Discordant Effects of Polyamine Depletion by DENSpm and DFMO on β-cell Cytokine Stress and Diabetes Outcomes in Mice.

Autor:	Hammoud B; Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA., Nelson JB; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., May SC; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Tersey SA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Mirmira RG; Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA.; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2024 Jan 16; Vol. 165 (3).
DOI:	10.1210/endocr/bqae001
Abstrakt:	Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β-cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA-sequencing analysis, however, suggests that the cellular responses to DENSpm and DFMO differ, with both showing effects on cellular proliferation but the latter showing additional effects on mRNA translation and protein-folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm, unlike DFMO, did not prevent or delay diabetes outcomes but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In nonobese diabetic (NOD) mice, short-term DENSpm administration resulted in a slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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