title: Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.
abstract: Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39-1.95], P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34-2.11], P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: Eric
authors.initials: E
authors.lastname: Fauman
authors.forename: Idil
authors.initials: I
authors.lastname: Erte
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Craig
authors.initials: C
authors.lastname: Hyde
authors.forename: Maria
authors.initials: M
authors.lastname: Psatha
authors.forename: Kirsten J
authors.initials: KJ
authors.lastname: Ward
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Mike
authors.initials: M
authors.lastname: Milburn
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Jeff
authors.initials: J
authors.lastname: Trimmer
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Rob P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Mary Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics; D004200:Diseases in Twins / Q000097:blood / Q000235:genetics; D005215:Fasting; D005260:Female; D055106:Genome-Wide Association Study; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000235:genetics; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D011236:Prediabetic State / Q000097:blood* / Q000235:genetics
chemical_list: D015415:Biomarkers; D001786:Blood Glucose