Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice

Gaurav Aggarwal, Vijaya Ramachandran, Naureen Javeed, Thiruvengadam Arumugam, Shamit Dutta, George G. Klee, Eric W Klee, Thomas Christopher Smyrk, William Bamlet, Jing Jing Han, Natalia B. Rumie Vittar, Mariza De Andrade, Debabrata Mukhopadhyay, Gloria M Petersen, Martin E Fernandez-Zapico, Craig D. Logsdon, Suresh T Chari

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Abstract

Background & Aims: 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.

Original languageEnglish (US)
JournalGastroenterology
Volume143
Issue number6
DOIs
StatePublished - Dec 2012

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Adrenomedullin
Pancreatic Neoplasms
Insulin Resistance
Cell Line
Insulin
Conditioned Culture Medium
Glucose
Messenger RNA
Glucose Intolerance
Microarray Analysis
Reverse Transcriptase Polymerase Chain Reaction
Heterografts
Type 2 Diabetes Mellitus
Small Interfering RNA
Fasting
Proteins

Keywords

  • Mechanisms
  • Mouse Model
  • Pancreas
  • Tumor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Aggarwal, G., Ramachandran, V., Javeed, N., Arumugam, T., Dutta, S., Klee, G. G., ... Chari, S. T. (2012). Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. Gastroenterology, 143(6). https://doi.org/10.1053/j.gastro.2012.08.044

Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. / Aggarwal, Gaurav; Ramachandran, Vijaya; Javeed, Naureen; Arumugam, Thiruvengadam; Dutta, Shamit; Klee, George G.; Klee, Eric W; Smyrk, Thomas Christopher; Bamlet, William; Han, Jing Jing; Rumie Vittar, Natalia B.; De Andrade, Mariza; Mukhopadhyay, Debabrata; Petersen, Gloria M; Fernandez-Zapico, Martin E; Logsdon, Craig D.; Chari, Suresh T.

In: Gastroenterology, Vol. 143, No. 6, 12.2012.

Research output: Contribution to journalArticle

Aggarwal, G, Ramachandran, V, Javeed, N, Arumugam, T, Dutta, S, Klee, GG, Klee, EW, Smyrk, TC, Bamlet, W, Han, JJ, Rumie Vittar, NB, De Andrade, M, Mukhopadhyay, D, Petersen, GM, Fernandez-Zapico, ME, Logsdon, CD & Chari, ST 2012, 'Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice', Gastroenterology, vol. 143, no. 6. https://doi.org/10.1053/j.gastro.2012.08.044
Aggarwal, Gaurav ; Ramachandran, Vijaya ; Javeed, Naureen ; Arumugam, Thiruvengadam ; Dutta, Shamit ; Klee, George G. ; Klee, Eric W ; Smyrk, Thomas Christopher ; Bamlet, William ; Han, Jing Jing ; Rumie Vittar, Natalia B. ; De Andrade, Mariza ; Mukhopadhyay, Debabrata ; Petersen, Gloria M ; Fernandez-Zapico, Martin E ; Logsdon, Craig D. ; Chari, Suresh T. / Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. In: Gastroenterology. 2012 ; Vol. 143, No. 6.
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abstract = "Background & Aims: 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.",
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AU - Ramachandran, Vijaya

AU - Javeed, Naureen

AU - Arumugam, Thiruvengadam

AU - Dutta, Shamit

AU - Klee, George G.

AU - Klee, Eric W

AU - Smyrk, Thomas Christopher

AU - Bamlet, William

AU - Han, Jing Jing

AU - Rumie Vittar, Natalia B.

AU - De Andrade, Mariza

AU - Mukhopadhyay, Debabrata

AU - Petersen, Gloria M

AU - Fernandez-Zapico, Martin E

AU - Logsdon, Craig D.

AU - Chari, Suresh T

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N2 - Background & Aims: 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.

AB - Background & Aims: 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.

KW - Mechanisms

KW - Mouse Model

KW - Pancreas

KW - Tumor

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