Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic islet β-cells. An understudied area is the role of lipid signaling. We find that the Ca2+-independent phospholipase A2β (iPLA2β) is induced under a diabetic milieu and that mitigation of iPLA2β activity attenuates β-cell death. iPLA2β hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid. When the fatty acid is arachidonic acid, it can be metabolized to bioactive eicosanoids, many of which are pro-inflammatory. To address our overarching hypothesis that iPLA2β-derived lipids (iDLs) contribute to T1D development, we investigated the role of immune cell-iDLs in this process by utilizing a splenocyte adoptive transfer protocol. Splenocytes were prepared from 12-week-old female spontaneous diabetes prone non-obese diabetic (NOD, WT) and NOD.iPLA2β+/- (HET) donor mice and transferred into 5-week-old female immunodeficient (NOD.scid) recipient mice. Our overall findings revealed that: (1) splenocyte-iPLA2β mRNA in HET donor mice was ca. 40% of that in WT donor mice, (2) temporal IPGTTs revealed that the recipient mice of the HET genotype were more glucose tolerant, compared to recipients of the WT splenocytes; (3) weekly blood glucose monitoring revealed that all WT recipient mice developed diabetes between 11-16 weeks of age. In contrast, onset of diabetes in the HET recipient mice was delayed 3 weeks and by 16 weeks of age, 50% of these mice remained diabetes-free, (4) HET donor T-cell differentiation to Th1 phenotype is mitigated, (5) HET donor T-cell production of select pro-inflammatory lipids (i.e., 6-keto PGF1α, PGE2, and DHETs) is decreased, relative to WT donors, and (5) similar lipid signatures are evident in the terminal plasma of recipient mice. These findings suggest that immune T-cell-iPLA2β is a critical contributor to T1D development and could be targeted for therapeutics.


T. White: None. C. Chalfant: None. S. Ramanadham: None.


National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.