Severe Pancreatic Dysfunction But Compensated Nutritional Status in Monogenic Pancreatic Disease Caused by Carboxyl-Ester Lipase Mutations

Tjora, Erling; Wathle, Gaute Kjellevold; Engjom, Trond; Erchinger, Friedemann; Molven, Anders; Aksnes, Lage; Haldorsen, Ingfrid S.; Njølstad, Pål R.; Ræder, Helge

doi:10.1097/mpa.0b013e3182920e9c

Cited by 24 publications

(15 citation statements)

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“…First, unsupervised clustering analysis of proteomics data correctly identified the diseased subjects. Second, we also detected increased levels of digestive enzymes in healthy subjects consistent with our anticipation of a greater abundance of pancreatic proteases in healthy subjects and consistent with proteomics findings in normal pancreatic juice by endoscopic retrograde cholangiopancreatography (25), by enzymatic findings (of elastase) in feces (3), and by enzymatic findings (of amylase, lipase, and chymotrypsin) in the secretin-stimulated duodenal juice of CEL -mutation carriers (26). Third, the increased levels of digestive enzymes were confirmed by immunoblotting (for amylase).…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

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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.

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Section: Discussionsupporting

confidence: 86%

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

et al. 2013

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“…У пациентки в нашей исследовательской работе наблюдалось агрессивное течение СД, с наличием осложнений и постпранди-альной гипергликемии. Заболевание характеризуется выявляемыми в раннем детском возрасте нарушени-ями работы поджелудочной железы, проявляющимися в экскреции липидов с калом и недостаточностью фе-кальной эластазы, сниженным уровнем витамина Е, аккумуляции жировой ткани в поджелудочной железе, а в возрасте после сорока лет -развитием СД и нейро-патологией, связанной с демиелинизацией [21]. 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.…”

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MODY in Siberia – molecular genetics and clinical characteristics

Ovsyannikova¹,

Rymar²,

Shakhtshneider³

et al. 2017

Diabetes mellitus

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Institution of Internal and Preventive Medicine, Novosibirsk, Russia The diagnosis of maturity onset diabetes of the young (MODY) has high clinical significance in young patients (no absolute need for exogenous insulin; normoglycaemia in most patients achieved by dieting or taking oral hypoglycaemic agents) and their relatives (high probability of first-degree relatives being carriers of mutations, which requires a thorough collection of family history and determination of the parameters of carbohydrate metabolism). Aim. This study aimed was to determine the clinical characteristics of different subtypes of MODY in a Siberian region. Materials and Methods. We performed an examination, biochemical and hormonal blood tests, ultrasound and molecular genetic testing of 20 patients with a clinical diagnosis of MODY.Results. Four subtypes of MODY were verified: MODY2 in 11 patients, MODY3 in two, MODY8 in one and MODY12 in two. Eleven patients (69%) (2,3,8,12) were diagnosed in the present study, which differed in their clinical characteristics, presence of complications and treatment strategies. Our knowledge of monogenic forms of diabetes is expanding with the development in molecular genetics, but several aspects related to them require further study.

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“…The details of duodenal aspiration, duodenal juice handling, and analysis are described elsewhere 19 , 20 but will be briefly described later.…”

Section: Methodsmentioning

confidence: 99%

Diagnostic Accuracy of a Short Endoscopic Secretin Test in Patients With Cystic Fibrosis

et al. 2015

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ObjectiveShort endoscopic secretin tests for exocrine pancreatic function are not properly evaluated in cystic fibrosis (CF).MethodsPatients with CF and healthy controls (HCs) underwent endoscopic collection of duodenal juice between 30 and 45 minutes after secretin stimulation. Duodenal juice was analyzed for HCO3− concentration and pancreatic enzyme activities. Stool was analyzed for fecal elastase.ResultsThirty-one patients with CF and 25 HCs were tested. Patients were classified as exocrine pancreatic sufficient (n = 13) or insufficient (n = 18). Both bicarbonate concentrations and enzyme activities in duodenal juice differentiated patients with CFI from patients with CFS and HC (P < 0.001). The population displays strong correlation between severe CF genotype in both alleles and pancreatic insufficient phenotype (P < 0.001).ConclusionsPancreatic exocrine insufficient CF patients could be differentiated from exocrine sufficient patients and HCs using short endoscopic secretin test.

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Severe Pancreatic Dysfunction But Compensated Nutritional Status in Monogenic Pancreatic Disease Caused by Carboxyl-Ester Lipase Mutations

Abstract: Pancreatic exocrine dysfunction in CEL-MODY is associated with severely reduced acinar and moderately reduced ductal dysfunction. Despite severely reduced exocrine pancreatic function, CEL-MODY patients revealed only minor signs of malnutrition.

Cited by 24 publications

References 33 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

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

MODY in Siberia – molecular genetics and clinical characteristics

Diagnostic Accuracy of a Short Endoscopic Secretin Test in Patients With Cystic Fibrosis

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