ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity
Xinyun Bi, … , Xiaoxi Li, Allan Zijian Zhao
Xinyun Bi, … , Xiaoxi Li, Allan Zijian Zhao
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1757-1771. https://doi.org/10.1172/JCI87388.
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Research Article Autoimmunity Endocrinology

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

Abstract

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the β cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D.

Authors

Xinyun Bi, Fanghong Li, Shanshan Liu, Yan Jin, Xin Zhang, Tao Yang, Yifan Dai, Xiaoxi Li, Allan Zijian Zhao

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Figure 1

ω-3 PUFAs ameliorate the development of T1D and normalize glucose metabolism in NOD mice.

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ω-3 PUFAs ameliorate the development of T1D and normalize glucose metabo...
(A) Blood glucose concentrations in 3 groups of NOD mice on varied diets were monitored weekly until 40 weeks of age. Sustained hyperglycemia for 2 consecutive weeks (>11.11 mmol/l) marked the onset of disease, which was used to create a life table to determine the incidence of diabetes (n = 15/group). Statistical calculation was done using a Mantel-Cox log-rank test. (B) Sections (4-μm-thick) of pancreas from 20-week-old NOD mice were formaldehyde fixed, paraffin embedded, and stained with H&E (n =7/group). Islets were sorted into the following 4 categories on the basis of the relative degree of immune infiltration: no insulitis (0), peri-insulitis (1), invasive insulitis (2), or severe insulitis (3). Representative pancreatic sections are shown in Supplemental Figure 1. The differences in severe insulitis between DHA plus EPA group and the control group (P < 0.0001) and between the DHA plus EPA group and the AA group (P = 0.0008) were significant. The finding of no insulitis in the DHA plus EPA group was increased compared with the control (P = 0.02) and AA (P < 0.0001) groups. Statistical calculation was done using Pearson’s χ2 test. (C) Glucose tolerance tests (GTTs) in NOD mice fed a control, AA, or DHA plus EPA diet (n = 15/group) at 20 weeks of age. (D) AUC for GTTs performed in 3 groups of NOD mice fed different diets. (E) Serum insulin concentrations during the GTT at the indicated time points (n = 10/group). (F) Insulin tolerance tests (n = 10/group). (C–E) *P < 0.05, **P < 0.01, and ***P < 0.0001 versus the control group (Student’s t test). Data are representative of 2 independent experiments. All values represent the mean ± SEM.