Central role and mechanisms of β-cell dysfunction and death in friedreich ataxia–associated diabetes
Article first published online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 6, pages 971–982, December 2012
How to Cite
Cnop, M., Igoillo-Esteve, M., Rai, M., Begu, A., Serroukh, Y., Depondt, C., Musuaya, A. E., Marhfour, I., Ladrière, L., Moles Lopez, X., Lefkaditis, D., Moore, F., Brion, J.-P., Cooper, J. M., Schapira, A. H. V., Clark, A., Koeppen, A. H., Marchetti, P., Pandolfo, M., Eizirik, D. L. and Féry, F. (2012), Central role and mechanisms of β-cell dysfunction and death in friedreich ataxia–associated diabetes. Ann Neurol., 72: 971–982. doi: 10.1002/ana.23698
- Issue published online: 31 DEC 2012
- Article first published online: 31 DEC 2012
- Accepted manuscript online: 20 JUL 2012 04:07AM EST
- Manuscript Accepted: 29 JUN 2012
- Manuscript Revised: 14 JUN 2012
- Manuscript Received: 27 FEB 2012
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.
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.
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.
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. ANN NEUROL 2012;72:971–982