Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid

Helge Ræder, Fiona E. McAllister, Erling Tjora, Shweta Bhatt, Ingfrid Haldorsen, Jiang Hu, Stefan M. Willems, Mette Vesterhus, Abdelfattah El Ouaamari, Manway Liu, Maria B. Ræder, Heike Immervoll, Dag Hoem, Georg Dimcevski, Pål R. Njølstad, Anders Molven, Steven P. Gygi, Rohit N. Kulkarni

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Abstract

Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MSbased measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes.

Original languageEnglish (US)
Pages (from-to)259-269
Number of pages11
JournalDiabetes
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014

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Pancreatic Cyst
Secretin
Mitogen-Activated Protein Kinases
Lipase
Esters
Mutation
Cytokines
Acinar Cells
Mason-Type Diabetes
Proteomics
Pancreas
Mass Spectrometry
Proteins
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ræder, Helge ; McAllister, Fiona E. ; Tjora, Erling ; Bhatt, Shweta ; Haldorsen, Ingfrid ; Hu, Jiang ; Willems, Stefan M. ; Vesterhus, Mette ; El Ouaamari, Abdelfattah ; Liu, Manway ; Ræder, Maria B. ; Immervoll, Heike ; Hoem, Dag ; Dimcevski, Georg ; Njølstad, Pål R. ; Molven, Anders ; Gygi, Steven P. ; Kulkarni, Rohit N. / Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid. In: Diabetes. 2014 ; Vol. 63, No. 1. pp. 259-269.
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abstract = "Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MSbased measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes.",
author = "Helge R{\ae}der and McAllister, {Fiona E.} and Erling Tjora and Shweta Bhatt and Ingfrid Haldorsen and Jiang Hu and Willems, {Stefan M.} and Mette Vesterhus and {El Ouaamari}, Abdelfattah and Manway Liu and R{\ae}der, {Maria B.} and Heike Immervoll and Dag Hoem and Georg Dimcevski and Nj{\o}lstad, {P{\aa}l R.} and Anders Molven and Gygi, {Steven P.} and Kulkarni, {Rohit N.}",
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Ræder, H, McAllister, FE, Tjora, E, Bhatt, S, Haldorsen, I, Hu, J, Willems, SM, Vesterhus, M, El Ouaamari, A, Liu, M, Ræder, MB, Immervoll, H, Hoem, D, Dimcevski, G, Njølstad, PR, Molven, A, Gygi, SP & Kulkarni, RN 2014, 'Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid', Diabetes, vol. 63, no. 1, pp. 259-269. https://doi.org/10.2337/db13-1012

Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid. / Ræder, Helge; McAllister, Fiona E.; Tjora, Erling; Bhatt, Shweta; Haldorsen, Ingfrid; Hu, Jiang; Willems, Stefan M.; Vesterhus, Mette; El Ouaamari, Abdelfattah; Liu, Manway; Ræder, Maria B.; Immervoll, Heike; Hoem, Dag; Dimcevski, Georg; Njølstad, Pål R.; Molven, Anders; Gygi, Steven P.; Kulkarni, Rohit N.

In: Diabetes, Vol. 63, No. 1, 01.01.2014, p. 259-269.

Research output: Contribution to journalArticle

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T1 - Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid

AU - Ræder, Helge

AU - McAllister, Fiona E.

AU - Tjora, Erling

AU - Bhatt, Shweta

AU - Haldorsen, Ingfrid

AU - Hu, Jiang

AU - Willems, Stefan M.

AU - Vesterhus, Mette

AU - El Ouaamari, Abdelfattah

AU - Liu, Manway

AU - Ræder, Maria B.

AU - Immervoll, Heike

AU - Hoem, Dag

AU - Dimcevski, Georg

AU - Njølstad, Pål R.

AU - Molven, Anders

AU - Gygi, Steven P.

AU - Kulkarni, Rohit N.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MSbased measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes.

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