Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure

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Title
Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure
Author(s)
Y K Kim; K H Joung; M J Ryu; S J Kim; H Kim; H K Chung; M H Lee; S E Lee; M J Choi; J Y Chang; H J Hong; K S Kim; S H Lee; G R Kweon; H Kim; Chul Ho Lee; H J Kim; M Shong
Bibliographic Citation
Diabetologia, vol. 58, no. 4, pp. 771-780
Publication Year
2015
Abstract
Aim/hypothesis: Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown.Methods: We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane.Results: Crif1beta?/? mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1beta?/? mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1beta?/? mice.Conclusions/interpretation: Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1beta?/? mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.
Keyword
Beta cell failureCRIF1Mitochondrial oxidative phosphorylation
ISSN
0012-186X
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00125-015-3506-y
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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