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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.
Introduction
Several prospective studies have identified dyslipidemia, particularly hypertriglyceridemia, as an independent predictor of incident type 2 diabetes mellitus (1-5). However, in contrast to a discrete metabolite such as glucose, plasma lipids are composed of dozens of distinct molecules. For example, combinations of various acyl chains esterified to a glycerol backbone generate numerous unique triacylglycerols (TAGs). Standard clinical measurement of TAGs relies on the measurement of total glycerol following acyl chain hydrolysis (6), thus obscuring this underlying diversity.
We have developed a liquid chromatography/mass spectrometry-based (LC/MS-based) lipid profiling platform that measures intact lipids across a variety of lipid classes: TAGs, cholesterol esters (CEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), lysophospharidylethanolamines (LPEs), diacylglycerols (DAGs), and sphingomyelins (SMs). Within each lipid class, this method further distinguishes analytes on the basis of total acyl chain carbon number and double bond content. These factors define each lipid's molecular weight, which in...