biostudies-literatureSims EKBLRD VAJuvenile Diabetes Research Foundation United States of AmericaNCATS NIH HHSIndiana UniversityNIDDK NIH HHSDoris Duke Charitable FoundationNIAID NIH HHSNational Institutes of HealthJDRFJohn Templeton Foundation101261https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694631biostudies-literatureUnknown4(11)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/m²) 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.Cell reports. MedicineInhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes.PMC10694631R01 DK121987U01 DK12778662288T32 AI153020UL1 TR002529P30 DK097512I01 BX00173320212583-SRA-2015-7-M-RR01 DK127236P30 DK020595R01 DK060581R01 DK133881R01 DK121929R01 DK127308R01 DK124906Blanchfield LMirmira RGMastrandrea LDNakayasu ESWoerner SESims EKHammoud BHull AWebb-Robertson BJKulkarni ALong SACabrera SSarkar SOuyang FEvans-Molina CPerkins SMEnriquez JRGerner EWTersey SAMastracci TLDiMeglio LAfalseInhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes.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/m²) 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.2023-01-01T00:00:00Z2023 Nov2026-06-23T03:20:59.485Z2025-02-19T04:25:28.226ZS-EPMC106946313791840410.1016/j.xcrm.2023.101261