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

• Published in: Cell reports. Medicine Vol. 4; no. 11; p. 101261
• Main Authors: Sims, Emily K., Kulkarni, Abhishek, Hull, Audrey, Woerner, Stephanie E., Cabrera, Susanne, Mastrandrea, Lucy D., Hammoud, Batoul, Sarkar, Soumyadeep, Nakayasu, Ernesto S., Mastracci, Teresa L., Perkins, Susan M., Ouyang, Fangqian, Webb-Robertson, Bobbie-Jo, Enriquez, Jacob R., Tersey, Sarah A., Evans-Molina, Carmella, Long, S. Alice, Blanchfield, Lori, Gerner, Eugene W., Mirmira, Raghavendra G., DiMeglio, Linda A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.11.2023; Cell Press; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Advanced Basic Science; Animals; Diabetes Mellitus, Type 1 - drug therapy; disease modification; Eflornithine - pharmacology; Eflornithine - therapeutic use; Humans; islet; Mice; ornithine decarboxylase; Ornithine Decarboxylase - genetics; Ornithine Decarboxylase - metabolism; Ornithine Decarboxylase Inhibitors - pharmacology; polyamines; prevention; Putrescine - metabolism; trial; type 1 diabetes; α-difluoromethylornithine; β cell; β cell stress; type 1 diabetes; α-difluoromethylornithine; β cell stress; β cell; ornithine decarboxylase; islet; polyamines; prevention; trial; disease modification
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101261

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. [Display omitted] •DFMO treatment is safe and preserves β cell function in subjects with T1D•β cell knockout of the DFMO target ODC in mice reduces hyperglycemia•DFMO treatment of human islets influences protein production and release pathways Sims et al. integrate experiments with β cell-specific knockout mice and human islets in vitro alongside a multicenter clinical trial to show that inhibition of polyamine biosynthesis is a safe approach to protect β cell function in individuals with recent-onset type 1 diabetes.