Abstract
BackgroundMetabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T2 was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T2 and thus, metabolic health.MethodsWater T2 measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T2. The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking.ResultsThe multi-step analysis unveiled five new proteins most predictive of water T2: hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T2 have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T2 that would not have been identified in a hypothesis-driven biomarker search.ConclusionsThe identification of new proteins associated with water T2 demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T2 and the pathophysiology of metabolic syndrome.
Highlights
Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis
In an observational cross-sectional study of 72 nondiabetic human subjects, we discovered that plasma and serum water Transverse relaxation time (T2) detect Metabolic syndrome (MetS)-associated abnormalities with high sensitivity and specificity [8]
Measured using benchtop nuclear magnetic resonance relaxometry [9], T2 refers to the time constant for the decay or “relaxation” of the transverse component of the Nuclear magnetic resonance (NMR) signal
Summary
Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. Metabolic syndrome (MetS) is a cluster of clinical findings that includes increased waist circumference, high blood pressure, high blood glucose, high triglycerides and/or low HDL-cholesterol [1, 2]. Metabolic syndrome is associated with a two-fold increased risk for atherosclerosis, a five-fold increased risk for type 2 diabetes [2] and an increased risk for some forms of cancer [4]. In an observational cross-sectional study of 72 nondiabetic human subjects, we discovered that plasma and serum water T2 detect MetS-associated abnormalities with high sensitivity and specificity [8]. As globulins are higher molecular weight than albumin, the net effect is to slow the rotational mobility of bound water and decrease water T2 [8, 9]
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