The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue
Open accessAbstract
The pancreatic autopsy findings of 11 children with Type 1 (insulin-dependent) diabetes mellitus are presented. Nine children died within 24 h of initial presentation. In these 'recent-onset' diabetic patients many islets were shrunken and insulin-deficient. However, large islets containing B cells were present also. Insulitis was present in eight recent-onset diabetic subjects; in these, 18% of insulin-containing islets were inflamed, but only 1% of insulin-deficient islets were thus affected. This finding supports the concept of an immunologically mediated destruction of B cells in the pathogenesis of Type 1 diabetes. Severe acinar cell atrophy was present surrounding insulin-deficient islets, but acinar tissue around insulin-containing islets was normal. These exocrine changes are thought to be related to islet-exocrine vascular connections and the effects of the various islet hormones on pancreatic acini.
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Although it is often stated that symptoms occur when 90-95% of β cells are lost, diagnosis of type 1 diabetes can occur when roughly two-thirds of the islets are devoid of insulin-producing cells.
“Although it is often stated that symptoms occur when 90–95% of β cells are lost, diagnosis of type 1 diabetes can occur when roughly two-thirds of the islets are devoid of insulin-producing cells.61,62”
From Type 1 diabetes (2014) · cites this paper as [61]
The Patients section says nine children died within 24 hours of diagnosis, and the Results and Discussion report many insulin-deficient islets in their pancreases. But the available Table 1 text does not provide usable counts, and no passage establishes that roughly two-thirds of islets lacked insulin-producing cells at diagnosis. The Discussion’s separate “two-thirds” figure describes the A-cell composition of insulin-deficient islets, not the proportion of islets affected. (LLM, conf=0.82)
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On the Etiology of Type 1 Diabetes
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Screening for pancreatic exocrine insufficiency in patients with diabetes mellitus
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“With regard to diabetes severity, islet beta cell loss is nearly complete at diabetes onset in BB rats [16], in contrast to that of NOD mice [21, 22] and humans, [23, 24] in both of which there is evidence for residual beta cell function early in diabetes.”
ResultPancreatic islet inflammation: an emerging role for chemokines
Collier, J. J., Sparer, T. E., Karlstad, M. D., & Burke, S. J. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0042 · Cited by 67 · see citing works
“It is our hope that understanding the inflammatory signaling-induced upregulation of chemokine production and chemokine/ chemokine receptor interactions will assist in the design of therapeutics relevant to improving β-cell mass and secretory function as a way to combat the growing incidence of T1D and T2D.”
InfluentialType 1 Diabetes Islet Autoantibody Markers
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Imaging of β-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus
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Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes
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“Insulitis may be detected at, or shortly after, the clinical diagnosis [23-25] and there is a spe-”
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Driver, J. P., Chen, Y., & Mathews, C. E. (2012) · The Review of Diabetic Studies · doi:10.1900/rds.2012.9.169 · Cited by 43 · see citing works
“Further, efforts such as the Network for Pancreatic Organ Donors with Diabetes (nPOD) [20, 21] and those in Europe [22-27] are highlighting differences between the insulitic lesion comparing individuals with T1D and autoantibody-positive organ donors.”
BackgroundImpact of genetic and non‐genetic factors in type 1 diabetes
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100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story
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“All rights rese plays a major role, as total b cell mass is estimated at 2% of mean pancreas weight [40]; however, insulitis-mediated lobular atrophy of acinar tissue has been observed [41], although the link between insulin secretion and exocrine atrophy is not well understood [36,42].”
BackgroundIntra‐islet proliferation of cytotoxic T lymphocytes contributes to insulitis progression
Graham, K., Krishnamurthy, B., Fynch, S., Ayala‐Perez, R., Slattery, R., Santamaria, P., Thomas, H., & Kay, T. (2012) · European Journal of Immunology · doi:10.1002/eji.201242435 · Cited by 42
Immunological Markers in the Diagnosis and Prediction of Autoimmune Type 1a Diabetes
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Immune intervention in type 1 diabetes
Michels, A. W., & Eisenbarth, G. S. (2011) · Seminars in Immunology · doi:10.1016/j.smim.2011.07.003 · Cited by 47 · see citing works
“Those patients (and presumably prediabetic autoantibody positive individuals) have lobular destruction of islet beta cells with areas with “normal appearing” islets interspersed with areas where all islets contain only non-beta cells (termed pseudoatrophic islets) [21,22].”
BackgroundLam, C. J., Chatterjee, A., Shen, E., Cox, A. R., & Kushner, J. A. (2018) · Diabetes · doi:10.2337/db18-0305 · Cited by 40 · see citing works
Use of the Electronic Medical Record to Assess Pancreas Size in Type 1 Diabetes
Virostko, J. M., Hilmes, M. A., Eitel, K. B., Moore, D. J., & Powers, A. C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158825 · Cited by 38 · see citing works
Kent, S. C., Mannering, S. I., Michels, A. W., & Babon, J. A. B. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0915-y · Cited by 36 · see citing works
Pathology of an Islet Transplant 2 Years After Transplantation: Evidence for a Nonimmunological Loss
Smith, R. N., Kent, S. C., Nagle, J., Selig, M., Iafrate, A., Najafian, N., Hafler, D. A., Auchincloss, H., Orbán, T., & Cagliero, E. (2008) · Transplantation · doi:10.1097/tp.0b013e318173a5da · Cited by 34 · see citing works
“There was no evidence of inflammation within or adjacent to the islets and no T cells (CD3) or macrophages (CD68) within or adjacent to the islets, so that there was no histological evidence of cell-mediated autoimmunity (isletitis) (27).”
BackgroundLoss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects
Bingley, P., Matthews, D. R., Williams, A., Bottazzo, G., & Gale, E. (2004) · Diabetologia · doi:10.1007/bf00400849 · Cited by 34 · see citing works
“In Type 1 diabetes the pattern of autoimmune attack appears to be random, and at the time of diagnosis normal islets are interspersed with islets in which Beta cells are scanty or absent [ 30 ].”
BackgroundApaolaza, P. S., Πετροπούλου, Π.-Ι., & Calvo, T. R. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.689799 · Cited by 35 · see citing works
Tang, X., Kusmartseva, I., Kulkarni, S., Posgai, A. L., Speier, S., Schatz, D. A., Haller, M. J., Campbell‐Thompson, M., Wasserfall, C. H., Roep, B. O., et al. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.11.010 · Cited by 33 · see citing works
DeSouza, S. V., Yoon, H. D., Singh, R. G., & Petrov, M. (2018) · Clinical anatomy (New York, N.Y. Print) · doi:10.1002/ca.23217 · Cited by 31 · see citing works
“Therefore, a reduction in β-cell insulin secretion and/or altered local insulin receptor activity would lead to parenchymal atrophy (Foulis and Stewart, 1984; Gilbeau et al., 1992).”
BackgroundIncreased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes
Moin, A. S. M., Butler, P. C., & Butler, A. E. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-3001 · Cited by 31 · see citing works
“Notably, none of these individuals had known clinical pancreatitis documented in life, consistent with accumulating data that subclinical subacute chronic pancreatitis is common in both T1D and T2D, the origin of which remains unknown (19).”
BackgroundWang, M., Yang, L., Sheng, X., Chen, W., Tang, H., Sheng, H., Xi, B., & Zang, Y. Q. (2011) · Cell Research · doi:10.1038/cr.2011.74 · Cited by 25 · see citing works
Hawa, M. I., Bonfanti, R., Valeri, C., Castelli, M. D., Beyan, H., & Leslie, R. D. G. (2005) · Diabetes Care · doi:10.2337/diacare.28.6.1415 · Cited by 26 · see citing works
“At diagnosis of classic type 1 diabetes, the islets are heavily infiltrated with lymphocytes and insulin secretion is absent or markedly reduced (2).”
BackgroundBeta-Cell Imaging: Call for Evidence-Based and Scientific Approach
Blomberg, B., Codreanu, I., Cheng, G., Werner, T., & Alavi, A. (2013) · Molecular Imaging and Biology · doi:10.1007/s11307-013-0620-4 · Cited by 26
Size of the Pancreas in Type I Diabetic Children and Adolescents
Chiarelli, F., Verrotti, A., Altobelli, E., Blasetti, A., & Morgese, G. (1995) · Diabetes Care · doi:10.2337/diacare.18.11.1504 · Cited by 25
“Autopsy findings have revealed a significant reduction of weight and size of the gland in patients with type I diabetes (3).”
BackgroundPancreatic volume is reduced in patients with latent autoimmune diabetes in adults
Lu, J., Hou, X., Pang, C., Zhang, L., Hu, C., Zhao, J., Bao, Y., & Jia, W. (2016) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2806 · Cited by 23 · see citing works
Scott, F. W., Pound, L. D., Patrick, C., Eberhard, C. E., & Crookshank, J. A. (2016) · Translational research · doi:10.1016/j.trsl.2016.09.001 · Cited by 24 · see citing works
Schludi, B., Moin, A. S. M., Montemurro, C., Gurlo, T., Matveyenko, A. V., Kirakossian, D., Dawson, D. W., Dry, S., Butler, P. C., & Butler, A. E. (2017) · JCI Insight · doi:10.1172/jci.insight.92282 · Cited by 26 · see citing works
“individuals had known clinical pancreatitis documented in their lifetimes, consistent with accumulating data that subclinical subacute chronic pancreatitis is common in both type I diabetes (T1D) and T2DM, the origin of which remains unknown (28).”
BackgroundNigi, L., Maccora, C., Dotta, F., & Sebastiani, G. (2019) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3264 · Cited by 24 · see citing works
“In support of this concept, a decline in exocrine function (evaluated by chymotrypsin and elastase stool measurement) has been observed (47,125).”
BackgroundMarkholst, H., & Lernmark, Å. (1988) · Pancreas · doi:10.1097/00006676-198804000-00005 · Cited by 21
Mundinger, T. O., & Taborsky, G. J. (2016) · Diabetologia · doi:10.1007/s00125-016-4026-0 · Cited by 19 · see citing works
“Indeed, immune cells in the islet are usually found only in individuals with very short diabetes duration [50] and then only in very small amounts [48].”
BackgroundBoğa, S., Köksal, A. R., Şen, İ., Yeniay, M. K., Ozguven, M. B. Y., Serin, E., Ertürk, Ş. M., Alkım, H., & Alkım, C. (2020) · Pancreatology · doi:10.1016/j.pan.2020.04.020 · Cited by 15 · see citing works
New Evidence of Exocrine Pancreatopathy in Pre-symptomatic and Symptomatic Type 1 Diabetes
Vecchio, F., Messina, G., Giovenzana, A., & Petrelli, A. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1223-5 · Cited by 18 · see citing works
Insulin secretion in health and disease: genomics, proteomics and single vesicle dynamics
Rutter, G. A., Varadi, A., Tsuboi, T., Parton, L. E., & Ravier, M. A. (2006) · Biochemical Society Transactions · doi:10.1042/bst20060247 · Cited by 15 · see citing works
Morphology of the Pancreas in Normal and Diabetic States
Clark, A. (2003) · Wiley eBooks · doi:10.1002/0470862092.d0202 · Cited by 5 · see citing works
Püttmann, S., Koch, J., Steinacker, J., Schmidt, S., Seufferlein, T., Kratzer, W., Schmidberger, J., & Manfras, B. (2018) · BMC Medical Imaging · doi:10.1186/s12880-018-0295-z · Cited by 17
Atkinson, M. (2014) · Diabetes · doi:10.2337/db14-1069 · Cited by 17 · see citing works
“Subsequent work led by Gepts (4), LeCompte (5), Foulis (6), and others in ensuing decades (7,8) taught us much regarding this inflammatory lesion.”
BackgroundPancreatic regeneration in type 1 diabetes: dreams on a deserted islet?
Atkinson, M. A., & Rhodes, C. J. (2005) · Diabetologia · doi:10.1007/s00125-005-1957-2 · Cited by 17
“Some may say that there is nothing new in this, and the work does, by and large, confirm earlier findings by Gepts & De Mey [4], Foulis & Stewart [5] and Lohr & Kloppel [6], among others.”
Takita, M., Jimbo, E., Fukui, T., Aida, K., Shimada, A., Oikawa, Y., Yagihashi, S., Miura, J., Babazono, T., & Kobayashi, T. (2019) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2018-02672 · Cited by 16
Li, X., Cheng, J., & Zhou, Z. (2016) · Journal of Diabetes · doi:10.1111/1753-0407.12376 · Cited by 16 · see citing works
Barmeier, H., Mcculloch, D., Neifing, J. L., Warnock, G., Rajotte, R., Palmer, J., & Lernmark, Å. (1991) · Diabetologia · doi:10.1007/bf00401518 · Cited by 15 · see citing works
“An immunological pathogenesis for Type 1 (insulin-dependent) diabetes mellitus is supported by the presence of inflammatory cells in the islets of Langerhans at onset [1-3] and of autoantibodies, reacting with pancreatic islet cells [4-6], insulin [7], or a Beta-cell Mr 64,000 (64K) protein [8], as early as several ye…”
Molecular biology of Type 1 (insulin-dependent) diabetes mellitus
Lernmark, Å. (1985) · Diabetologia · doi:10.1007/bf00282232 · Cited by 15
“Recent studies with morphometric techniques [4-5], which allow a quantitative measure of both the total volume or mass of the endocrine pancreas of individual cell types visualized by sensitive and specific immunocytochemical techniques, have shown that Type I diabetes in man is associated with a specific loss of the…”
BackgroundRecovery of Islet β-Cell Function in Streptozotocin- Induced Diabetic Mice
Yin, D., Tao, J., Lee, D. D., Shen, J., Hara, M., Lopez, J. P., Kuznetsov, A., Philipson, L. H., & Chong, A. S. (2006) · Diabetes · doi:10.2337/db05-1275 · Cited by 99 · see citing works
Gál, E., Dolenšek, J., Stožer, A., Czakó, L., Èbert, A., & Venglovecz, V. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.715043 · Cited by 18 · see citing works
Autonomic Neuropathy in Diabetes Mellitus and Obesity: An Update
Katsilambros, N. L., Boulton, A. J. M., Tentolouris, N., Kokkinos, A. D., & Liatis, S. (2011) · Experimental Diabetes Research · doi:10.1155/2011/607309 · Cited by 13 · see citing works
Reddy, S., Chai, R., Rodrigues, J. A., Hsu, T.-H., & Robinson, E. (2008) · Journal of Molecular Histology · doi:10.1007/s10735-007-9122-5 · Cited by 14
“In earlier studies by others, pancreatic samples from children with new onset type 1 diabetes also showed insulitis that was often patchy, in a majority of cases and in a majority of islets (Foulis and Stewart 1984; Foulis et al. 1986, 1991).”
BackgroundSalah, N., Madkour, S. S., & Soliman, K. S. (2022) · Pediatric Radiology · doi:10.1007/s00247-022-05363-1 · Cited by 13
“Studies have shown inflammation in the pancreas in the preclinical and early stages of type 1 diabetes [35].”
BackgroundImpaired glucagon secretion in patients with fulminant type 1 diabetes mellitus
Komada, H., Hirota, Y., Sakaguchi, K., Okuno, Y., Ogawa, W., & Seino, S. (2018) · Endocrine · doi:10.1007/s12020-018-1750-x · Cited by 13 · see citing works
- Authors
- Foulis, A. K., & Stewart, J. A.
- Affiliations
- Western Infirmary (GB)
- ORCID
- Stewart, J.A.
- Venue
- Diabetologia
- Published
- 1984-06
- Volume
- 26
- Issue
- 6
- Pages
- 456-61
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2019605333
- Cited by
- 233
- References
- 19
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 16 · 2015: 9 · 2014: 6 · 2013: 4 · 2012: 12
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hospital for Sick Children
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, recent-onset diabetes, pancreatic islets, insulin content, insulitis, beta cell destruction, islet atrophy, acinar cell atrophy, exocrine pancreas, islet hormones, pediatric diabetes, autopsy findings
- MeSH terms
- Atrophy, Child, Child, Preschool, Diabetes Mellitus, Type 1, Diabetic Coma, Female, Humans, Immunoenzyme Techniques, Insulin, Islets of Langerhans, Male, Pancreas
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