study of nPOD donors demonstrates that islet-infiltrating CD8 + T cells are autoreactive. CrossRefGoogle Scholar
  23. 23.
    • Leete P, Willcox A, Krogvold L, Dahl-Jorgensen K, Foulis AK, Richardson SJ, et al. Differential insulitic profiles determine the extent of beta-cell destruction and the age at onset of type 1 diabetes. Diabetes. 2016;65(5):1362–9. Study of the EADB cohort reporting different insulitis profiles according to the abundance of CD20 + B lymphocytes. CrossRefGoogle Scholar
  24. 24.
    Morgan NG. Bringing the human pancreas into focus: new paradigms for the understanding of type 1 diabetes. Diabet Med. 2017;34(7):879–86.CrossRefGoogle Scholar
  25. 25.
    Klinke DJ. Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans. PLoS One. 2011;6(11):e26873.CrossRefGoogle Scholar
  26. 26.
    Klinke DJ. Extent of beta cell destruction is important but insufficient to predict the onset of type 1 diabetes mellitus. PLoS One. 2008;3(1):e1374.CrossRefGoogle Scholar
  27. 27.
    • Shields BM, McDonald TJ, Oram R, Hill A, Hudson M, Leete P, et al. C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care, 2018. 41(7):1486–92. This study reports that loss of C-peptide plateaus 7 years after diagnosis, with implications for future interventions and correlations with pathology findings. CrossRefGoogle Scholar
  28. 28.
    • Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, et al. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia. 2016;59(11):2448–58. Joint study of the EADB, nPOD, and DiViD cohort defines hyperexpression of HLA class I molecules as a defining feature of T1D pathology using a multitude of methodologies. CrossRefGoogle Scholar
  29. 29.
    Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, et al. Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia. 2012;55(9):2417–20.CrossRefGoogle Scholar
  30. 30.
    • Krogvold L, Edwin B, Buanes T, Frisk G, Skog O, Anagandula M, et al. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes. 2015;64(5):1682–7. DiViD study reporting evidence for low-grade enterovirus infections in the pancreas from patients with recent onset T1D. CrossRefGoogle Scholar
  31. 31.
    de Beeck AO, Eizirik DL. Viral infections in type 1 diabetes mellitus—why the beta cells? Nat Rev Endocrinol. 2016;12(5):263–73.CrossRefGoogle Scholar
  32. 32.
    Bogdani M. Thinking outside the cell: a key role for hyaluronan in the pathogenesis of human type 1 diabetes. Diabetes. 2016;65(8):2105–14.CrossRefGoogle Scholar
  33. 33.
    Morgan NG, Leete P, Foulis AK, Richardson SJ. Islet inflammation in human type 1 diabetes mellitus. IUBMB Life. 2014;66(11):723–34.CrossRefGoogle Scholar
  34. 34.
    Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009;52(6):1143–51.CrossRefGoogle Scholar
  35. 35.
    Kundu R, Knight R, Dunga M, Peakman M. In silico and ex vivo approaches indicate immune pressure on capsid and non-capsid regions of coxsackie B viruses in the human system. PLoS One. 2018;13(6):e0199323.CrossRefGoogle Scholar
  36. 36.
    Bogdani M, Johnson PY, Potter-Perigo S, Nagy N, Day AJ, Bollyky PL, et al. Hyaluronan and hyaluronan binding proteins accumulate in both human type 1 diabetic islets and lymphoid tissues and associate with inflammatory cells in insulitis. Diabetes. 2014;27Google Scholar
  37. 37.
    Kuipers HF, Rieck M, Gurevich I, Nagy N, Butte MJ, Negrin RS, et al. Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization. Proc Natl Acad Sci U S A. 2016;113(5):1339–44.CrossRefGoogle Scholar
  38. 38.
    Nagy N, Kaber G, Johnson PY, Gebe JA, Preisinger A, Falk BA, et al. Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest. 2015;125(10):3928–40.CrossRefGoogle Scholar
  39. 39.
    Korpos E, Kadri N, Kappelhoff R, Wegner J, Overall CM, Weber E, et al. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes. 2013;62(2):531–42.CrossRefGoogle Scholar
  40. 40.
    Bogdani M, Korpos E, Simeonovic CJ, Parish CR, Sorokin L, Wight TN. Extracellular matrix components in the pathogenesis of type 1 diabetes. Curr Diab Rep. 2014;14(12):552.CrossRefGoogle Scholar
  41. 41.
    Simeonovic CJ, Popp SK, Starrs LM, Brown DJ, Ziolkowski AF, Ludwig B, et al. Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLoS One. 2018;13(2):e0191360.CrossRefGoogle Scholar
  42. 42.
    Richardson SJ, Morgan NG. Enteroviral infections in the pathogenesis of type 1 diabetes: new insights for therapeutic intervention. Curr Opin Pharmacol. 2018;43:11–9.CrossRefGoogle Scholar
  43. 43.
    Morgan NG, Richardson SJ. Enteroviruses as causative agents in type 1 diabetes: loose ends or lost cause? Trends Endocrinol Metab. 2014;25(12):611–9.CrossRefGoogle Scholar
  44. 44.
    Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG. Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia. 2013;56(1):185–93.CrossRefGoogle Scholar
  45. 45.
    Gallagher GR, Brehm MA, Finberg RW, Barton BA, Shultz LD, Greiner DL, et al. Viral infection of engrafted human islets leads to diabetes. Diabetes. 2015;64(4):1358–69.CrossRefGoogle Scholar
  46. 46.
    Kim KW, Ho A, Alshabee-Akil A, Hardikar AA, Kay TW, Rawlinson WD, et al. Coxsackievirus B5 infection induces dysregulation of microRNAs predicted to target known type 1 diabetes risk genes in human pancreatic islets. Diabetes. 2016;65(4):996–1003.CrossRefGoogle Scholar
  47. 47.
    Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013;9(1):25–53.CrossRefGoogle Scholar
  48. 48.
    Brozzi F, Eizirik DL. ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Ups J Med Sci. 2016;121(2):133–9.CrossRefGoogle Scholar
  49. 49.
    Marroqui L, Lopes M, dos Santos RS, Grieco FA, Roivainen M, Richardson SJ, et al. Differential cell autonomous responses determine the outcome of coxsackievirus infections in murine pancreatic alpha and beta cells. elife. 2015;4:e06990.CrossRefGoogle Scholar
  50. 50.
    Eizirik DL, Coomans de Brachene A. Checks and balances—the limits of beta-cell endurance to ER stress. Diabetes. 2017;66(6):1467–9.CrossRefGoogle Scholar
  51. 51.
    Eizirik DL, Miani M, Cardozo AK. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia. 2013;56(2):234–41.CrossRefGoogle Scholar
  52. 52.
    Sims EK, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F, et al. Elevations in the fasting serum proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. Diabetes Care. 2016;39(9):1519–26.CrossRefGoogle Scholar
  53. 53.
    Krogvold L, Skog O, Sundstrom G, Edwin B, Buanes T, Hanssen KF, 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. 2015;64(7):2506–12.CrossRefGoogle Scholar
  54. 54.
    Burch TC, Morris MA, Campbell-Thompson M, Pugliese A, Nadler JL, Nyalwidhe JO. Proteomic analysis of disease stratified human pancreas tissue indicates unique signature of type 1 diabetes. PLoS One. 2015;10(8):e0135663.CrossRefGoogle Scholar
  55. 55.
    Grzesik WJ, Nadler JL, Machida Y, Nadler JL, Imai Y, Morris MA. Expression pattern of 12-lipoxygenase in human islets with type 1 diabetes and type 2 diabetes. J Clin Endocrinol Metab. 2015;100(3):E387–95.CrossRefGoogle Scholar
  56. 56.
    Imai Y, Dobrian AD, Morris MA, Taylor-Fishwick DA, Nadler JL. Lipids and immunoinflammatory pathways of beta cell destruction. Diabetologia. 2016;59(4):673–8.CrossRefGoogle Scholar
  57. 57.
    Holm LJ, Krogvold L, Hasselby JP, Kaur S, Claessens LA, Russell MA, et al. Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia. 2018;61(7):1650–61.CrossRefGoogle Scholar
  58. 58.
    Nyalwidhe JO, Grzesik WJ, Burch TC, Semeraro ML, Waseem T, Gerling IC, et al. Comparative quantitative proteomic analysis of disease stratified laser captured microdissected human islets identifies proteins and pathways potentially related to type 1 diabetes. PLoS One. 2017;12(9):e0183908.CrossRefGoogle Scholar
  59. 59.
    Marre ML, James EA, Piganelli JD. beta cell ER stress and the implications for immunogenicity in type 1 diabetes. Front Cell Dev Biol. 2015;3:67.CrossRefGoogle Scholar
  60. 60.
    Phelps EA, Cianciaruso C, Michael IP, Pasquier M, Kanaani J, Nano R, et al. Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of ER stress and autoimmunity. Diabetes. 2016;65(9):2686–99.CrossRefGoogle Scholar
  61. 61.
    Campbell-Thompson ML, Kaddis JS, Wasserfall C, Haller MJ, Pugliese A, Schatz DA, et al. The influence of type 1 diabetes on pancreatic weight. Diabetologia. 2016;59(1):217–21.CrossRefGoogle Scholar
  62. 62.
    Campbell-Thompson M, Wasserfall C, Montgomery EL, Atkinson MA, Kaddis JS. Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA. 2012;308(22):2337–9.CrossRefGoogle Scholar
  63. 63.
    Virostko J, Hilmes M, Eitel K, Moore DJ, Powers AC. Use of the electronic medical record to assess pancreas size in type 1 diabetes. PLoS One. 2016;11(7):e0158825.CrossRefGoogle Scholar
  64. 64.
    Kondrashova A, Nurminen N, Lehtonen J, Hyoty M, Toppari J, Ilonen J, et al. Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children. Pediatr Diabetes. 2018;19(3):398–402.CrossRefGoogle Scholar
  65. 65.
    Bonnet-Serrano F, Diedisheim M, Mallone R, Larger E. Decreased alpha-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: an analysis based on the nPOD repository. PLoS One. 2018;13(1):e0191528.CrossRefGoogle Scholar
  66. 66.
    Rodriguez-Calvo T, Ekwall O, Amirian N, Zapardiel-Gonzalo J, von Herrath MG. Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes. 2014;63(11):3880–90.CrossRefGoogle Scholar
  67. 67.
    Mohapatra S, Majumder S, Smyrk TC, Zhang L, Matveyenko A, Kudva YC, et al. Diabetes mellitus is associated with an exocrine pancreatopathy: conclusions from a review of literature. Pancreas. 2016;45(8):1104–10.CrossRefGoogle Scholar
  68. 68.
    Wenzlau JM, Hutton JC. Novel diabetes autoantibodies and prediction of type 1 diabetes. Curr Diab Rep. 2013;13(5):608–15.CrossRefGoogle Scholar
  69. 69.
    Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes. 2005;54(Suppl 2):S25–31.CrossRefGoogle Scholar
  70. 70.
    Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473–9.CrossRefGoogle Scholar
  71. 71.
    Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark A, Hagopian WA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 2015;58(5):980–7.CrossRefGoogle Scholar
  72. 72.
    Sosenko JM, Skyler JS, Beam CA, Krischer JP, Greenbaum CJ, Mahon J, et al. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes. 2013;62(12):4179–83.CrossRefGoogle Scholar
  73. 73.
    Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964–74.CrossRefGoogle Scholar
  74. 74.
    •• Burke GW 3rd, Posgai AL, Wasserfall CH, Atkinson MA, Pugliese A. Raising awareness: the need to promote allocation of pancreata from rare nondiabetic donors with pancreatic islet autoimmunity to type 1 diabetes research. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2016;17(1):306–7. This article advocates for allocating pancreata from non-diabetic donors with autoantibodies to research, to help obtain organs that inform about pancreas pathology in the preclinical disease stages. CrossRefGoogle Scholar
  75. 75.
    Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, et al. Alpha cell function and gene expression are compromised in type 1 diabetes. Cell Rep. 2018;22(10):2667–76.CrossRefGoogle Scholar
  76. 76.
    Chmelova H, Cohrs CM, Chouinard JA, Petzold C, Kuhn M, Chen C, et al. Distinct roles of beta-cell mass and function during type 1 diabetes onset and remission. Diabetes. 2015;64(6):2148–60.CrossRefGoogle Scholar
  77. 77.
    Marciniak A, Cohrs CM, Tsata V, Chouinard JA, Selck C, Stertmann J, et al. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nat Protoc. 2014;9(12):2809–22.CrossRefGoogle Scholar
  78. 78.
    Gianani R, Putnam A, Still T, Yu L, Miao D, Gill RG, et al. Initial results of screening of nondiabetic organ donors for expression of islet autoantibodies. J Clin Endocrinol Metab. 2006;91(5):1855–61.CrossRefGoogle Scholar
  79. 79.
    In't Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M, et al. Screening for insulitis in adult autoantibody-positive organ donors. Diabetes. 2007;56(9):2400–4.CrossRefGoogle Scholar
  80. 80.
    Wiberg A, Granstam A, Ingvast S, Harkonen T, Knip M, Korsgren O, et al. Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies. Clin Exp Immunol. 2015;182(3):278–88.CrossRefGoogle Scholar
  81. 81.
    Rodriguez-Calvo T, Zapardiel-Gonzalo J, Amirian N, Castillo E, Lajevardi Y, Krogvold L, et al. Increase in pancreatic proinsulin and preservation of beta cell mass in autoantibody positive donors prior to type 1 diabetes onset. Diabetes. 2017;30Google Scholar
  82. 82.
    Rodriguez-Calvo T, Suwandi JS, Amirian N, Zapardiel-Gonzalo J, Anquetil F, Sabouri S, et al. Heterogeneity and lobularity of pancreatic pathology in type 1 diabetes during the prediabetic phase. J Histochem Cytochem. 2015;63(8):626–36.CrossRefGoogle Scholar
  83. 83.
    Mirmira RG, Sims EK, Syed F, Evans-Molina C. Biomarkers of beta-cell stress and death in type 1 diabetes. Curr Diab Rep. 2016;16(10):95.CrossRefGoogle Scholar
  84. 84.
    Roder ME, Knip M, Hartling SG, Karjalainen J, Akerblom HK, Binder C. Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The childhood diabetes in Finland study group. J Clin Endocrinol Metab. 1994;79(6):1570–5.PubMedGoogle Scholar
  85. 85.
    Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia. 2006;49:261–70.CrossRefGoogle Scholar
  86. 86.
    Sherry NA, Tsai EB, Herold KC. Natural history of {beta}-cell function in type 1 diabetes. Diabetes. 2005;54(Suppl 2):S32–9.CrossRefGoogle Scholar
  87. 87.
    Greenbaum CJ, Anderson AM, Dolan LM, Mayer-Davis EJ, Dabelea D, Imperatore G, et al. Preservation of beta-cell function in autoantibody-positive youth with diabetes. Diabetes Care. 2009;32(10):1839–44.CrossRefGoogle Scholar
  88. 88.
    Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care. 2012;35(7):1436–45.CrossRefGoogle Scholar
  89. 89.
    Sherr JL, Ghazi T, Wurtz A, Rink L, Herold KC. Characterization of residual beta cell function in long-standing type 1 diabetes. Diabetes Metab Res Rev. 2014;30(2):154–62.CrossRefGoogle Scholar
  90. 90.
    Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia. 2014;57(1):187–91.CrossRefGoogle Scholar
  91. 91.
    Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, et al. Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846–53.CrossRefGoogle Scholar
  92. 92.
    Wang L, Lovejoy NF, Faustman DL. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care. 2012;35(3):465–70.CrossRefGoogle Scholar
  93. 93.
    Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite type 1 diabetes TrialNet data. Diabetes. 2012;61(8):2066–73.CrossRefGoogle Scholar
  94. 94.
    Oram RA, McDonald TJ, Shields BM, Hudson MM, Shepherd MH, Hammersley S, et al. Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors. Diabetes Care. 2015;38(2):323–8.CrossRefGoogle Scholar
  95. 95.
    Marre ML, McGinty JW, Chow IT, DeNicola ME, Beck NW, Kent SC, et al. Modifying enzymes are elicited by ER stress, generating epitopes that are selectively recognized by CD4+ T cells in patients with type 1 diabetes. Diabetes. 2018;13Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Teresa Rodriguez-Calvo
    • 1
  • Sarah J. Richardson
    • 2
  • Alberto Pugliese
    • 3
    • 4
  1. 1.Institute for Diabetes ResearchHelmholtz Diabetes Center at Helmholtz Zentrum MünchenMunichGermany
  2. 2.Islet Biology Exeter (IBEx), Institute of Biomedical and Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
  3. 3.Diabetes Research Institute, Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, Leonard Miller School of MedicineUniversity of MiamiMiamiUSA
  4. 4.Diabetes Research InstituteMiamiUSA

Personalised recommendations