Lipid mediators and biomarkers associated with type 1 diabetes development
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
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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Research Article Endocrinology Inflammation

Lipid mediators and biomarkers associated with type 1 diabetes development

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 1

Effects of temporal FKGK18 regimen on T1D incidence and islet phenotype.

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Effects of temporal FKGK18 regimen on T1D incidence and islet phenotype....
Female NOD mice were administered FKGK18 (20 mg/kg, 3 × weekly) or vehicle (PBS-T) starting at 4 or 8 weeks of age. (A and B) Diabetes incidence. Blood glucose was monitored weekly in the 4-week (A; n = 17 and 15 for PBS-T and FKGK18 groups, respectively) and 8-week (B; n = 15 each in the PBS-T and FKGK18 groups) regimen groups for up to 30 weeks. Two consecutive readings of ≥ 275 mg/dL were recorded as onset of T1D (†P < 0.05). (C–F) Glucose tolerance test (GTT). Overnight fasted mice were administered glucose (2 g/kg, i.p.), glucose levels in blood from tail vein were monitored over a 2-hour period, and AUC were generated. (C and D) Four-week group at 14 weeks of age; n = 5 each in the PBS-T and FKGK18 groups. (E and F) Eight-week group at 25 weeks of age; n = 7 and 5 for PBS-T and FKGK18 groups, respectively. (G–I) Phenotype parameters in the 8-week regimen group. (G) Urinary PGE2 metabolites (PGEMs, n = 6 in each group, 18 weeks of age). (H and I) β Cell mass (PBS-T, n = 15; FKGK18, n = 14) (H) and circulating insulin (n = 15 in each group) (I) were determined at sacrifice (PBS-T, 14–30 weeks of age; FKGK18, 16–36 weeks of age). (J and K) Islet infiltration. Paraffin sections (10 μm) of pancreas were prepared and stained with H&E. Percent infiltration for each islet was calculated as the value of noninfiltrated area subtracted from total islet area (% infiltrate = 100 × [(total area – noninfiltrated area)/(total area)]) using ImageJ software. (PBS-T, n = 14 and 166 islets; FKGK18, n = 15 and 260 islets). (J) Islet Infiltration Range. (K) Average islet infiltration. (L and M) Islet immune cell phenotype. Paraffin sections (10 μm) of pancreas were prepared and stained for CD4+-T cells or B (B220) cells. Data presented are mean ± SEM of CD4+ T cells or B cells per islet. (L) Quantitation of CD4± T cells per islet (PBS-T, n = 14 and 223 islets; FKGK18, n = 15 and 290 islets). (M) Quantitation of B cells per islet (PBS-T, n = 14 and 213 islets; FKGK18, n = 15 and 328 islets). Statistical analyses: (A and B) Mantel-Cox test; (D–M) Student’s t test.