Metabolomic profiling of the Dietary Approaches to Stop Hypertension (DASH) diet provides novel insights for the nutritional epidemiology of type 2 diabetes mellitus (T2DM)

Adherence to the DASH diet is inversely associated with T2DM risk. Metabolic changes due to DASH adherence and their potential relationship with incident T2DM have not been described. The objective is to determine metabolite clusters associated with adherence to a DASH-like diet in the Insulin Resistance Atherosclerosis Study (IRAS) cohort and explore if the clusters predicted 5-year incidence of T2DM. The current study included the 570 non-diabetic multi-ethnic participants aged 40 - 69 years. Adherence to a DASH-like diet was determined a priori through an 80-point scale for absolute intakes of the eight DASH food groups. Quantitative measurements of 87 metabolites (acylcarnitines, amino acids, bile acids, sterols, and fatty acids) were obtained at baseline. Metabolite clusters related to DASH adherence were determined through partial least squares (PLS) analysis using R. Multivariable-adjusted logistic regression (MLR) was used to explore the associations between metabolite clusters and incident T2DM. A group of acylcarnitines and fatty acids loaded strongly on the two components retained under PLS. Among strongly loading metabolites, a select group of acylcarnitines had over 50% of their individual variance explained by the PLS model. Component 2 was inversely associated with incident T2DM (Odds ratio (OR): 0.89; 95% Confidence interval (CI) 0.80-0.99, p-value = 0.043) after adjustment for demographic and metabolic covariates. Component 1 was not associated with T2DM risk (OR: 1.02; 95% CI 0.88-1.19, p-value = 0.74). Adherence to a DASH-type diet may contribute to reduced T2DM risk in part through modulations in acylcarnitine and fatty acid physiology.

Risk of diabetes associated with fatty acids in the de novo lipogenesis pathway is independent of insulin sensitivity and response: the Insulin Resistance Atherosclerosis Study (IRAS)

ObjectiveTo examine the associations of fatty acids in the de novo lipogenesis (DNL) pathway, specifically myristic acid (14:0), palmitic acid (16:0),cis-palmitoleic acid (c16:1 n-7),cis-myristoleic acid (c14:1n5), stearic acid (18:0) andcis-oleic acid (c18:1 n-9), with 5-year risk of type 2 diabetes. We hypothesized that DNL fatty acids are associated with risk of type 2 diabetes independent of insulin sensitivity.Research design and methodsWe evaluated 719 (mean age 55.1±8.5 years, 44.2% men, 42.3% Caucasians) participants from the Insulin Resistance Atherosclerosis Study. Multivariable logistic regression models with and without adjustment of insulin sensitivity were used to assess prospective associations of DNL fatty acids with incident type 2 diabetes.ResultsType 2 diabetes incidence was 20.3% over 5 years. In multivariable regression models, palmitic, palmitoleic, myristic, myristoleic and oleic acids were associated with increased risk of type 2 diabetes (p<0.05). Palmitic acid had the strongest association (OR per standard unit of palmitic acid 1.46; 95% CI 1.23 to 1.76; p<0.001), which remained similar with addition of insulin sensitivity and acute insulin response (AIR) to the model (OR 1.36; 95% CI 1.09 to 1.70, p=0.01). Oleic and palmitoleic acids were also independently associated with incident type 2 diabetes. In multivariable models, ratios of fatty acids corresponding to stearoyl CoA desaturase-1 and Elovl6 enzymatic activity were significantly associated with risk of type 2 diabetes independent of insulin sensitivity and AIR.ConclusionsWe observed associations of DNL fatty acids with type 2 diabetes incidence independent of insulin sensitivity.

Urinary F2-Isoprostanes and Metabolic Markers of Fat Oxidation

Metabolomic studies of increased fat oxidation showed increase in circulating acylcarnitines C2, C8, C10, and C12 and decrease in C3, C4, and C5. We hypothesize that urinary F2-isoprostanes reflect intensity of fatty acid oxidation and are associated with circulating C2, C8, C10, and C12 directly and with C3, C4, and C5 inversely. Four urinary F2-isoprostane isomers and serum acylcarnitines are quantified using LC-MS/MS within the Insulin Resistance Atherosclerosis Study nondiabetic cohort (n= 682). Cross-sectional associations between fasting urinary F2-isoprostanes (summarized as a composite index) and the selected acylcarnitines are examined using generalized linear models. F2-isoprostane index is associated with C2 and C12 directly and with C5 inversely: the adjusted beta coefficients are 0.109, 0.072, and −0.094, respectively (P< 0.05). For these acylcarnitines and for F2-isoprostanes, the adjusted odds ratios (ORs) of incident diabetes are calculated from logistic regression models: the ORs (95% CI) are 0.77 (0.60–0.97), 0.79 (0.62–1.01), 1.18 (0.92–1.53), and 0.51 (0.35–0.76) for C2, C12, C5, and F2-isoprostanes, respectively. The direction of the associations between urinary F2-isoprostanes and three acylcarnitines (C2, C5, and C12) supports our hypothesis. The inverse associations of C2 and C12 and with incident diabetes are consistent with the suggested protective role of efficient fat oxidation.

Abstract 23: Metabolomic Features Associated With Incident Hypertension - Results From Insulin Resistance Atherosclerosis Study

Background: Clinically-defined metabolic traits and specific dietary patterns are associated with risk for hypertension (HTN); however, the precise metabolomic features that underlie these associations are not yet well understood. A more detailed understanding of these metabolomic features may shed new light on the pathogenesis of HTN and identify novel therapeutic targets. Hypothesis: We hypothesized that there is a metabolic signature associated with high risk for incident HTN. Methods: Ninety three metabolites were quantified by liquid chromatography and mass spectrometry in baseline serum from a subset of the Insulin Resistance Atherosclerosis Study (IRAS) participants (N=500). Unsupervised hierarchical cluster analysis (cluster depth = 2, 3, 4) and principal component analysis (PCA) were performed to define distinct metabolomic phenotypes and orthogonal projections of the metabolomics data. Multivariable negative binomial regression models were used to model the association between metabolomic cluster assignments or metabolomics-derived principal components (PCs) with 5-year incident HTN (blood pressure >=140/90 mmHg or new use of anti-HTN medication), after adjusting for age, gender, race, body mass index, baseline systolic blood pressure and insulin resistance measured by intravenous glucose tolerance test. Results: Of 500 individuals, 133 (26%) developed incident HTN. Cluster analysis identified a subset of participants (N= 154, 31%) with a distinct metabolic phenotype associated with increased risk of incident HTN (adjusted RR 1.65; 95% CI 1.21 - 2.25, p = 0.002). This metabolically defined phenotype was characterized by elevated levels of fatty acids involved in de-novo fatty acid synthesis (saturated fatty acids; SFAs, omega 6 polyunsaturated fatty acid; PUFAs) as well as acylcarnitines (involved in fatty acid catabolism). Separately, PC 1 (SFAs and Omega 6 PUFAs) and PC 3 (acylcarnitines) were also significantly associated with incident HTN (Adjusted RR: 1.47, 95% CI 1.25 - 1.73, p <0.0001; and RR 1.20, 95% CI 1.03 - 1.39, p = 0.01). Among SFAs and omega 6 PUFAs, levels of palmitic acid and di-homo-gamma linoleic acid (immediate precursor of arachidonic acid) were the strongest predictors of hypertension (p<0.0001). Acylcarnitine palmitate was the metabolite with strongest association with hypertension in acylcarnitine group (p<0.0001). Conclusion: Hierarchical cluster analysis and PCA uncovered a specific metabolomic signature associated with risk of HTN characterized by elevated levels of metabolites involved in de novo fatty acid synthesis (SFAs and omega 6 PUFAs) and fatty acid catabolism (acylcarnitines). These metabolic perturbation preceded HTN by up to five years. More research is needed to clarify the precise molecular mechanisms that account for this novel association of metabolites with HTN which is independent of the known major risk factors.