title: GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.
abstract: 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.
  
  
  
  Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA).
  
  
  
  A case report and in vitro mechanistic studies.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Liron
authors.initials: L
authors.lastname: Danielpur
authors.affiliation: 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.
authors.forename: Yang-Sung
authors.initials: YS
authors.lastname: Sohn
authors.affiliation: 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.
authors.forename: Ola
authors.initials: O
authors.lastname: Karmi
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Fogel
authors.affiliation: 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.
authors.forename: Adar
authors.initials: A
authors.lastname: Zinger
authors.affiliation: 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.
authors.forename: Abdulsalam
authors.initials: A
authors.lastname: Abu-Libdeh
authors.affiliation: 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.
authors.forename: Tal
authors.initials: T
authors.lastname: Israeli
authors.affiliation: 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.
authors.forename: Yael
authors.initials: Y
authors.lastname: Riahi
authors.affiliation: 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.
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.affiliation: 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.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birk
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Zangen
authors.affiliation: 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.
authors.forename: Ron
authors.initials: R
authors.lastname: Mittler
authors.affiliation: 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.
authors.forename: Zvi-Ioav
authors.initials: ZI
authors.lastname: Cabantchik
authors.affiliation: 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.
authors.forename: Erol
authors.initials: E
authors.lastname: Cerasi
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nechushtai
authors.affiliation: 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.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
mesh_terms: D019588:Aging, Premature / Q000188:drug therapy*; D000818:Animals; D000077270:Exenatide; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D009896:Optic Atrophy / Q000188:drug therapy*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists