Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes
Year: 2023
Type: article
Study design: Clinical Trial
Abstract: 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.
Source: Cell Reports Medicine
Authors: Emily K. Sims, Abhishek Kulkarni, Audrey Hull, Stephanie E. Woerner, Susanne Cabrera, Lucy D. Mastrandrea, Batoul Hammoud, Soumyadeep Sarkar, Ernesto S. Nakayasu, Teresa L. Mastracci, Susan M. Perkins, Fangqian Ouyang, Bobbie-Jo Webb-Robertson, Jacob R. Enriquez, Sarah A. Tersey, Carmella Evans-Molina, S. Alice Long, Lori Blanchfield, Eugene W. Gerner, Raghavendra G. Mirmira, Linda A. DiMeglio
Institutions: Indiana University Indianapolis, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, University of Chicago, Nationwide Children's Hospital, Medical College of Wisconsin, University at Buffalo, State University of New York, Pacific Northwest National Laboratory, Richard L. Roudebush VA Medical Center, Benaroya Research Institute, Cancer Prevention Pharmaceuticals (United States)
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: U.S. Department of Veterans Affairs, Doris Duke Charitable Foundation, John Templeton Foundation, Indiana University, University of Chicago, Juvenile Diabetes Research Foundation United States of America, Pediatric Endocrine Society, Diabetes Research Connection, National Institutes of Health, Diabetes Research and Training Center, University at Buffalo, School of Medicine, Indiana University, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Pacific Northwest National Laboratory, JDRF
Awards: G1074056680, G1097536129, G2750665950, Beta cell extracellular vesicles in health and disease, β cell miRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis, G4935204731, G5514976981, Exocrine-Endocrine Crosstalk and Determinants of Beta Cell Growth, G74223059, G7524921127, Indiana Clinical and Translational Sciences Institute, G8203734410, G8673008718, COVID-19 Fund to Retain Clinical Scientists, G8857125704, G9000001850, Interferon Signaling in the T1D Islet Microenvironment, Integrated Islet Distribution Program (U24) - 2021, Polyamines and Hypusine in Type 1 Diabetes Pathogenesis, Immunoengineering Postdoctoral Training Program - Resubmission - 1, Indiana Diabetes Research Center, Control of beta cell function and survival by RYR2-mediated calcium signals, Transcriptional and Translational Mechanisms Governing Beta Cell Function, Diabetes Research and Training Center , Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes
OpenAlex ID: W4388141948