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

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Abstract

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.

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References

  1. M.A. Atkinson, G.S. Eisenbarth, A.W. Michels, Type 1 diabetes. Lancet 383, 69–82 (2014)

    Article  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. R.D. Leslie, Predicting adult-onset autoimmune diabetes: clarity from complexity. Diabetes 59, 330–331 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed Central  PubMed  Google Scholar 

  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. 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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. G. Kilimnik, J. Jo, V. Periwal, M.C. Zielinski, M. Hara, Quantification of islet size and architecture. Islets 4, 167–172 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. R. Vracko, Basal lamina layering in diabetes mellitus. Evidence for accelerated rate of cell death and cell regeneration. Diabetes 23, 94–104 (1974)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  29. J.C. Henquin, J. Rahier, Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720–1725 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. J. Rahier, R.M. Goebbels, J.C. Henquin, Cellular composition of the human diabetic pancreas. Diabetologia 24, 366–371 (1983)

    Article  CAS  PubMed  Google Scholar 

  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)

    CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    PubMed  Google Scholar 

  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)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC1027, Chicago, IL, USA

    Ananta Poudel & Manami Hara

  2. Department of Surgery, The University of Chicago, Chicago, IL, USA

    Omid Savari, J. Michael Millis & Piotr Witkowski

  3. Laboratory of Biological Modeling, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Deborah A. Striegel & Vipul Periwal

  4. Department of Pathology and Laboratory Medicine, NorthShore University Health System, Evanston, IL, USA

    Jerome Taxy

  5. Department of Pathology, The University of Florida, Gainesville, FL, USA

    Mark A. Atkinson

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Poudel, A., Savari, O., Striegel, D.A. et al. Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes. Endocrine 49, 693–702 (2015). https://doi.org/10.1007/s12020-015-0534-9

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