title: Central role and mechanisms of β-cell dysfunction and death in friedreich ataxia-associated diabetes.
abstract: OBJECTIVE
  Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused in almost all cases by homozygosity for a GAA trinucleotide repeat expansion in the frataxin gene. Frataxin is a mitochondrial protein involved in iron homeostasis. FRDA patients have a high prevalence of diabetes, the pathogenesis of which is not known. We aimed to evaluate the relative contribution of insulin resistance and β-cell failure and the pathogenic mechanisms involved in FRDA diabetes.
  
  
  METHODS
  Forty-one FRDA patients, 26 heterozygous carriers of a GAA expansion, and 53 controls underwent oral and intravenous glucose tolerance tests. β-Cell proportion was quantified in postmortem pancreas sections from 9 unrelated FRDA patients. Using an in vitro disease model, we studied how frataxin deficiency affects β-cell function and survival.
  
  
  RESULTS
  FRDA patients had increased abdominal fat and were insulin resistant. This was not compensated for by increased insulin secretion, resulting in a markedly reduced disposition index, indicative of pancreatic β-cell failure. Loss of glucose tolerance was driven by β-cell dysfunction, which correlated with abdominal fatness. In postmortem pancreas sections, pancreatic islets of FRDA patients had a lower β-cell content. RNA interference-mediated frataxin knockdown impaired glucose-stimulated insulin secretion and induced apoptosis in rat β cells and human islets. Frataxin deficiency sensitized β cells to oleate-induced and endoplasmic reticulum stress-induced apoptosis, which could be prevented by the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.
  
  
  CONCLUSIONS
  Pancreatic β-cell dysfunction is central to diabetes development in FRDA as a result of mitochondrial dysfunction and higher sensitivity to metabolic and endoplasmic reticulum stress-induced β-cell death.
authors.affiliation: Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Brussels, Belgium. mcnop@ulb.ac.be
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Audrey
authors.initials: A
authors.lastname: Begu
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Serroukh
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.forename: Anyishai E
authors.initials: AE
authors.lastname: Musuaya
authors.forename: Ihsane
authors.initials: I
authors.lastname: Marhfour
authors.forename: Laurence
authors.initials: L
authors.lastname: Ladrière
authors.forename: Xavier
authors.initials: X
authors.lastname: Moles Lopez
authors.forename: Dionysios
authors.initials: D
authors.lastname: Lefkaditis
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moore
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cooper
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.forename: Anne
authors.initials: A
authors.lastname: Clark
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Koeppen
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Françoise
authors.initials: F
authors.lastname: Féry
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000818:Animals; D050218:Body Fat Distribution; D003920:Diabetes Mellitus / Q000209:etiology* / Q000473:pathology*; D004734:Energy Metabolism / Q000235:genetics; D005192:Family Health; D005260:Female; D005434:Flow Cytometry; D005621:Friedreich Ataxia / Q000150:complications* / Q000235:genetics; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D033862:Iron-Binding Proteins / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D051381:Rats; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000096923:Frataxin
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D033862:Iron-Binding Proteins; D000096923:Frataxin