Differential effects of polyamine depletion by DENSpm and DFMO on beta cell stress reponses and type 1 diabetes outcomes in mice
Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting ß cells.  In ß 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 ß 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 currently being tested for efficacy in cancer clinical trials.  In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse ß cells.  RNA sequencing analysis, however, suggests that the cellular reponses to DENSpm and DFMO differ, with the two sharing similar effects on cellular proliferation, but the latter showing greater effects on mRNA translation and protein folding pathways.  In the low-dose streptozotocin-induced mouse model of T1D, DENSpm administration did not prevent or delay diabetes outcome, but did result in improvements in glucose tolerance and reductions in islet oxidative stress.  In non-obese diabetic (NOD) mice, short-term DENSpm administration resulted in 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 ß 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. Overall design: MIN6 ß cells were treated with vehicle, 5 mM DFMO, or 10 µM DENSpm with or without a proinflammatory cytokine mix (100 ng/lg IFN-?, 50 mg/ml TNF-a, and 25 ng/ml IL-1ß) for 24 h prior to RNA isolation.