Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans.

AIMS/HYPOTHESIS: We sought to evaluate if the cellular localisation and molecular species of diacylglycerol (DAG) were related to insulin sensitivity in human skeletal muscle. METHODS: Healthy sedentary obese controls (Ob; n = 6; mean±SEM age 39.5 ± 2.3 years; mean ± SEM BMI 33.3 ± 1.4 kg/m(2)), individuals with type 2 diabetes (T2D; n = 6; age 44 ± 1.8 years; BMI 30.1 ± 2.3 kg/m(2)), and lean endurance-trained athletes (Ath; n = 10; age 35.4 ± 3.1 years; BMI 23.3 ± 0.8 kg/m(2)) were studied. Insulin sensitivity was determined using an IVGTT. Muscle biopsy specimens were taken after an overnight fast, fractionated using ultracentrifugation, and DAG species measured using liquid chromatography/MS/MS. RESULTS: Total muscle DAG concentration was higher in the Ob (mean ± SEM 13.3 ± 1.0 pmol/µg protein) and T2D (15.2 ± 1.0 pmol/µg protein) groups than the Ath group (10.0 ± 0.78 pmol/µg protein, p = 0.002). The majority (76-86%) DAG was localised in the membrane fraction for all groups, but was lowest in the Ath group (Ob, 86.2 ± 0.98%; T2D, 84.2 ± 1.2%; Ath, 75.9 ± 2.7%; p = 0.008). There were no differences in cytoplasmic DAG species (p > 0.12). Membrane DAG species C18:0/C20:4, Di-C16:0 and Di-C18:0 were significantly more abundant in the T2D group. Cytosolic DAG species were negatively related to activation of protein kinase C (PKC)ε but not PKCθ, whereas membrane DAG species were positively related to activation of PKCε, but not PKCθ. Only total membrane DAG (r = -0.624, p = 0.003) and Di-C18:0 (r = -0.595, p = 0.004) correlated with insulin sensitivity. Disaturated DAG species were significantly lower in the Ath group (p = 0.001), and significantly related to insulin sensitivity (r = -0.642, p = 0.002). CONCLUSIONS/INTERPRETATION: These data indicate that both cellular localisation and composition of DAG influence the relationship to insulin sensitivity. Our results suggest that only saturated DAG in skeletal muscle membranes are related to insulin resistance in humans.

Metabolomics and cancer preventive behaviors in the BC Generations Project.

Metabolomics can detect metabolic shifts resulting from lifestyle behaviors and may provide insight on the relevance of changes to carcinogenesis. We used non-targeted nuclear magnetic resonance to examine associations between metabolic measures and cancer preventive behaviors in 1319 participants (50% male, mean age 54 years) from the BC Generations Project. Behaviors were dichotomized: BMI < 25 kg/m2, ≥ 5 servings of fruits or vegetables/day, ≤ 2 alcoholic drinks/day for men or 1 drink/day for women and ≥ 30 min of moderate or vigorous physical activity/day. Linear regression was used to estimate coefficients and 95% confidence intervals with a false discovery rate (FDR) of 0.10. Of the 218 metabolic measures, 173, 103, 71 and 6 were associated with BMI, fruits and vegetables, alcohol consumption and physical activity. Notable findings included negative associations between glycoprotein acetyls, an inflammation-related metabolite with lower BMI and greater fruit and vegetable consumption, a positive association between polyunsaturated fatty acids and fruit and vegetable consumption and positive associations between high-density lipoprotein subclasses with lower BMI. These findings provide insight into metabolic alterations in the context of cancer prevention and the diverse biological pathways they are involved in. In particular, behaviors related to BMI, fruit and vegetable and alcohol consumption had a large metabolic impact.