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

Diabetes. 2013 Dec;62(12):4270-6. doi: 10.2337/db13-0570. Epub 2013 Jul 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Biomarkers / blood*
  • Blood Glucose / genetics
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / genetics
  • Diseases in Twins / blood
  • Diseases in Twins / genetics
  • Fasting
  • Female
  • Genome-Wide Association Study
  • Glucose Tolerance Test
  • Humans
  • Hyperglycemia / blood*
  • Hyperglycemia / genetics
  • Male
  • Metabolomics
  • Middle Aged
  • Prediabetic State / blood*
  • Prediabetic State / genetics

Substances

  • Biomarkers
  • Blood Glucose