University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
University of California, Davis, Davis, CA, USA.
Diabetologia. 2021 Aug;64(8):1785-1794. doi: 10.1007/s00125-021-05457-9. Epub 2021 Apr 24.
AIMS/HYPOTHESIS: Oxylipins are lipid mediators derived from polyunsaturated fatty acids. Some oxylipins are proinflammatory (e.g. those derived from arachidonic acid [ARA]), others are pro-resolving of inflammation (e.g. those derived from α-linolenic acid [ALA], docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and others may be both (e.g. those derived from linoleic acid [LA]). The goal of this study was to examine whether oxylipins are associated with incident type 1 diabetes.
We conducted a nested case-control analysis in the Diabetes Autoimmunity Study in the Young (DAISY), a prospective cohort study of children at risk of type 1 diabetes. Plasma levels of 14 ARA-derived oxylipins, ten LA-derived oxylipins, six ALA-derived oxylipins, four DHA-derived oxylipins and two EPA-related oxylipins were measured by ultra-HPLC-MS/MS at multiple timepoints related to autoantibody seroconversion in 72 type 1 diabetes cases and 71 control participants, which were frequency matched on age at autoantibody seroconversion (of the case), ethnicity and sample availability. Linear mixed models were used to obtain an age-adjusted mean of each oxylipin prior to type 1 diabetes. Age-adjusted mean oxylipins were tested for association with type 1 diabetes using logistic regression, adjusting for the high risk HLA genotype HLA-DR3/4,DQB1*0302. We also performed principal component analysis of the oxylipins and tested principal components (PCs) for association with type 1 diabetes. Finally, to investigate potential critical timepoints, we examined the association of oxylipins measured before and after autoantibody seroconversion (of the cases) using PCs of the oxylipins at those visits.
The ARA-related oxylipin 5-HETE was associated with increased type 1 diabetes risk. Five LA-related oxylipins, two ALA-related oxylipins and one DHA-related oxylipin were associated with decreased type 1 diabetes risk. A profile of elevated LA- and ALA-related oxylipins (PC1) was associated with decreased type 1 diabetes risk (OR 0.61; 95% CI 0.40, 0.94). A profile of elevated ARA-related oxylipins (PC2) was associated with increased diabetes risk (OR 1.53; 95% CI 1.03, 2.29). A critical timepoint analysis showed type 1 diabetes was associated with a high ARA-related oxylipin profile at post-autoantibody-seroconversion but not pre-seroconversion.
CONCLUSIONS/INTERPRETATION: The protective association of higher LA- and ALA-related oxylipins demonstrates the importance of both inflammation promotion and resolution in type 1 diabetes. Proinflammatory ARA-related oxylipins may play an important role once the autoimmune process has begun.
目的/假设：氧化脂是源自多不饱和脂肪酸的脂质介质。一些氧化脂具有促炎作用（例如源自花生四烯酸[ARA]的那些），其他则具有抗炎作用（例如源自α-亚麻酸[ALA]、二十二碳六烯酸[DHA]和二十碳五烯酸[EPA]的那些），而其他可能兼具两者的特性（例如源自亚油酸[LA]的那些）。本研究的目的是检验氧化脂是否与 1 型糖尿病的发生有关。
我们在儿童糖尿病自身免疫研究（DAISY）中进行了一项嵌套病例对照分析，这是一项针对 1 型糖尿病高危儿童的前瞻性队列研究。在 72 例 1 型糖尿病病例和 71 例对照参与者中，在与自身抗体转化相关的多个时间点，通过超高效液相色谱-串联质谱法（UPLC-MS/MS）测量了 14 种源自 ARA 的氧化脂、10 种源自 LA 的氧化脂、6 种源自 ALA 的氧化脂、4 种源自 DHA 的氧化脂和 2 种与 EPA 相关的氧化脂。使用线性混合模型获得每个氧化脂在发生 1 型糖尿病之前的年龄调整均值。使用逻辑回归检验年龄调整后的氧化脂与 1 型糖尿病的相关性，调整了高风险 HLA 基因型 HLA-DR3/4、DQB1*0302。我们还对氧化脂进行了主成分分析，并检验了与 1 型糖尿病相关的主成分（PCs）。最后，为了研究潜在的关键时间点，我们使用这些就诊时的氧化脂 PC 来检验在病例自身抗体转化前后测量的氧化脂与 1 型糖尿病的关联。
与 1 型糖尿病风险增加相关的是 ARA 相关的氧化脂 5-HETE。五种 LA 相关的氧化脂、两种 ALA 相关的氧化脂和一种 DHA 相关的氧化脂与 1 型糖尿病风险降低相关。升高的 LA 和 ALA 相关氧化脂（PC1）谱与 1 型糖尿病风险降低相关（OR 0.61；95%CI 0.40，0.94）。升高的 ARA 相关氧化脂谱（PC2）与糖尿病风险增加相关（OR 1.53；95%CI 1.03，2.29）。关键时间点分析显示，在自身抗体转化后，与高 ARA 相关氧化脂谱相关的是 1 型糖尿病，但在转化前无相关性。
结论/解释：较高的 LA 和 ALA 相关氧化脂的保护相关性表明，在 1 型糖尿病中，炎症促进和缓解都很重要。一旦自身免疫过程开始，促炎的 ARA 相关氧化脂可能会发挥重要作用。
