The [Delta]F508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional [Beta]-Cell Mass in Mice

Cystic fibrosis (CF) is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF-related diabetes affects 50% of adult CF patients. How CFTR deficiency predisposes to diabetes is unknown. Herein, we examined the impact of the most frequent cftr mutation in humans...

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Published inDiabetes (New York, N.Y.) Vol. 64; no. 12; p. 4112
Main Authors Fontés, Ghislaine, Ghislain, Julien, Benterki, Isma, Zarrouki, Bader, Trudel, Dominique, Berthiaume, Yves, Poitout, Vincent
Format Journal Article
LanguageEnglish
Published New York American Diabetes Association 01.12.2015
Subjects
Cells
Cystic fibrosis
Insulin resistance
Membranes
Mutation
Rodents
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Summary:Cystic fibrosis (CF) is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF-related diabetes affects 50% of adult CF patients. How CFTR deficiency predisposes to diabetes is unknown. Herein, we examined the impact of the most frequent cftr mutation in humans, deletion of phenylalanine at position 508 (...F508), on glucose homeostasis in mice. We compared ...F508 mutant mice with wild-type (WT) littermates. Twelve-week-old male ...F508 mutants had lower body weight, improved oral glucose tolerance, and a trend toward higher insulin tolerance. Glucose-induced insulin secretion was slightly diminished in ...F508 mutant islets, due to reduced insulin content, but ...F508 mutant islets were not more sensitive to proinflammatory cytokines than WT islets. Hyperglycemic clamps confirmed an increase in insulin sensitivity with normal ...-cell function in 12- and 18-week-old ...F508 mutants. In contrast, 24-week-old ...F508 mutants exhibited insulin resistance and reduced ...-cell function. ...-Cell mass was unaffected at 11 weeks of age but was significantly lower in ...F508 mutants versus controls at 24 weeks. This was not associated with gross pancreatic pathology. We conclude that the ...F508 CFTR mutation does not lead to an intrinsic ...-cell secretory defect but is associated with insulin resistance and a ...-cell mass deficit in aging mutants. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0012-1797
1939-327X