Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans

Abstract

Dyslipidemia is an independent risk factor for type 2 diabetes, although exactly which of the many plasma lipids contribute to this remains unclear. We therefore investigated whether lipid profiling can inform diabetes prediction by performing liquid chromatography/mass spectrometry-based lipid profiling in 189 individuals who developed type 2 diabetes and 189 matched disease-free individuals, with over 12 years of follow up in the Framingham Heart Study. We found that lipids of lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk. This pattern was strongest for triacylglycerols (TAGs) and persisted after multivariable adjustment for age, sex, BMI, fasting glucose, fasting insulin, total triglycerides, and HDL cholesterol. A combination of 2 TAGs further improved diabetes prediction. To explore potential mechanisms that modulate the distribution of plasma lipids, we performed lipid profiling during oral glucose tolerance testing, pharmacologic interventions, and acute exercise testing. Levels of TAGs associated with increased risk for diabetes decreased in response to insulin action and were elevated in the setting of insulin resistance. Conversely, levels of TAGs associated with decreased diabetes risk rose in response to insulin and were poorly correlated with insulin resistance. These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment.

The potential of novel biomarkers to improve risk prediction of type 2 diabetes

“…These studies showed that elevated levels of branched-chain and aromatic amino acids and lower levels of glycine are associated with incident type 2 diabetes or deteriorating glucose homeostasis [84,[86][87][88][89][90]. In addition, various lipid species and lipid fractions [85,[87][88][89][90], as well as other small metabolites [87,89,91], showed significant associations with the risk of type 2 diabetes or incident impaired glucose metabolism after adjustment for multiple confounders. Some of the aforementioned studies compared the accuracy of prediction models without and with metabolites (Table 2) and found fairly modest improvements in AROCs for models that included metabolomics in addition to established risk factors for type 2 diabetes [84,88,89,91].…”

“…Very recently, data on lipids and small metabolites have become available from prospective studies, and these are summarised in Table 2 [84][85][86][87][88][89][90][91]. These studies showed that elevated levels of branched-chain and aromatic amino acids and lower levels of glycine are associated with incident type 2 diabetes or deteriorating glucose homeostasis [84,[86][87][88][89][90].…”

Anbefalt nordisk kosthold og risikomarkører for hjerte- og karsykdom

“…In addition, a significant change in the plasma lipidomic profile (all types of lipid metabolites in plasma) was observed between the groups in the SYS-DIET study (25). Profiling of all lipids in the blood can more sensitively register metabolic changes and specific lipid metabolites linked to risk of disease (33). In the SYS-DIET study, the level of metabolites (plasmalogens) with antioxidant properties increased, and the level of metabolites (ceramides) that are linked to the development of insulin resistance was reduced in the group with a Nordic diet (25).…”

Potential Nutrigenomic Approaches to Reduce the High Incidence of Obesity in Qatar

“…Diet can modulate metabolite phenotype, and targeted analyses are performed to evaluate the effect of specific diets on metabolic disorders [75]. Several metabolomics studies have already been performed in the field of obesity and T2DM [76,77]. Metabolites from lipids, amino acids, and carbohydrates pathways are associated with BMI [78].…”