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

被引：11

作者：

Sims, Emily K. ^{[1
]}

Kulkarni, Abhishek ^{[2
,3
]}

Hull, Audrey ^{[1
,4
]}

Woerner, Stephanie E. ^{[1
]}

Cabrera, Susanne ^{[5
]}

Mastrandrea, Lucy D. ^{[6
]}

Hammoud, Batoul ^{[7
]}

Sarkar, Soumyadeep ^{[8
]}

Nakayasu, Ernesto S. ^{[8
]}

Mastracci, Teresa L. ^{[9
]}

Perkins, Susan M. ^{[10
]}

Ouyang, Fangqian ^{[10
]}

Webb-Robertson, Bobbie-Jo ^{[8
]}

Enriquez, Jacob R. ^{[2
,3
]}

Tersey, Sarah A. ^{[2
,3
]}

Evans-Molina, Carmella ^{[1
,11
,12
,13
]}

Long, S. Alice ^{[14
]}

Blanchfield, Lori ^{[14
]}

Gerner, Eugene W. ^{[15
]}

Mirmira, Raghavendra G. ^{[2
,3
,7
]}

Dimeglio, Linda A. ^{[1
]}

机构：

[1] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Ctr Diabet & Metab Dis, Div Pediat Endocrinol & Diabetol, Indianapolis, IN 46202 USA

[2] Univ Chicago, Kovler Diabet Ctr, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[4] Nationwide Childrens Hosp, Pediat Residency Program, Columbus, OH 43205 USA

[5] Med Coll Wisconsin, Dept Pediat, Sect Endocrinol & Diabet, Milwaukee, WI 53226 USA

[6] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Div Pediat Endocrinol, Buffalo, NY 14203 USA

[7] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA

[8] Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99354 USA

[9] Indiana Univ Purdue Univ Indianapolis, Dept Biol, Indianapolis, IN 46202 USA

[10] Indiana Univ Sch Med, Dept Biostat & Hlth Data Sci, Indianapolis, IN 46202 USA

[11] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA

[12] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

[13] Roudebush VA Med Ctr, Indianapolis, IN 46202 USA

[14] Benaroya Res Inst, Ctr Translat Immunol, Seattle, WA 98101 USA

[15] Canc Prevent Pharmaceut, Tucson, AZ 85718 USA

来源：

CELL REPORTS MEDICINE | 2023年 / 4卷 / 11期

关键词：

DOUBLE-BLIND; ONSET; DFMO; IDENTIFICATION; LOCALIZATION; INFLAMMATION; MULTICENTER; DYSFUNCTION; PROINSULIN; PEPTIDES;

D O I：

10.1016/j.xcrm.2023.101261

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：20

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