TY - JOUR
T1 - Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes
AU - Sims, Emily K.
AU - Kulkarni, Abhishek
AU - Hull, Audrey
AU - Woerner, Stephanie E.
AU - Cabrera, Susanne
AU - Mastrandrea, Lucy D.
AU - Hammoud, Batoul
AU - Sarkar, Soumyadeep
AU - Nakayasu, Ernesto S.
AU - Mastracci, Teresa L.
AU - Perkins, Susan M.
AU - Ouyang, Fangqian
AU - Webb-Robertson, Bobbie Jo
AU - Enriquez, Jacob R.
AU - Tersey, Sarah A.
AU - Evans-Molina, Carmella
AU - Long, S. Alice
AU - Blanchfield, Lori
AU - Gerner, Eugene W.
AU - Mirmira, Raghavendra G.
AU - DiMeglio, Linda A.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/11/21
Y1 - 2023/11/21
N2 - 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.
AB - 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.
KW - disease modification
KW - islet
KW - ornithine decarboxylase
KW - polyamines
KW - prevention
KW - trial
KW - type 1 diabetes
KW - α-difluoromethylornithine
KW - β cell
KW - β cell stress
UR - https://www.scopus.com/pages/publications/85177078558
U2 - 10.1016/j.xcrm.2023.101261
DO - 10.1016/j.xcrm.2023.101261
M3 - Article
C2 - 37918404
AN - SCOPUS:85177078558
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 11
M1 - 101261
ER -