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

Journal Article · · Cell Reports Medicine
 [1];  [2];  [3];  [1];  [4];  [5];  [2];  [6];  [6];  [7];  [1];  [1];  [6];  [2];  [2];  [8];  [9];  [9];  [10];  [2] more »;  [1] « less
  1. Indiana University School of Medicine, Indianapolis IN (United States)
  2. Univ. of Chicago, IL (United States)
  3. Indiana University School of Medicine, Indianapolis IN (United States); Nationwide Children's Hospital Pediatric Residency Program, Columbus, OH (United States)
  4. Medical College of Wisconsin, Milwaukee, WI (United States)
  5. Univ. at Buffalo, NY (United States)
  6. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
  7. Indiana Univ.-Purdue Univ. Indianapolis (IUPUI), Indianapolis, IN (United States)
  8. Indiana University School of Medicine, Indianapolis IN (United States); Roudebush VA Medical Center, Indianapolis, IN (United States)
  9. Benaroya Research Inst., Seattle, WA (United States)
  10. Cancer Prevention Pharmaceuticals, Tucson, AZ (United States)
+ Show Author Affiliations
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.
Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
2332845
Report Number(s):
PNNL-SA--194634
Journal Information:
Cell Reports Medicine, Journal Name: Cell Reports Medicine Journal Issue: 11 Vol. 4; ISSN 2666-3791
Publisher:
Cell PressCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
disease modification
islet
ornithine decarboxylase
polyamines
prevention
trial
type 1 diabetes
α-difluoromethylornithine
β cell
β cell stress