GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome

Context: Type 2 Wolfram syndrome (T2-WFS) is a neuronal and beta-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying beta-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. Objective: Unraveling the mechanisms of beta-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). Design and Setting: A case report and in vitro mechanistic studies. Patient and Methods: We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of beta-cell dysfunction and the effects of GLP-1-RA. Results: Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. Conclusion: NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to beta-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores beta-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.