The oxylipin profile is associated with development of type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY)

Abstract

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. Methods 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. ResultsThe 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-autoantibodyseroconversion 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.

Lipid metabolism in type 1 diabetes mellitus: Pathogenetic and therapeutic implications

“…The DAISY study detected serum oxylipins at four time points during disease progression in high-risk genotypes of children with T1DM, including 9 and 15 months of age, pre-seroconversion, postseroconversion and diagnosis. LA-related oxylipins including 13-hydroxyoctadecadienoic acid, 9-hydroxylinoleic acid, 9hydroxyoctadeca-10,12,15-trienoic acid, 12,13-epoxy-9octadecenoic acid, and 9 (10)-epoxy-12Z-octadecenoic acid were inversely associated with T1DM, while 5-hydroxy-6,8,11,14-eicosatetraenoic acid, an ARA-related oxylipin, was associated with an increased risk of T1DM (21). However, a meta-analysis shows no association between w-6 PUFAs intake and the risk of preclinical or clinical T1DM in child (46).…”

“…Indeed, higher ω-3 PUFA levels in erythrocyte membranes were also found to be associated with a reduced risk of islet autoimmunity in the DAISY study ( 42 , 44 ). DHA-derived oxylipins are highly protective against T1DM ( 21 ). A recent lipidomic analysis of serum free fatty acids in childhood-onset T1DM showed that patients with T1DM may partially affect the activity of lipid elongases and thus the metabolic profile of PUFAs ( 45 ).…”

“…ARA is a precursor to a number of potent pro-inflammatory mediators including well-described prostaglandins and leukotrienes, thus ω-6 PUFAs and their derivatives are generally predisposed to promoting inflammation ( 58 , 59 ). Interestingly, oxylipins derived from LA also exert some anti-inflammatory effects ( 21 ). The DAISY study detected serum oxylipins at four time points during disease progression in high-risk genotypes of children with T1DM, including 9 and 15 months of age, pre-seroconversion, post-seroconversion and diagnosis.…”

“…The metabolomic profiling in German BABYDIAB study ( 14 ) revealed that islet autoantibody-positive children had higher concentrations of odd-chain triglycerides (TGs) and polyunsaturated fatty acid (PUFA)-containing phospholipids in serum than autoantibody-negative children did. The American Diabetes Autoimmunity Study in the Young (DAISY) cohort study ( 21 ) demonstrated that plasma arachidonic acid (ARA)-derived oxylipin levels were highly associated with an increased risk of T1DM, whereas increased α-linolenic acid (ALA) and linoleic acid (LA)-related oxylipin levels were associated with a reduced risk of T1DM in children at genetic risk. The Environmental Determinants of Diabetes in the Young (TEDDY) study ( 18 ), a multinational multicenter cohort of young people with diabetes, also suggested that disturbances in lipid metabolism occur one year prior to seroconversion in children with T1DM, as evidenced by the upregulation of fatty acids, cholesterol, and phosphatidylethanolamines, and the downregulation of sphingomyelins, phosphatidylcholines, TGs, and ceramides.…”

Dietary fatty acid intake in childhood and the risk of islet autoimmunity and type 1 diabetes: the DIPP birth cohort study

“…In biomarker studies higher proportion of some SFAs, MUFA, and conjugated linoleic acids have been associated with an increased risk of islet autoimmunity with some inconsistency [16][17][18]. Recently, some linoleic acid and alpha-linolenic acidrelated oxylipins were reported to be associated with a decreased risk of T1D in the DAISY study [19].…”