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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.

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 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.

SUBMITTER: Ræder H

PROVIDER: S-EPMC3868055 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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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 H McAllister Fiona E FE Tjora Erling E Bhatt Shweta S Haldorsen Ingfrid I Hu Jiang J Willems Stefan M SM Vesterhus Mette M El Ouaamari Abdelfattah A Liu Manway M Ræder Maria B MB Immervoll Heike H Hoem Dag D Dimcevski Georg G Njølstad Pål R PR Molven Anders A Gygi Steven P SP Kulkarni Rohit N RN

Diabetes 20130923 1

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 pro ...[more]

PMID: 24062244

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Project description:The analysis of secretin-stimulated pancreatic fluid is being evaluated as an approach to improve the early detection of pancreatic cancer and pancreatic precursor neoplasms. The method of pancreatic fluid sampling may have a significant impact on tumor marker measurements. The aim of this study was to compare concentrations of mutant DNA in pancreatic fluid from patients who had samples collected from both the pancreatic duct and duodenal lumen.Thirty-six participants enrolled in the Cancer of the Pancreas Screening studies at Johns Hopkins Hospital who had secretin-stimulated pancreatic fluid collected from the duodenum during endoscopic ultrasound (EUS) and from the pancreatic duct during subsequent endoscopic retrograde cholangiopancreatography. Mutant KRAS and GNAS DNA concentrations were measured in pancreatic fluid samples using digital high-resolution melt-curve analysis and pyrosequencing and were related total DNA concentrations in these samples.Thirty-four patients had subtle parenchymal abnormalities by EUS; seven had small pancreatic cysts; none had pancreatic cancer. KRAS mutations were detected in 29 of 36 (80.6%) pancreatic duct fluid samples. Of these 29 patients, 23 had mutations detected in their duodenal fluid (79.3%). Patients with detectable pancreatic fluid but not duodenal fluid KRAS mutations had lower average pancreatic duct fluid KRAS mutation concentrations (P=0.01). Patients with KRAS or GNAS mutations detected in pancreatic fluid but not duodenal fluid had higher total DNA concentrations in their duodenal compared with pancreatic fluid (P=0.03). KRAS and GNAS mutation concentrations were higher in pancreatic duct fluid samples than in matching duodenal fluid samples (for KRAS: 2.62 vs. 0.39%, P<0.0001).KRAS and GNAS mutation concentrations are significantly lower in secretin-stimulated pancreatic fluid samples collected from the duodenum compared with samples collected from the pancreatic duct. Efforts to improve the purity of pancreatic fluid collections from the duodenum could improve the detection of mutations arising from the pancreas.

Project description:IntroductionMutations of CEL gene were first reported to cause a new type of maturity-onset diabetes of the young (MODY) denoted as MODY8 and then were also found in patients with type 1 (T1D) and type 2 diabetes (T2D). However, its genotype-phenotype relationship has not been fully determined and how carboxyl ester lipase (CEL) variants result in diabetes remains unclear. The aim of our study was to identify pathogenic variants of CEL in patients with diabetes and confirm their pathogenicity.Research design and methodsAll five patients enrolled in our study were admitted to Shandong Provincial Hospital and diagnosed with diabetes in the past year. Whole-exome sequencing was performed to identify pathogenic variants in three patients with MODY-like diabetes, one newborn baby with T1D and one patient with atypical T2D, as well as their immediate family members. Then the consequences of the identified variants were predicted by bioinformatic analysis. Furthermore, pathogenic effects of two novel CEL variants were evaluated in HEK293 cells transfected with wild-type and mutant plasmids. Finally, we summarized all CEL gene variants recorded in Human Gene Mutation Database and analyzed the mutation distribution of CEL.ResultsFive novel heterozygous variants were identified in CEL gene and they were predicted to be pathogenic by bioinformatic analysis. Moreover, in vitro studies indicated that the expression of CELR540C was remarkably increased, while p.G729_T739del variant did not significantly affect the expression of CEL. Both novel variants obviously abrogated the secretion of CEL. Furthermore, we summarized all reported CEL variants and found that 74.3% of missense mutations were located in exons 1, 3, 4, 10 and 11 and most missense variants clustered near catalytic triad, Arg-83 and Arg-443.ConclusionOur study identified five novel CEL variants in patients with different subtypes of diabetes, expanding the gene mutation spectrum of CEL and confirmed the pathogenicity of several novel variants.

Dataset Information

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.

Publications

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.

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