title: Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis.
abstract: OBJECTIVE
  Diabetes associated with autoimmune chronic pancreatitis (ACP) is a subtype of diabetes that is responsive to corticosteroid treatment of progressive endocrine and exocrine dysfunction. However, little is known about pathological changes of islet and exocrine pancreas in ACP.
  
  
  METHODS
  We examined pancreatic specimens obtained on biopsy from four diabetic men with ACP (mean [range]: age 62 years [48-78], duration of ACP 3 months [1-5], duration of diabetes 1 month [0-3]) morphologically, immunohistochemically, and morphometrically.
  
  
  RESULTS
  The pancreatic specimens in all cases exhibited inflammatory cell infiltration surrounding ductal cells and extensive fibrosis. Some islets were infiltrated with mononuclear cells with disrupted beta-cells. The subsets of T-cells infiltrated to the islets were mainly CD8(+). Islet beta-cell volume was decreased; the mean percentage area of beta-cells in the islets in four cases with ACP were 16% (range 13-20) (P = 0.0015 vs. type 2 diabetic patients, 48% [27-73], n = 8; P = 0.0002 vs. nondiabetic control subjects, 58% [39-77], n = 7). Preserved ductal cells were surrounded predominantly by CD8(+) or CD4(+) T-cells. Some cytokeratin 19-positive ductal cells contained insulin and glucagon, representing upregulated differentiation of islet cells from ductal cells. Insulin promoter factor-1 (IPF-1) was hyperexpressed in insulin-containing ductal cells.
  
  
  CONCLUSIONS
  Diabetes associated with ACP is caused by T-cell-mediated mechanisms primarily involving islet beta-cells as well as pancreatic ductal cells. In ACP, ductal islet precursor cells were associated with IPF-1 hyperexpression, suggesting a critical role of IPF-1 on islet cell differentiation and eventual beta-cell restoration.
authors.affiliation: Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
authors.forename: M
authors.initials: M
authors.lastname: Okubo
authors.forename: T
authors.initials: T
authors.lastname: Murase
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: G
authors.initials: G
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Matsushita
authors.forename: Y
authors.initials: Y
authors.lastname: Endo
authors.forename: H
authors.initials: H
authors.lastname: Yoshizaki
authors.forename: T
authors.initials: T
authors.lastname: Kosuge
authors.forename: M
authors.initials: M
authors.lastname: Sakamoto
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000208:Acute Disease; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000368:Aged; D044466:Asian People; D001327:Autoimmune Diseases / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D007564:Japan; D008297:Male; D008875:Middle Aged; D010183:Pancreatic Ducts / Q000473:pathology*; D010195:Pancreatitis / Q000150:complications* / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
chemical_list: D000305:Adrenal Cortex Hormones