Physicians' Academy for Cardiovascular Education

Novel insights into causal pathways in type 2 diabetes

A Mendelian Randomization Study of Metabolite Profile, Fasting Glucose and Type 2 Diabetes

Liu J, Bert van Klinken J, Semiz S, et al. - Diabetes 2017; published online ahead of print


Type 2 diabetes (T2DM) is associated with higher circulating concentrations of triglycerides and lower concentrations of HDL-C, as well as with dysregulation of phospholipids, branched-chain amino-acids, keto-acid metabolites and other metabolites such as acyl-carnitines [1-3]. Potential causal relationships between these associations have not been clarified in existing studies.

In this study, potential causal metabolic pathways in glucose homeostasis were investigated, using genetic predictors from published metabolite genome-wide association studies (GWAS), guided by pathway-based evidence to select instrumental variables. Subsequently, Mendelian randomization (MR) was performed between selected metabolic markers and glucose/T2DM.

The observational associations between metabolites and fasting glucose/T2DM were tested in the Erasmus Rucphen Family (ERF) study, a prospective family-based study in the Southwest of the Netherlands [4]. In total, 562 metabolic markers including sub-fractions of lipoproteins, triglycerides, phospholipids, ceramides, amino-acids, acyl-carnitines and small intermediate compounds, were measured by five different metabolomics platforms. Metabolites associated with glucose in the ERF study (n = 124) were candidates for MR.

For each metabolite associated with glucose, a two-sample bi-directional MR was performed, and it was tested if genetically varying levels of a particular metabolite affect the risk for elevated glucose and T2DM, and if a genetically increased risk of T2DM or elevated glucose is associated with circulating levels of a particular metabolite.

Main results


Mendelian randomization provided evidence for potentially causal metabolic pathways of glucose homeostasis and T2DM. These findings indicate that an increase of large HDL particles might have a decreasing effect on glucose, while the opposite is the case with triglycerides and small HDL particles, suggesting them as targets for glucose management.


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