title: Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure.
abstract: OBJECTIVE
  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
  Crif1(beta-/-) 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, Crif1(beta-/-) 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 Crif1(beta-/-) mice.
  
  
  CONCLUSIONS
  Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.
authors: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 301-721, Korea.
authors: Yong Kyung
authors: YK
authors: Kim
authors: Kyong Hye
authors: KH
authors: Joung
authors: Min Jeong
authors: MJ
authors: Ryu
authors: Soung Jung
authors: SJ
authors: Kim
authors: Hyeongseok
authors: H
authors: Kim
authors: Hyo Kyun
authors: HK
authors: Chung
authors: Min Hee
authors: MH
authors: Lee
authors: Seong Eun
authors: SE
authors: Lee
authors: Min Jeong
authors: MJ
authors: Choi
authors: Joon Young
authors: JY
authors: Chang
authors: Hyun Jung
authors: HJ
authors: Hong
authors: Koon Soon
authors: KS
authors: Kim
authors: Sang-Hee
authors: SH
authors: Lee
authors: Gi Ryang
authors: GR
authors: Kweon
authors: Hail
authors: H
authors: Kim
authors: Chul-Ho
authors: CH
authors: Lee
authors: Hyun Jin
authors: HJ
authors: Kim
authors: Minho
authors: M
authors: Shong
mesh_terms: D000367:Age Factors; D000818:Animals; D001343:Autophagy; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D000077270:Exenatide; D005838:Genotype; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054795:Incretins / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001786:Blood Glucose; D018797:Cell Cycle Proteins; C527307:Crif1 protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists