Pancreas Pathology During the Natural History of Type 1 Diabetes
Purpose of review
We provide an overview of pancreas pathology in type 1 diabetes (T1D) in the context of its clinical stages.
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.
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.
KeywordsType 1 diabetes Insulitis β cell Pancreas Islet autoimmunity
Exeter Archival Diabetes Biobank
Diabetes Virus Detection Study
Glutamic acid decarboxylase
Human leukocyte antigen class I
Maturity onset diabetes of the young
Non-obese diabetic mouse
Network for Pancreatic Organ Donors with Diabetes
Type 2 diabetes
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 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
- 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
- 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
- 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.• 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
- 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.• 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
- 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.• 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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