Lipid mediators and biomarkers associated with type 1 diabetes development. JCI Insight 2020 Aug 20;5(16)
Date
08/21/2020Pubmed ID
32814707Pubmed Central ID
PMC7455134DOI
10.1172/jci.insight.138034Scopus ID
2-s2.0-85089714319 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Nelson AJ, Stephenson DJ, Bone RN, Cardona CL, Park MA, Tusing YG, Lei X, Kokotos G, Graves CL, Mathews CE, Kramer J, Hessner MJ, Chalfant CE, Ramanadham SAuthor
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAnimals
Biomarkers
Child
Diabetes Mellitus, Type 1
Eicosanoids
Fatty Acids
Female
Group IV Phospholipases A2
Humans
Ketones
Lipid Metabolism
Lipids
Macrophages, Peritoneal
Male
Mice, Inbred C57BL
Mice, Inbred NOD
Naphthalenes
