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

In preclinical models, a-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing beta cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with beta cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during beta cell stress. In a random-ized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:pla-cebo) 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. Tran-scriptomics 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 beta cell function in T1D through islet cell-autonomous effects.