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Lipid mediators and biomarkers associated with type 1 diabetes development
Alexander J. Nelson, … , Charles E. Chalfant, Sasanka Ramanadham
Alexander J. Nelson, … , Charles E. Chalfant, Sasanka Ramanadham
Published August 20, 2020
Citation Information: JCI Insight. 2020;5(16):e138034. https://doi.org/10.1172/jci.insight.138034.
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Research Article Endocrinology Inflammation

Lipid mediators and biomarkers associated with type 1 diabetes development

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Abstract

Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2β-derived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2β reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D.

Authors

Alexander J. Nelson, Daniel J. Stephenson, Robert N. Bone, Christopher L. Cardona, Margaret A. Park, Ying G. Tusing, Xiaoyong Lei, George Kokotos, Christina L. Graves, Clayton E. Mathews, Joanna Kramer, Martin J. Hessner, Charles E. Chalfant, Sasanka Ramanadham

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Figure 6

Comparison of select plasma lipids at T1D onset.

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Comparison of select plasma lipids at T1D onset.
NOD mice were treated w...
NOD mice were treated with PBS-T or with FKGK18, starting at 10 days of age, and sacrificed at the onset of T1D (d) or at 30 weeks if they remained nondiabetic (nd). Plasma was prepared from these mice and processed for lipidomics analyses. The data (mean ± SEM) represent pmol of each lipid species in 100 or 50 μL plasma. (A) LTC4. (B) 15-HETE. (C) 5-HETE. (D) PGD2. (E) AA. (F) So1P/So. (G) EET/DHET. (H) Resolvin D2. (I) DHA. n = 3, 4, and 4 for PBS-T (P [nd]), PBS-T (P [d]), and FKGK18 (FK [nd]), respectively. P (d) significantly different from the other groups, †P < 0.05; δP < 0.01; ΔP < 0.000001. One-way ANOVA.

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