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. Interpretation 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.

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

“…It is plausible that the mitochondrial dysfunction that occurs in FA makes DM apparent at younger ages than in the general population 37. Aging is also accompanied by changes in body composition that may hasten onset of DM (increased fat mass, particularly visceral), and individuals with FA may also demonstrate these changes at comparatively younger ages 38. It has also been previously reported that the presence of a point mutation in the frataxin gene also is associated with increased likelihood of DM,39 although we did not detect a statistically significant association in this analysis.…”

RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

“…Human and rat b-cells were transfected with 30 nmol/L small interfering RNA (siRNA) and lipofectamine RNAiMAX (Invitrogen) diluted in Opti-MEM I (Invitrogen) as described (43), resulting in a transfection efficiency of .90% (43,44). After overnight transfection, the cells were cultured for 48 h before further use.…”

Emerging Therapies in Friedreich’s Ataxia

“…Specifically, glucagon-like peptide 1 (GLP-1) and forskolin were found to reduce cell death, normalize free radical production and increase frataxin by 1.5–2 fold [37]. In a similar study of β-cells, analogs of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) have been found in vitro to partially protect frataxin-deficient islet cells from apoptosis [38]. These compounds have not yet been tested in human FRDA patients.…”