Sims, Emily K.Kulkarni, AbhishekHull, AudreyWoerner, Stephanie E.Cabrera, SusanneMastrandrea, Lucy D.Hammoud, BatoulSarkar, SoumyadeepNakayasu, Ernesto S.Mastracci, Teresa L.Perkins, Susan M.Ouyang, FangqianWebb-Robertson, Bobbie-JoEnriquez, Jacob R.Tersey, Sarah A.Evans-Molina, CarmellaLong, S. AliceBlanchfield, LoriGerner, Eugene W.Mirmira, Raghavendra G.DiMeglio, Linda A.2024-05-102024-05-102023Sims EK, Kulkarni A, Hull A, et al. Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes. Cell Rep Med. 2023;4(11):101261. doi:10.1016/j.xcrm.2023.101261https://hdl.handle.net/1805/40638In 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalDisease modificationIsletOrnithine decarboxylasePolyaminesPreventionTrialType 1 diabetesα-difluoromethylornithineβ cellβ cell stressArticle