Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach

Cristina Menni, Eric Fauman, Idil Erte, John R B Perry, Gabi Kastenmüller, So-Youn Shin, Ann-Kristin Petersen, Craig Hyde, Maria Psatha, Kirsten J Ward, Wei Yuan, Mike Milburn, Colin N A Palmer, Timothy M Frayling, Jeff Trimmer, Jordana T Bell, Christian Gieger, Rob P Mohney, Mary Julia Brosnan, Karsten SuhreNicole Soranzo, Tim D Spector

Research output: Contribution to journalArticle (Academic Journal)peer-review

221 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4270-6
Number of pages7
JournalDiabetic Medicine
Volume62
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • Aged
  • Biological Markers
  • Blood Glucose
  • Diabetes Mellitus, Type 2
  • Diseases in Twins
  • Fasting
  • Female
  • Genome-Wide Association Study
  • Glucose Tolerance Test
  • Humans
  • Hyperglycemia
  • Male
  • Metabolomics
  • Middle Aged
  • Prediabetic State

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