title: A novel test for IGT utilizing metabolite markers of glucose tolerance.
abstract: The oral glucose tolerance test (OGTT) is the only method to diagnose patients having impaired glucose tolerance (IGT), but its use has diminished considerably in recent years. Metabolomic profiling studies have identified a number of metabolites whose fasting levels are associated with dysglycemia and type 2 diabetes. These metabolites may serve as the basis of an alternative test for IGT. Using the stable isotope dilution technique, quantitative assays were developed for 23 candidate biomarker metabolites. These metabolites were measured in fasting plasma samples taken just prior to an OGTT from 1623 nondiabetic subjects: 955 from the Relationship between Insulin Sensitivity and Cardiovascular Disease Study (RISC Study; 11.7% IGT) and 668 subjects from the Diabetes Mellitus and Vascular Health Initiative (DMVhi) cohort from the DEXLIFE project (11.8% IGT). The associations between metabolites, anthropometric, and metabolic parameters and 2hPG values were assessed by Pearson correlation coefficients and Random Forest classification analysis to rank variables for their ability to distinguish IGT from normal glucose tolerance (NGT). Multivariate logistic regression models for estimating risk of IGT were developed and evaluated using AUCs calculated from the corresponding ROC curves. A model based on the fasting plasma levels of glucose, α-hydroxybutyric acid, β-hydroxybutyric acid, 4-methyl-2-oxopentanoic acid, linoleoylglycerophosphocholine, oleic acid, serine and vitamin B5 was optimized in the RISC cohort (AUC = 0.82) and validated in the DMVhi cohort (AUC = 0.83). A novel, all-metabolite-based test is shown to be a discriminate marker of IGT. It requires only a single fasted blood draw and may serve as a more convenient surrogate for the OGTT or as a means of identifying subjects likely to be IGT.
authors.affiliation: Metabolon, Inc, Durham, NC, USA jcobb@metabolon.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Cobb
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Eckhart
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Regis
authors.initials: R
authors.lastname: Perichon
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Wulff
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Adam
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wolfert
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Button
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Lawton
authors.affiliation: Metabolon, Inc, Durham, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Elverson
authors.affiliation: Vhi Healthcare, Dublin, Ireland.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carr
authors.affiliation: Vhi Healthcare, Dublin, Ireland Deceased.
authors.forename: Margaret
authors.initials: M
authors.lastname: Sinnott
authors.affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis* / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000175:diagnosis* / Q000378:metabolism*; D005951:Glucose Tolerance Test / Q000592:standards; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose
keywords: IGT; OGTT; biomarkers; metabolomics