Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes
Emily K. Sims, Abhishek Kulkarni, Audrey Hull, Stéphanie Woerner, Susanne M. Cabrera, Lucy D. Mastrandrea, Batoul Hammoud, Soumyadeep Sarkar, Ernesto 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
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.