Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl-phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl-phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21–0.44], factor 2 3.82 [2.64–5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tübingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D.

The prevalence of obesity is increasing worldwide, and this epidemic is accompanied by a high incidence of type 2 diabetes mellitus and cardiovascular disease.¹ Although overall obesity delineates an important risk factor for these diseases, it is recognized that body fat distribution additionally represents an independent determinant. For any given amount of total body fat, individuals with a selective excess of intra-abdominal (visceral) adipose tissue, estimated by an increased waist circumference, are at substantially higher risk of being insulin resistant and having a cardiovascular risk profile.^2-8 Excess visceral fat accumulation results from the inability of adipose tissue to appropriately store the excess energy. According to this hypothesis, energy is deposited as fat intra-abdominally and in ectopic depots such as the liver and the skeletal muscle, resulting in an increased risk of type 2 diabetes mellitus and cardiovascular disease. In contrast, when extra energy is directed toward the subcutaneous depots or is burned within the mitochondria in the liver and muscle, the individual, although having a positive energy balance, will be protected against the development of these diseases.⁹ Accordingly, it may be possible to identify a metabolically benign fat distribution phenotype even in the obese spectrum. Such individuals may be protected from type 2 diabetes mellitus and cardiovascular disease.