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 Ræder1,2,3⇑,
- Fiona E. McAllister4,
- Erling Tjora2,3,
- Shweta Bhatt1,
- Ingfrid Haldorsen5,6,
- Jiang Hu1,
- Stefan M. Willems4,
- Mette Vesterhus7,
- Abdelfattah El Ouaamari1,
- Manway Liu8,
- Maria B. Ræder3,
- Heike Immervoll9,10,11,
- Dag Hoem12,
- Georg Dimcevski7,
- Pål R. Njølstad2,3,
- Anders Molven9,10,
- Steven P. Gygi4 and
- Rohit N. Kulkarni1
- 1Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- 2Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
- 3KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
- 4Department of Cell Biology, Harvard Medical School, Boston, MA
- 5Department of Radiology, Haukeland University Hospital, Bergen, Norway
- 6Section for Radiology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- 7Department of Medicine, Haukeland University Hospital, Bergen, Norway
- 8Department of Biomedical Engineering, Boston University, Boston, MA
- 9Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- 10Department of Pathology, Haukeland University Hospital, Bergen, Norway
- 11Department of Pathology, Ålesund Hospital, Ålesund, Norway
- 12Department of Surgery, Haukeland University Hospital, Bergen, Norway
- Corresponding author: Helge Ræder, .
F.E.M. and E.T. contributed equally.
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 MS-based 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1012/-/DC1.
- Received June 28, 2013.
- Accepted September 16, 2013.
- © 2014 by the American Diabetes Association.
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