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Menni, C.* ; Fauman, E.* ; Erte, I.* ; Perry, J.R.* ; Kastenmüller, G. ; Shin, S.Y.* ; Petersen, A.-K. ; Hyde, C.* ; Psatha, M.* ; Ward, K.J.* ; Yuan, W.* ; Milburn, M.V.* ; Palmer, C.N.* ; Frayling, T.M.* ; Trimmer, J.* ; Bell, J.T.* ; Gieger, C. ; Mohney, R.P.* ; Brosnan, M.J.* ; Suhre, K. ; Soranzo, N.* ; Spector, T.D.*

Biomarkers for type 2 diabetes and impaired fasting glucose using a non-targeted metabolomics approach.

Diabetes 62, 4270-4276 (2013)

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Using a non-targeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycaemia in a large population-based cohort of 2,204 females (115 Type 2 Diabetes-T2D cases, 192 individuals with impaired fasting glucose- IFG and 1,897 controls) 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 (OR=1.65, 95%CI=1.39,1.95, P=8.46x10(-9)) and was moderately heritable (h(2)=0.20). The association was replicated in an independent population (n=720, OR=1.68, 95%CI=1.34, 2.11, P=6.52x10(-6)) and validated in 189 Twins with urine metabolomics taken at the same time as plasma (OR=1.87, 95%CI=1.27,2.75, P=1x10(-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 non-targeted 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.

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