22.01.2015 | 11.00 Uhr

Metabolic signature in pre-diabetes allows life style or medical intervention in risk individuals

Jerzy Adamski, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, GERm

Type 2 diabetes mellitus (T2D) is a frequent human disease affecting over 280 millions people worldwide. T2D can be prevented in pre-diabetic individuals with impaired glucose tolerance (IGT). Detection of IGT and early T2D is essential for development of personalized strategies to prevent T2D. We were searching for new biomarkers of pre-diabetes in human and used a metabolomics approach to accomplish this.

We quantified 140 metabolites for 4297 fasting serum samples by targeted metabolomics using combined FIA- and LC-MS Biocrates (Innsbruck, Austria) p180 assay. For discovery phase samples were retrieved from population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort and for the replication phase 2500 samples from randomly drawn subcohort of the European Prospective Investigation into Cancer and Nutrition EPIC-Potsdam cohort.

Our study revealed significant metabolic variation in pre-diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4 x 10-4 to 2.1 x 10-13. Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were replicated (EPIC)-Potsdam cohort. Using metabolite–protein network analysis, we identified seven T2D-related genes (PPARG, TCF7L2, HNF1A, GCK, IGF1, IRS1 and IDE) that are associated with these three IGT-specific metabolites by multiple interactions with four enzymes (CAC, CrAT, ALAS-H and cPLA2). The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to T2D. Metabolites associated with high risk of T2D found in this study were independently replicated recently. The biomarkers were patented and a network for the clinical validation and translational implementation is being developed.

The metabolite-based testing would be permitting early risk stratification in population, early life style or medical intervention in risk individuals. This would lower the incidence of T2D or delay its progression. New diagnostic assay would find a huge application worldwide and facilitate individualized therapy.