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 9

β Cell regeneration and modulation of Th cell subsets after lentivirus and dietary therapy with ω-3 PUFAs in diabetic NOD mice.

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β Cell regeneration and modulation of Th cell subsets after lentivirus a...
Mice were sacrificed at 9 weeks of age following lentivirus treatment and DHA plus EPA dietary intervention, and pancreases were harvested. (A) Concentrations of nonfasting serum glucagon levels in nondiabetic mice; diabetic NOD mice (nonfasting blood glucose level for 2 consecutive weeks <20 mmol/l) before treatment; and diabetic NOD mice (nonfasting blood glucose level for 2 consecutive weeks >11.1 mmol/l) after ω-3 PUFA therapy (n = 5–7/group). *P < 0.05, **P < 0.01, and ***P < 0.0001 versus the nondiabetic group (Student’s t test). Data are representative of 2 independent experiments. (B–D) mRNA expression of Pdx1, Pax4, and Arx measured by RT-PCR in pancreases from NOD mice that received ω-3 PUFA therapy. *P < 0.05, **P < 0.01, and ***P < 0.0001 compared with the lenti-con group (n = 3 per group) (Student’s t test). Data are representative of 3 independent experiments. (E–N) Quantification (n = 4–10 per group) of the percentage of intracellular staining of IFN-γ+, IL-4+, IL-7+, and CD25+FoxP3+ Th cells in LNs and spleens of diabetic NOD mice that received ω-3 PUFA therapy. Representative flow cytometric images are shown in Supplemental Figure 8. Data are representative of 3 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.0001 compared with the lenti-con group (Student’s t test). All values represent the mean ± SEM.