title: Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.
abstract: OBJECTIVE
  New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer.
  
  
  METHODS
  Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls).
  
  
  RESULTS
  Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not.
  
  
  CONCLUSIONS
  Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Aggarwal
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Naureen
authors.initials: N
authors.lastname: Javeed
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.forename: Shamit
authors.initials: S
authors.lastname: Dutta
authors.forename: George G
authors.initials: GG
authors.lastname: Klee
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: William
authors.initials: W
authors.lastname: Bamlet
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Han
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Rumie Vittar
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: Suresh T
authors.initials: ST
authors.lastname: Chari
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D053607:Adrenomedullin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D023421:Models, Animal; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D007328:Insulin; D034741:RNA, Small Interfering; D053607:Adrenomedullin; D005947:Glucose