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.

ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents

“…Heterozygous mutations in CEL , which encodes a pancreatic lipase, cause an autosomal dominant disorder of pancreatic exocrine insufficiency and diabetes . Importantly, the exocrine component of the syndrome is initiated already in childhood, 10 to 30 years before diabetes develops, and can be revealed by lowered fecal elastase and/or pancreatic lipomatosis . Other autosomal dominant monogenic diseases affecting mainly the exocrine pancreas that can lead to diabetes sooner or later include cystic fibrosis ( CFTR ), hereditary pancreatitis ( PRSS1 and SPINK1 ), and pancreatic agenesis/hypoplasia ( GATA6 )…”

MODY in Siberia – molecular genetics and clinical characteristics

“…Было показано, что у пациентов с MODY, обусловленным мутациями в гене CEL, параллельно с манифестацией диабета в поджелудочной железе формируются множе-ственные кисты, их количество коррелирует с возрастом пациентов. Известно, что такие кисты поджелудочной железы являются факторами риска для развития онко-логического процесса, из этого было сделано заклю-чение, что пациенты с MODY 8 имеют повышенный риск развития рака поджелудочной железы [22]. Таким образом, у пациентки с данным подтипом СД оправ-дано проведение ежегодного УЗИ брюшной полости для скрининга рака поджелудочной железы.…”

Carboxyl-Ester Lipase Maturity-Onset Diabetes of the Young Disease Protein Biomarkers in Secretin-Stimulated Duodenal Juice

“…The selected targeted proteomics peptides were based on the most differentially expressed proteins from the discovery study. 3 The healthy controls were unrelated to the family. (B) Amylase quantities are measured with SRM by the signature peptide TGSGDIENYNDATQVR for healthy controls and CEL mutation carriers.…”

“…3 Clearly, diabetes development heralds a more severe and advanced disease stage in these patients. Because CEL mutation carriers develop age-dependent disease stages in such a predictable manner, studies of protein biomarker levels in these CEL mutation carriers before and after diabetes development may provide important information about pathogenic proteins as well as provide potential diagnostic and therapeutic proteins markers in general 4 to be further explored more generally in pancreatic disease.…”