Jun Liu, Jan Bert van Klinken, Sabina Semiz, Ko Willems van Dijk, Aswin Verhoeven, Thomas Hankemeier, Amy C Harms, Eric Sijbrands, Nuala A Sheehan, Cornelia M van Duijn, Ayşe Demirkan

Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for non-specific effects. We focused on 124 circulating metabolites which correlate with fasting glucose in the Erasmus Rucphen Family study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected fourteen paths with potential causal effects by MR, following pathway based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose level and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated high-density lipoprotein (HDL) components i.e. S-HDL-triglycerides might have a causal role of elevating glucose levels. In contrast, large (L) and extra-large (XL) HDL lipid components i.e. XL-HDL-cholesterol, XL-HDL-free cholesterol, XL-HDL-phospholipids, L-HDL-cholesterol and L-HDL-free cholesterol as well as HDL-cholesterol seem to be protective against increasing fasting glucose, but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine, and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high resolution metabolomics over classical biochemistry.