The ΔF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional β-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, deletion of phenylalanine at position 508 (ΔF508), on glucose homeostasis in mice. We compared ΔF508 mutant mice with wild-type (WT) littermates. Twelve-week-old male ΔF508 mutants had lower body weight, improved oral glucose tolerance, and a trend toward higher insulin tolerance. Glucose-induced insulin secretion was slightly diminished in ΔF508 mutant islets, due to reduced insulin content, but ΔF508 mutant islets were not more sensitive to proinflammatory cytokines than WT islets. Hyperglycemic clamps confirmed an increase in insulin sensitivity with normal β-cell function in 12- and 18-week-old ΔF508 mutants. In contrast, 24-week-old ΔF508 mutants exhibited insulin resistance and reduced β-cell function. β-Cell mass was unaffected at 11 weeks of age but was significantly lower in ΔF508 mutants versus controls at 24 weeks. This was not associated with gross pancreatic pathology. We conclude that the ΔF508 CFTR mutation does not lead to an intrinsic β-cell secretory defect but is associated with insulin resistance and a β-cell mass deficit in aging mutants.
Montreal Diabetes Research Center, University of Montreal, Quebec, Canada University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Ghislaine
G
Fontés
Montreal Diabetes Research Center, University of Montreal, Quebec, Canada University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Julien
J
Ghislain
Montreal Diabetes Research Center, University of Montreal, Quebec, Canada University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada.
Isma
I
Benterki
Montreal Diabetes Research Center, University of Montreal, Quebec, Canada University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
Bader
B
Zarrouki
University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada.
Dominique
D
Trudel
University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Yves
Y
Berthiaume
Montreal Diabetes Research Center, University of Montreal, Quebec, Canada University of Montreal Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada Department of Medicine, University of Montreal, Montreal, Quebec, Canada vincent.poitout@umontreal.ca.
Vincent
V
Poitout
D000375:Aging; D000818:Animals; D003433:Crosses, Genetic; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation; D046509:Tissue Culture Techniques
C505032:CFTR protein, human; D007328:Insulin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator