BES2018 BES 2018 GLP-1 analogs protect beta cells and prevent diabetes in models of Wolfram syndrome (1 abstracts)
GLP-1 analogs protect beta cells and prevent diabetes in models of Wolfram syndrome
Igoillo-Esteve Mariana 1 , Toivonen Sanna 1 , Salpea Paraskevi 1 , Cosentino Cristina 1 , Rajaei Bahareh 1 , Musuaya Anyishai 1 , Pachera Nathalie 1 , Marchetti Piero 2 , Brown Cris 3 , Urano Fumihiko 3 , L Eizirik Decio 1 & Cnop Miriam 1,
1ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium; 2Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy; 3Department of Medicine, Washington University School of Medicine, Washington, WA, USA; 4Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Background and aims: Wolfram syndrome is a rare autosomal recessive orphan disease. The clinical manifestations are young onset diabetes, optic nerve atrophy and deafness. Most Wolfram patients carry mutations in WFS1. WFS1 deficiency results in endoplasmic reticulum (ER) stress, leading to neurodegeneration and pancreatic β-cell dysfunction and death. Glucagon-like peptide-1 (GLP-1) analogs and the cAMP inducer forskolin have been shown to protect β-cells from ER stress. Our aim is to evaluate the therapeutic potential of GLP-1 analogs for Wolfram syndrome.
Materials and methods: WFS1 was silenced in clonal human EndoC-βH1 β-cells and human islets by RNA interference. Wolfram syndrome patients’ induced pluripotent stem cells (iPSCs) were differentiated into β-like cells. Synthetic ER stress was induced by tunicamycin (5 μg/ml). β-cell apoptosis was evaluated by Hoechst 33342/propidium iodide staining. Expression of ER stress markers was examined by qPCR. Whole body wfs1 knockout (KO) mice (homozygous exon 8 deletion on 129S background) were treated for 8 weeks with dulaglutide (1 mg/kg) by intraperitoneal injection every 4 days. Glucose tolerance was evaluated before, during and at the end of treatment by intraperitoneal glucose tolerance tests.
Results: WFS1 silencing (>70% knockdown, n=6, P<0.001) sensitized EndoC-βH1 cells to tunicamycin-induced apoptosis (29±3% apoptosis in WFS1-deficient cells vs 12±1% apoptosis in control cells, n=5, P<0.01) and increased mRNA expression of the ER stress marker CHOP (P<0.001). Exendin and forskolin protected WFS1-deficient EndoC-βH1 cells from ER stress (29±3% apoptosis with tunicamycin alone vs 22±1% with tunicamycin + exendin or 10±0.3% with tunicamycin + forskolin, n=5, P<0.01). iPSCs from 4 Wolfram syndrome patients were successfully differentiated in vitro into β-like cells using a 7-stage protocol. Forskolin protected Wolfram iPSC-β-like cells from tunicamycin-induced apoptosis (n=4, P<0.001) and increased expression of the ER chaperone BiP. Wfs1 KO and wild type mice had comparable glucose tolerance at weaning (4 weeks of age). By age 6 weeks wfs1 KO mice developed glucose intolerance (n=17, P<0.01) and by age 10 weeks they developed diabetes. Dulaglutide administration, started at weaning, fully prevented the development of glucose intolerance in wfs1 KO mice after 4 and 8 weeks of treatment (n=3 per group, P<0.05).
Conclusion: cAMP induction by exendin and forskolin protects WFS1-deficient β-cells from ER stress-induced apoptosis. In vivo, dulaglutide treatment prevented diabetes development in wfs1 KO mice. These findings provide further evidence for the protective properties of GLP-1 analogs in the context of β-cell ER stress, and suggest that GLP-1 analogs hold preventive and therapeutic potential for Wolfram syndrome-related diabetes.
Volume 57
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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