, Volume 49, Issue 3, pp 693–702 | Cite as

Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes

  • Ananta Poudel
  • Omid Savari
  • Deborah A. Striegel
  • Vipul Periwal
  • Jerome Taxy
  • J. Michael Millis
  • Piotr Witkowski
  • Mark A. Atkinson
  • Manami HaraEmail author
Original Article


Previous studies describing the symptomatic onset of type 1 diabetes (T1D) and rate of beta-cell loss (C-peptide) support the notion that childhood onset T1D exhibits more severe beta-cell depletion compared to adult onset T1D. To test this notion, we performed whole pancreas analyses in two T1D cases, one of childhood onset (7-year old, onset at 1.5-year) along with an adult onset case (43-year old with onset at 27-year). Both cases were matched for age and gender with control subjects. Striking regional differences in beta-cell loss were observed in both T1D cases, with severity of loss in the order of tail > body > head regions. In contrast, pancreatic alpha- and delta-cell mass was similar in controls and T1D patients. In the childhood onset T1D case, no intra-islet beta-cells were detected while in the adult onset case, beta-cell containing islets were found, exclusively in the head region. In the latter case, considerable numbers of small cellular clusters negative for three major endocrine hormones were observed, in islets with or without beta-cells. Ultrastructural analysis suggests these cells correspond to degenerating beta-cells, with empty granular membranes and abnormal morphology of nuclei with intranuclear pseudo-inclusions, adjacent to healthy alpha- and delta-cells. These results support a hypothesis that during T1D development in childhood, beta-cells are more susceptible to autoimmune destruction or immune attack is more severe, while beta-cell death in the adult onset T1D may be more protracted and incomplete. In addition, T1D may be associated with the formation of “empty” beta-cells, an interesting population of cells that may represent a key facet to the disorder’s pathogenesis.


Type 1 diabetes Childhood onset Adult onset Pancreatic islets Beta-cells 



The study is supported by US Public Health Service Grant DK-020595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, AG-042151, and a gift from the Kovler Family Foundation. The authors would like to acknowledge the generosity and support of Dr. Martin Jendrisak and the entire team of the Gift of Hope Organ & Tissue Donor Network in Chicago for providing the human pancreas tissues used in the present study.


The authors have nothing to disclose.


  1. 1.
    M.A. Atkinson, G.S. Eisenbarth, A.W. Michels, Type 1 diabetes. Lancet 383, 69–82 (2014)PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    D. Dabelea, E.J. Mayer-Davis, S. Saydah, G. Imperatore, B. Linder, J. Divers, R. Bell, A. Badaru, J.W. Talton, T. Crume, A.D. Liese, A.T. Merchant, J.M. Lawrence, K. Reynolds, L. Dolan, L.L. Liu, R.F. Hamman, SEARCH for Diabetes in Youth Study, Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 311, 1778–1786 (2014)PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    R.D. Leslie, Predicting adult-onset autoimmune diabetes: clarity from complexity. Diabetes 59, 330–331 (2010)PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    J. Karjalainen, P. Salmela, J. Ilonen, H.M. Surcel, M. Knip, A comparison of childhood and adult type I diabetes mellitus. N. Engl. J. Med. 320, 881–886 (1989)PubMedCrossRefGoogle Scholar
  5. 5.
    A. Schiffrin, S. Suissa, G. Weitzner, P. Poussier, D. Lalla, Factors predicting course of beta-cell function in IDDM. Diabetes Care 15, 997–1001 (1992)PubMedCrossRefGoogle Scholar
  6. 6.
    E. Sabbah, K. Savola, T. Ebeling, P. Kulmala, P. Vähäsalo, J. Ilonen, P.I. Salmela, M. Knip, Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes. Diabetes Care 23, 1326–1332 (2000)PubMedCrossRefGoogle Scholar
  7. 7.
    E.B. Tsai, N.A. Sherry, J.P. Palmer, K.C. Herold, The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 49, 261–270 (2006)PubMedCrossRefGoogle Scholar
  8. 8.
    M.P. Gallagher, R.S. Goland, C.J. Greenbaum, Making progress: preserving beta cells in type 1 diabetes. Ann. N. Y. Acad. Sci. 1243, 119–134 (2011)PubMedCrossRefGoogle Scholar
  9. 9.
    S.R. Merger, R.D. Leslie, B.O. Boehm, The broad clinical phenotype of Type 1 diabetes at presentation. Diabetes Med. 30, 170–178 (2013)CrossRefGoogle Scholar
  10. 10.
    D. Pipeleers, M. Chintinne, B. Denys, G. Martens, B. Keymeulen, F. Gorus, Restoring a functional beta-cell mass in diabetes. Diabetes Obes. Metab. 10(Suppl 4), 54–62 (2008)PubMedCrossRefGoogle Scholar
  11. 11.
    S. Madsbad, O.K. Faber, C. Binder, P. McNair, C. Christiansen, I. Transbtfl, Prevalence of residual beta-cell function in insulin-dependent diabetics in relation to age at onset and duration of diabetes. Diabetes 27(Suppl 1), 262–264 (1978)PubMedCrossRefGoogle Scholar
  12. 12.
    The Diabetes Control and Complications Trial Research Group, Effects of age, duration and treatment of insulin dependent diabetes-mellitus on residual beta-cell function—observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J. Clin. Endocrinol. Metab. 65, 30–36 (1987)CrossRefGoogle Scholar
  13. 13.
    The Diabetes Control and Complications Trial Research Group, Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial—a randomized, controlled trial. Ann. Intern. Med. 128, 517–523 (1998)CrossRefGoogle Scholar
  14. 14.
    J.J. Meier, A. Bhushan, A.E. Butler, R.A. Rizza, P.C. Butler, Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48, 2221–2228 (2005)PubMedCrossRefGoogle Scholar
  15. 15.
    K. Miller, A. Kim, G. Klimnik, J. Jo, U. Moka, V. Periwal, M. Hara, Islet formation during neonatal development. PLoS ONE 4, e7739 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    A. Kim, G. Kilimnik, C. Guo, J. Sung, J. Jo, V. Periwal, P. Witkowski, P. Dilorio, M. Hara. Computer-assisted large-scale visualization and quantification of pancreatic islet mass, size distribution and architecture. J. Vis. Exp. 49, (2011). doi:  10.3791/2471
  17. 17.
    X. Wang, M.C. Zielinski, R. Misawa, P. Wen, T.Y. Wang, C.Z. Wang, P. Witkowski, M. Hara, Quantitative analysis of pancreatic polypeptide cell distribution in the human pancreas. PLoS ONE 8, e55501 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    X. Wang, R. Misawa, M.C. Zielinski, P. Cowen, J. Jo, V. Periwal, C. Ricordi, A. Khan, J. Szust, J. Shen, J.M. Millis, P. Witkowski, M. Hara, Regional differences in islet distribution in the human pancreas–preferential beta-cell loss in the head region in patients with type 2 diabetes. PLoS ONE 8, e67454 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    G. Kilimnik, J. Jo, V. Periwal, M.C. Zielinski, M. Hara, Quantification of islet size and architecture. Islets 4, 167–172 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    M. Brissova, M.J. Fowler, W.E. Nicholson, A. Chu, B. Hirshberg, D.M. Harlan, A.C. Powers, Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J. Histochem. Cytochem. 53, 1087–1097 (2005)PubMedCrossRefGoogle Scholar
  21. 21.
    O. Cabrera, D.M. Berman, N.S. Kenyon, C. Ricordi, P.O. Berggren, A. Caicedo, The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. U.S.A. 103, 2334–2339 (2006)PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    G. Kilimnik, B. Zhao, J. Jo, V. Periwal, P. Witkowski, R. Misawa, M. Hara, Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes. PLoS ONE 6, e27445 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    R. Vracko, Basal lamina layering in diabetes mellitus. Evidence for accelerated rate of cell death and cell regeneration. Diabetes 23, 94–104 (1974)PubMedCrossRefGoogle Scholar
  24. 24.
    K.L. Graham, R.M. Sutherland, S.I. Mannering, Y. Zhao, J. Chee, B. Krishnamurthy, H.E. Thomas, A.M. Lew, T.W. Kay, Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease. Rev. Diabetes Stud. 9, 148–168 (2012)CrossRefGoogle Scholar
  25. 25.
    L. Ding, C. Gysemans, C. Mathieu, β-Cell differentiation and regeneration in type 1 diabetes. Diabetes Obes. Metab. 15(Suppl 3), 98–104 (2013)PubMedCrossRefGoogle Scholar
  26. 26.
    K.M. Andralojc, A. Mercalli, K.W. Nowak, L. Albarello, R. Calcagno, L. Luzi, E. Bonifacio, C. Doglioni, L. Piemonti, Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia 52, 486–493 (2009)PubMedCrossRefGoogle Scholar
  27. 27.
    A. Willcox, S.J. Richardson, A.J. Bone, A.K. Foulis, N.G. Morgan, Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 155, 173–181 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    M.L. Campbell-Thompson, M.A. Atkinson, A.E. Butler, N.M. Chapman, G. Frisk, R. Gianani, B.N. Giepmans, M.G. von Herrath, H. Hyöty, T.W. Kay, O. Korsgren, N.G. Morgan, A.C. Powers, A. Pugliese, S.J. Richardson, P.A. Rowe, S. Tracy, P.A. In’t Veld, The diagnosis of insulitis in human type 1 diabetes. Diabetologia 56, 2541–2543 (2013)PubMedCrossRefGoogle Scholar
  29. 29.
    J.C. Henquin, J. Rahier, Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720–1725 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    J. Rahier, R.M. Goebbels, J.C. Henquin, Cellular composition of the human diabetic pancreas. Diabetologia 24, 366–371 (1983)PubMedCrossRefGoogle Scholar
  31. 31.
    A. Clark, C.A. Wells, I.D. Buley, J.K. Cruickshank, R.I. Vanhegan, D.R. Matthews, G.J. Cooper, R.R. Holman, R.C. Turner, Islet amyloid, increased alpha-cells, reduced beta-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 9, 151–159 (1988)PubMedGoogle Scholar
  32. 32.
    K.H. Yoon, S.H. Ko, J.H. Cho, J.M. Lee, Y.B. Ahn, K.H. Song, S.J. Yoo, M.I. Kang, B.Y. Cha, K.W. Lee, H.Y. Son, S.K. Kang, H.S. Kim, I.K. Lee, S. Bonner-Weir, Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J. Clin. Endocrinol. Metab. 88, 2300–2308 (2003)PubMedCrossRefGoogle Scholar
  33. 33.
    S.A. Greeley, R.N. Naylor, L.H. Philipson, G.I. Bell, Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr. Diabetes Rep. 11, 519–532 (2011)CrossRefGoogle Scholar
  34. 34.
    N.A. Sherry, J.A. Kushner, M. Glandt, T. Kitamura, A.M. Brillantes, K.C. Herold, Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55, 3238–3245 (2006)PubMedCrossRefGoogle Scholar
  35. 35.
    R. Gianani, M. Campbell-Thompson, S.A. Sarkar, C. Wasserfall, A. Pugliese, J.M. Solis, S.C. Kent, B.J. Hering, E. West, A. Steck, S. Bonner-Weir, M.A. Atkinson, K. Coppieters, M. von Herrath, G.S. Eisenbarth, Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia 53, 690–698 (2010)PubMedCrossRefGoogle Scholar
  36. 36.
    R. Kanakatti Shankar, C. Pihoker, L.M. Dolan, D. Standiford, A. Badaru, D. Dabelea, B. Rodriguez, M.H. Black, G. Imperatore, A. Hattersley, S. Ellard, L.K. Gilliam, SEARCH for Diabetes in Youth Study Group, Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for diabetes in youth study. Pediatr. Diabetes 14, 174–180 (2013)PubMedGoogle Scholar
  37. 37.
    C. Pihoker, L.K. Gilliam, S. Ellard, D. Dabelea, C. Davis, L.M. Dolan, C.J. Greenbaum, G. Imperatore, J.M. Lawrence, S.M. Marcovina, E. Mayer-Davis, B.L. Rodriguez, A.K. Steck, D.E. Williams, A.T. Hattersley, Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for diabetes in youth. J. Clin. Endocrinol. Metab. 98, 4055–4062 (2013)PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ananta Poudel
    • 1
  • Omid Savari
    • 2
  • Deborah A. Striegel
    • 3
  • Vipul Periwal
    • 3
  • Jerome Taxy
    • 4
  • J. Michael Millis
    • 2
  • Piotr Witkowski
    • 2
  • Mark A. Atkinson
    • 5
  • Manami Hara
    • 1
    Email author
  1. 1.Department of MedicineThe University of ChicagoChicagoUSA
  2. 2.Department of SurgeryThe University of ChicagoChicagoUSA
  3. 3.Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  4. 4.Department of Pathology and Laboratory MedicineNorthShore University Health SystemEvanstonUSA
  5. 5.Department of PathologyThe University of FloridaGainesvilleUSA

Personalised recommendations