title: Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans.
abstract: OBJECTIVE
  Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases?
  
  
  METHODS
  Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy.
  
  
  RESULTS
  Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour.
  
  
  CONCLUSIONS
  One or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumour-distant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.
authors.affiliation: Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 24-130 Warren Hall, 900 Veteran Avenue, Los Angeles, CA 90095-7073, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Meier
authors.forename: A E
authors.initials: AE
authors.lastname: Butler
authors.forename: R
authors.initials: R
authors.lastname: Galasso
authors.forename: R A
authors.initials: RA
authors.lastname: Rizza
authors.forename: P C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D015992:Body Mass Index; D002455:Cell Division / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D015408:Gastrinoma / Q000473:pathology* / Q000601:surgery; D005755:Gastrins / Q000097:blood; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology; D007515:Islets of Langerhans / Q000473:pathology; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000601:surgery; D015043:Zollinger-Ellison Syndrome / Q000473:pathology / Q000601:surgery
chemical_list: D005755:Gastrins