Central Role and Mechanisms of β-Cell Dysfunction and Death in Friedreich Ataxia-Associated Diabetes

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 beta-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. beta-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 beta-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 beta-cell failure. Loss of glucose tolerance was driven by beta-cell dysfunction, which correlated with abdominal fatness. In postmortem pancreas sections, pancreatic islets of FRDA patients had a lower beta-cell content. RNA interference-mediated frataxin knockdown impaired glucose-stimulated insulin secretion and induced apoptosis in rat beta cells and human islets. Frataxin deficiency sensitized beta 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. Interpretation: Pancreatic beta-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 beta-cell death. ANN NEUROL 2012;72:971-982