%0 Randomized Controlled Trial
%T Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes.
%A Sims EK
%A Kulkarni A
%A Hull A
%A Woerner SE
%A Cabrera S
%A Mastrandrea LD
%A Hammoud B
%A Sarkar S
%A Nakayasu ES
%A Mastracci TL
%A Perkins SM
%A Ouyang F
%A Webb-Robertson BJ
%A Enriquez JR
%A Tersey SA
%A Evans-Molina C
%A Long SA
%A Blanchfield L
%A Gerner EW
%A Mirmira RG
%A DiMeglio LA
%J Cell Rep Med
%V 4
%N 11
%D 2023 11 21
%M 37918404
%F 16.988
%R 10.1016/j.xcrm.2023.101261
%X 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.