Plasma phospholipid n-3 and n-6 polyunsaturated fatty acids in relation to cardiometabolic markers and gestational diabetes: A longitudinal study within the prospective NICHD Fetal Growth Studies

Abstract

BackgroundDespite dietary recommendations of polyunsaturated fatty acids (PUFAs) for cardiometabolic health, n-3 and n-6 PUFAs and their interplay in relation to diabetes risk remain debated. Importantly, data among pregnant women are scarce. We investigated individual plasma phospholipid n-3 and n-6 PUFAs in early to midpregnancy in relation to subsequent risk of gestational diabetes mellitus (GDM).Methods and findingsWithin the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton Cohort (n = 2,802), individual plasma phospholipid n-3 and n-6 PUFAs levels were measured at gestational weeks (GWs) 10–14, 15–26, 23–31, and 33–39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used, adjusting for major risk factors for GDM. After adjusting for covariates, individual n-3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were inversely correlated with insulin-resistance markers, whereas individual n-6 dihomo-gamma-linolenic acid (DGLA) was positively correlated with insulin-resistance markers. At GW 15–26, a standard deviation (SD) increase in total n-3 PUFAs and individual n-3 DPA was associated with a 36% (adjusted odds ratio 0.64; 95% CI 0.42–0.96; P = 0.042) and 33% (0.67; 95% CI 0.45–0.99; P = 0.047) lower risk of GDM, respectively; however, the significance did not persist after post hoc false-discovery rate (FDR) correction (FDR-corrected P values > 0.05). Associations between total n-6 PUFAs and GDM were null, whereas associations with individual n-6 PUFAs were differential. Per SD increase, gamma-linolenic acid (GLA) at GWs 10–14 and DGLA at GWs 10–14 and 15–26 were significantly associated with a 1.40- to 1.95-fold higher risk of GDM, whereas docosatetraenoic acid (DTA) at GW 15–26 was associated with a 45% (0.55; 95% CI 0.37–0.83) lower risk of GDM (all FDR-corrected P values < 0.05). Null associations were observed for linoleic acid (LA) in either gestational window in relation to risk of GDM. Women with high (≥median) n-3 PUFAs and low (<median) n-6 PUFAs levels had a 64% (95% CI 0.14–0.95; P value = 0.039) lower risk of GDM versus women with low n-3 and high n-6 PUFAs. Limitations include the inability to distinguish between exogenous and endogenous influences on circulating PUFA levels and the lack of causality inherent in observational studies.ConclusionsOur findings may suggest a potential role of primarily endogenously metabolized plasma phospholipid n-6 PUFAs including GLA, DGLA, and DTA in early to midpregnancy in the development of GDM. Null findings on primarily diet-derived n-3 EPA and DHA and n-6 LA do not provide strong evidence to suggest a beneficial role in prevention of GDM, although not excluding the potential benefit of EPA and DHA on glucose–insulin homeostasis given the inverse associations with insulin-resistance markers. Our findings highlight the importance of assessing individual circulating PUFAs to investigate their distinct pathophy...

Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: A nested case-control study

“…The similarity in longitudinal profiles between eicosanoids and fatty acids is expected, as fatty acid metabolism directly influences eicosanoid production [ 12 ]. Our observations are consistent with epidemiologic evidence of changes in fatty acid levels across pregnancy [ 31 – 34 ]. However, this comparison must be interpreted cautiously, as these prior studies primarily quantified esterified or total fatty acids and we measured free fatty acid levels.…”

Changes in Metabolites During an Oral Glucose Tolerance Test in Early and Mid-Pregnancy: Findings from the PEARLS Randomized, Controlled Lifestyle Trial

“…Although these metabolite differences were not statistically significant in single metabolite analyses, this metabolic profile was significantly different during early versus mid-pregnancy. In previous studies, some of these metabolites have been linked to insulin resistance, pregnancy, or both [23][24][25][26][27][28][29][30][31]. Previous studies have observed relative decreases in fatty acids post-OGTT among pregnant women [19,20], but this is the first study to measure metabolites during both early and mid-pregnancy.…”

“…Studies suggest that acyl carnitines are tightly regulated, decrease in women during pregnancy [26,27], and have been associated with maternal and child overweight and obesity [28]. Docosapentaenoate (DPA), a fatty acid, has been inversely correlated with insulin resistance markers, and circulating levels tend to decrease during pregnancy [29]. Bile acids are tightly regulated during pregnancy and increases are indicative of intrahepatic cholestasis of pregnancy [30,31].…”

Association of n-6 PUFAs with the risk of diabetic retinopathy in diabetic patients

“…It is reported that D6D, elongase and D5D play a key role in the metabolic pathway of LA ( 29 ). Abundant evidences containing animal experiment ( 30 ), cross-sectional research ( 23 ) and cohort study ( 24 ) reveal that abnormal PUFAs metabolism in diabetic patients is closely related to the activities of desaturation and elongase depending on the comparison between diabetic patients and their counterparts. In the current study, the association between the levels of PUFAs and the presence of DR do not achieve significant level.…”

“…In addition, the activities of desaturase and elongase are closely linked to the metabolism of n-6 PUFAs, so we have also explored the activities of desaturase and elongase, in which these activities are estimated from the product-to-precursor ratios of some individual fatty acids in serum ( 23 ). The 18:3 n-6/18:2 n-6 (GLA/LA), 20:4 n-6/20:3 n-6 (AA/DGLA) and 20:3 n-6/18:3 n-6 (DGLA/GLA) are commonly suggested to represent the activities of D6D, delta 5-desaturase (D5D) and elongase, respectively ( 24 ).…”