Liron Danielpur1, Yang-Sung Sohn1, Ola Karmi1, Chen Fogel1, Adar Zinger1, Abdulsalam Abu-Libdeh1, Tal Israeli1, Yael Riahi1, Orit Pappo1, Ruth Birk1, David H Zangen1, Ron Mittler1, Zvi-Ioav Cabantchik1, Erol Cerasi1, Rachel Nechushtai1, Gil Leibowitz1. 1. Endocrinology and Metabolism Service (L.D., C.F., T.I., Y.R., E.C., G.L.), Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; The Alexander Silberman Life Science Institute and the Wolfson Centre for Applied Structural Biology (Y.-S.S., O.K., Z.-I.C., R.N.), Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 9190401, Israel; Department of Nutrition (C.F., R.B.), Faculty of Health Sciences, Ariel University, Ariel 40700, Israel; Gastroenterology Service (A.Z.), Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Makassed Islamic Hospital (A.A.-L.), Pediatric Department, Division of Pediatric Endocrinology, Mount of Olives 19482, Jerusalem; Department of Pathology (O.P.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Division of Pediatric Endocrinology (D.H.Z.), Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; and BioDiscovery Institute and Department of Biological Sciences (R.M.), University of North Texas, Denton, Texas 76203.
Abstract
CONTEXT: Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. OBJECTIVE: Unraveling the mechanisms of β-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 β-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 β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-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.
CONTEXT: Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. OBJECTIVE: Unraveling the mechanisms of β-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-RAexenatide 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 ratinsulinoma cells and studied the mechanisms of β-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 β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-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.
Authors: Colin H Lipper; Ola Karmi; Yang Sung Sohn; Merav Darash-Yahana; Heiko Lammert; Luhua Song; Amy Liu; Ron Mittler; Rachel Nechushtai; José N Onuchic; Patricia A Jennings Journal: Proc Natl Acad Sci U S A Date: 2017-12-19 Impact factor: 11.205
Authors: Ola Karmi; Yang-Sung Sohn; Sara I Zandalinas; Linda Rowland; Skylar D King; Rachel Nechushtai; Ron Mittler Journal: Free Radic Biol Med Date: 2021-09-20 Impact factor: 7.376