Dataset Information

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

ABSTRACT: Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or ?-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

SUBMITTER: Nowak C

PROVIDER: S-EPMC5074591 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

Nowak Christoph C Salihovic Samira S Ganna Andrea A Brandmaier Stefan S Tukiainen Taru T Broeckling Corey D CD Magnusson Patrik K PK Prenni Jessica E JE Wang-Sattler Rui R Peters Annette A Strauch Konstantin K Meitinger Thomas T Giedraitis Vilmantas V Ärnlöv Johan J Berne Christian C Gieger Christian C Ripatti Samuli S Lind Lars L Pedersen Nancy L NL Sundström Johan J Ingelsson Erik E Fall Tove T

PLoS genetics 20161021 10

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 ...[more]

PMID: 27768686

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Project description:BackgroundNumerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D.MethodsIndependent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = - 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = - 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = - 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Project description:Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline (blood samples collected from 2007 to 2010) were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19.

Project description:BackgroundHigher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 ones, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear.ObjectiveTo investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity.DesignWe first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, bidirectional two-sample Mendelian randomization (MR) analyses were performed to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity using summary statistics from existing genome-wide association studies.ResultsIn the observational association analysis, total PUFAs, omega-3 PUFAs, omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. The forward MR analysis indicated that arachidonic acid (AA) and docosapentaenoic acid (DPA-n3) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.96 (0.94, 0.99) and 0.89 (0.81, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs.ConclusionsOur observational analysis supported that higher circulating PUFAs, either omega-3 or omega-6, are protective against severe COVID-19, while omega-3 PUFAs, especially DHA, were also associated with reducing COVID-19 susceptibility. Our MR analysis further supported causal associations of AA and DPA-n3 with a lower risk of severe COVID-19.

Dataset Information

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

Publications

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

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