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: Helge Ræder, Mette Vesterhus, Abdelfattah El Ouaamari, Joao A Paulo, Fiona E McAllister, Chong Wee Liew, Jiang Hu, Dan Kawamori, Anders Molven, Steven P Gygi, Pål R Njølstad, C Ronald Kahn, Rohit N Kulkarni
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e60229 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23565203 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ceruletide
• Carboxylesterase
• Glucose

Topics

• Animals
• Animals, Genetically Modified
• Body Weight
• Carboxylesterase (genetics, metabolism)
• Ceruletide (administration & dosage, pharmacology)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Diet
• Disease Models, Animal
• Gene Expression
• Gene Order
• Glucose (metabolism)
• Islets of Langerhans (metabolism)
• Mice
• Mutation
• Pancreas, Exocrine (cytology, physiology)
• Phenotype