{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:03:44Z","timestamp":1792047824174,"version":"4.4.0"},"reference-count":61,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,12,31]],"date-time":"2012-12-31T00:00:00Z","timestamp":1356912000000},"content-version":"vor","delay-in-days":30,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>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 \u03b2\u2010cell failure and the pathogenic mechanisms involved in FRDA diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Forty\u2010one FRDA patients, 26 heterozygous carriers of a GAA expansion, and 53 controls underwent oral and intravenous glucose tolerance tests. \u03b2\u2010Cell proportion was quantified in postmortem pancreas sections from 9 unrelated FRDA patients. Using an in vitro disease model, we studied how frataxin deficiency affects \u03b2\u2010cell function and survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>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 \u03b2\u2010cell failure. Loss of glucose tolerance was driven by \u03b2\u2010cell dysfunction, which correlated with abdominal fatness. In postmortem pancreas sections, pancreatic islets of FRDA patients had a lower \u03b2\u2010cell content. RNA interference\u2013mediated frataxin knockdown impaired glucose\u2010stimulated insulin secretion and induced apoptosis in rat \u03b2 cells and human islets. Frataxin deficiency sensitized \u03b2 cells to oleate\u2010induced and endoplasmic reticulum stress\u2010induced apoptosis, which could be prevented by the incretins glucagon\u2010like peptide\u20101 and glucose\u2010dependent insulinotropic polypeptide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>Pancreatic \u03b2\u2010cell dysfunction is central to diabetes development in FRDA as a result of mitochondrial dysfunction and higher sensitivity to metabolic and endoplasmic reticulum stress\u2010induced \u03b2\u2010cell death. 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