Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity

A. Martin-Pagola, G. Sisino, G. Allende, J. Dominguez-Bendala, R. Gianani, H. Reijonen, G. T. Nepom, C. Ricordi, P. Ruiz, Junichiro Sageshima, G. Ciancio, G. W. Burke, A. Pugliese

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Aim/hypothesis: We investigated whether beta cell neoformation occurs in the transplanted pancreas in patients with type 1 diabetes who had received a simultaneous pancreas-kidney transplant (SPK) and later developed recurrence of autoimmunity. Methods: We examined pancreas transplant biopsies from nine SPK patients with or without recurrent autoimmunity or recurrent diabetes and from 16 non-diabetic organ donors. Tissues were analysed by immunohistochemistry and immunofluorescence. Results: Numerous cytokeratin-19 (CK-19)+ pancreatic ductal cells stained for insulin in six SPK recipients with recurrent autoimmunity, in five of whom diabetes requiring insulin therapy recurred. These cells also stained for the transcription factor pancreatic-duodenal homeobox-1 (Pdx-1), which is implicated in pancreatic development and beta cell differentiation. The number of insulin+ ductal cells varied, being highest in the patient with the most severe beta cell loss and lowest in the normoglycaemic patient. In the patient with the most severe beta cell loss, we detected insulin+CK-19+Pdx-1+ cells staining for the proliferation-related Ki-67 antigen (Ki-67), indicating proliferation. We were unable to detect Ki-67+ beta cells within the islets in any SPK patient. Some insulin+CK-19- ductal cells contained chromogranin A, suggesting further endocrine differentiation. Insulin + cells were rarely noted in the pancreas transplant ducts in three SPK patients without islet autoimmunity and in six of 16 non-diabetic organ donors; these insulin+ cells were never CK-19+. Conclusions/interpretation: Insulin+ pancreatic ductal cells, some apparently proliferating, were found in the transplanted pancreas with recurrent islet autoimmunity/diabetes. Replicating beta cells were not detected within islets. The observed changes may represent attempts at tissue remodelling and beta cell regeneration involving ductal cells in the human transplanted pancreas, possibly stimulated by hyperglycaemia and chronic inflammation.

Original languageEnglish (US)
Pages (from-to)1803-1813
Number of pages11
JournalDiabetologia
Volume51
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Autoimmunity
Type 1 Diabetes Mellitus
Pancreas
Insulin
Recurrence
Keratin-19
Proteins
Transplants
Kidney
Homeobox Genes
Tissue Donors
Ki-67 Antigen
Chromogranin A
Insulin-Secreting Cells
Islets of Langerhans
Hyperglycemia
Fluorescent Antibody Technique
Regeneration
Cell Differentiation
Transcription Factors

Keywords

  • Insulin
  • Pancreas transplantation
  • Pancreatic ducts
  • Pdx-1
  • Recurrence of autoimmunity
  • Regeneration
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Martin-Pagola, A., Sisino, G., Allende, G., Dominguez-Bendala, J., Gianani, R., Reijonen, H., ... Pugliese, A. (2008). Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity. Diabetologia, 51(10), 1803-1813. https://doi.org/10.1007/s00125-008-1105-x

Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity. / Martin-Pagola, A.; Sisino, G.; Allende, G.; Dominguez-Bendala, J.; Gianani, R.; Reijonen, H.; Nepom, G. T.; Ricordi, C.; Ruiz, P.; Sageshima, Junichiro; Ciancio, G.; Burke, G. W.; Pugliese, A.

In: Diabetologia, Vol. 51, No. 10, 01.10.2008, p. 1803-1813.

Research output: Contribution to journalArticle

Martin-Pagola, A, Sisino, G, Allende, G, Dominguez-Bendala, J, Gianani, R, Reijonen, H, Nepom, GT, Ricordi, C, Ruiz, P, Sageshima, J, Ciancio, G, Burke, GW & Pugliese, A 2008, 'Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity', Diabetologia, vol. 51, no. 10, pp. 1803-1813. https://doi.org/10.1007/s00125-008-1105-x
Martin-Pagola, A. ; Sisino, G. ; Allende, G. ; Dominguez-Bendala, J. ; Gianani, R. ; Reijonen, H. ; Nepom, G. T. ; Ricordi, C. ; Ruiz, P. ; Sageshima, Junichiro ; Ciancio, G. ; Burke, G. W. ; Pugliese, A. / Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity. In: Diabetologia. 2008 ; Vol. 51, No. 10. pp. 1803-1813.
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AU - Martin-Pagola, A.

AU - Sisino, G.

AU - Allende, G.

AU - Dominguez-Bendala, J.

AU - Gianani, R.

AU - Reijonen, H.

AU - Nepom, G. T.

AU - Ricordi, C.

AU - Ruiz, P.

AU - Sageshima, Junichiro

AU - Ciancio, G.

AU - Burke, G. W.

AU - Pugliese, A.

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N2 - Aim/hypothesis: We investigated whether beta cell neoformation occurs in the transplanted pancreas in patients with type 1 diabetes who had received a simultaneous pancreas-kidney transplant (SPK) and later developed recurrence of autoimmunity. Methods: We examined pancreas transplant biopsies from nine SPK patients with or without recurrent autoimmunity or recurrent diabetes and from 16 non-diabetic organ donors. Tissues were analysed by immunohistochemistry and immunofluorescence. Results: Numerous cytokeratin-19 (CK-19)+ pancreatic ductal cells stained for insulin in six SPK recipients with recurrent autoimmunity, in five of whom diabetes requiring insulin therapy recurred. These cells also stained for the transcription factor pancreatic-duodenal homeobox-1 (Pdx-1), which is implicated in pancreatic development and beta cell differentiation. The number of insulin+ ductal cells varied, being highest in the patient with the most severe beta cell loss and lowest in the normoglycaemic patient. In the patient with the most severe beta cell loss, we detected insulin+CK-19+Pdx-1+ cells staining for the proliferation-related Ki-67 antigen (Ki-67), indicating proliferation. We were unable to detect Ki-67+ beta cells within the islets in any SPK patient. Some insulin+CK-19- ductal cells contained chromogranin A, suggesting further endocrine differentiation. Insulin + cells were rarely noted in the pancreas transplant ducts in three SPK patients without islet autoimmunity and in six of 16 non-diabetic organ donors; these insulin+ cells were never CK-19+. Conclusions/interpretation: Insulin+ pancreatic ductal cells, some apparently proliferating, were found in the transplanted pancreas with recurrent islet autoimmunity/diabetes. Replicating beta cells were not detected within islets. The observed changes may represent attempts at tissue remodelling and beta cell regeneration involving ductal cells in the human transplanted pancreas, possibly stimulated by hyperglycaemia and chronic inflammation.

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KW - Pancreas transplantation

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KW - Recurrence of autoimmunity

KW - Regeneration

KW - Type 1 diabetes

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