Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes.

Autor:	Sims EK; Division of Pediatric Endocrinology and Diabetology, Herman B. Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: eksims@iu.edu., Kulkarni A; Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Hull A; Division of Pediatric Endocrinology and Diabetology, Herman B. Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Nationwide Children's Hospital Pediatric Residency Program, Columbus, OH 43205, USA., Woerner SE; Division of Pediatric Endocrinology and Diabetology, Herman B. Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Cabrera S; Department of Pediatrics, Section of Endocrinology and Diabetes, Medical College of Wisconsin, Milwaukee, WI 53226, USA., Mastrandrea LD; Division of Pediatric Endocrinology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA., Hammoud B; Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA., Sarkar S; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Nakayasu ES; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Mastracci TL; Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA., Perkins SM; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Ouyang F; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Webb-Robertson BJ; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Enriquez JR; Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Tersey SA; Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Evans-Molina C; Division of Pediatric Endocrinology and Diabetology, Herman B. Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medicine and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush VA Medical Center, Indianapolis, IN 46202, USA., Long SA; Benaroya Research Institute, Center for Translational Immunology, Seattle, WA 98101, USA., Blanchfield L; Benaroya Research Institute, Center for Translational Immunology, Seattle, WA 98101, USA., Gerner EW; Cancer Prevention Pharmaceuticals, Tucson, AZ 85718, USA., Mirmira RG; Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA. Electronic address: mirmira@uchicago.edu., DiMeglio LA; Division of Pediatric Endocrinology and Diabetology, Herman B. Wells Center for Pediatric Research, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Nov 21; Vol. 4 (11), pp. 101261. Date of Electronic Publication: 2023 Nov 01.
DOI:	10.1016/j.xcrm.2023.101261
Abstrakt:	In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing β cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with β cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during β cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m 2 ) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve β cell function in T1D through islet cell-autonomous effects. Competing Interests: Declaration of interests R.G.M., L.A.D., and E.W.G. are coauthors on a patent application using DFMO for treatment of β cell dysfunction in T1D. E.W.G. is an employee of Cancer Prevention Pharmaceuticals. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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