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 C. 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

doi: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

Gaurav Aggarwal, Vijaya Ramachandran, Naureen Javeed, Thiruvengadam Arumugam, Shamit Dutta, George G. Klee, Eric W. Klee, Thomas C. 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

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

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 language	English (US)
Pages (from-to)	1510-1517.e1
Journal	Gastroenterology
Volume	143
Issue number	6
DOIs	https://doi.org/10.1053/j.gastro.2012.08.044
State	Published - Dec 2012

Keywords

Mechanisms
Mouse Model
Pancreas
Tumor

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2012.08.044

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Aggarwal, G., Ramachandran, V., Javeed, N., Arumugam, T., Dutta, S., Klee, G. G., Klee, E. W., Smyrk, T. C., Bamlet, W., Han, J. J., Rumie Vittar, N. B., De Andrade, M., Mukhopadhyay, D., Petersen, G. M., Fernandez-Zapico, M. E., Logsdon, C. D., & 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), 1510-1517.e1. https://doi.org/10.1053/j.gastro.2012.08.044

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, pp. 1510-1517.e1. https://doi.org/10.1053/j.gastro.2012.08.044

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

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.",

keywords = "Mechanisms, Mouse Model, Pancreas, Tumor",

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

note = "Funding Information: Funding Dr Chari was supported by grants from the National Institutes of Health ( R01 CA 100685 ) and the Mayo Clinic Pancreas Cancer SPORE ( P50 CA 102701 ); Dr Fernandez-Zapico, Dr George Klee, and Dr Petersen were supported by the Mayo Clinic Pancreas Cancer SPORE ( P50 CA 102701 ); and Dr Logsdon was supported by funds from the Lockton Endowment and the Lustgarten Foundation. Dr Mukhopadhyay and Shamit Dutta were supported by funding from NIH ( R01 CA150190 ). ",

year = "2012",

month = dec,

doi = "10.1053/j.gastro.2012.08.044",

language = "English (US)",

volume = "143",

pages = "1510--1517.e1",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "6",

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TY - JOUR

T1 - Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice

AU - Aggarwal, Gaurav

AU - Ramachandran, Vijaya

AU - Javeed, Naureen

AU - Arumugam, Thiruvengadam

AU - Dutta, Shamit

AU - Klee, George G.

AU - Klee, Eric W.

AU - Smyrk, Thomas C.

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.

N1 - Funding Information: Funding Dr Chari was supported by grants from the National Institutes of Health ( R01 CA 100685 ) and the Mayo Clinic Pancreas Cancer SPORE ( P50 CA 102701 ); Dr Fernandez-Zapico, Dr George Klee, and Dr Petersen were supported by the Mayo Clinic Pancreas Cancer SPORE ( P50 CA 102701 ); and Dr Logsdon was supported by funds from the Lockton Endowment and the Lustgarten Foundation. Dr Mukhopadhyay and Shamit Dutta were supported by funding from NIH ( R01 CA150190 ).

PY - 2012/12

Y1 - 2012/12

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

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