title: Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young).
abstract: BACKGROUND
  CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas.
  
  
  METHODS
  We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure.
  
  
  RESULTS
  Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation.
  
  
  CONCLUSIONS
  In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein.
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America. helge.rader@uib.no
authors.forename: Helge
authors.initials: H
authors.lastname: Ræder
authors.forename: Mette
authors.initials: M
authors.lastname: Vesterhus
authors.forename: Abdelfattah
authors.initials: A
authors.lastname: El Ouaamari
authors.forename: Joao A
authors.initials: JA
authors.lastname: Paulo
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McAllister
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Kawamori
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001835:Body Weight; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism; D002108:Ceruletide / Q000008:administration & dosage / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D005947:Glucose / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D009154:Mutation; D046790:Pancreas, Exocrine / Q000166:cytology / Q000502:physiology; D010641:Phenotype
chemical_list: D002108:Ceruletide; D043182:Carboxylesterase; D005947:Glucose
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