Novel insights into causal pathways in type 2 diabetes
A Mendelian Randomization Study of Metabolite Profile, Fasting Glucose and Type 2 DiabetesLiterature - Liu J, Bert van Klinken J, Semiz S, et al. - Diabetes 2017; published online ahead of print
- 124 metabolites significantly associated with fasting glucose (90 positive and 34 negative correlations) in the control population, consisting of 36 phospholipids, 20 triglycerides, 24 small molecular compounds and 44 lipoprotein particle sub-fractions. 112 of them also associated with T2DM.
- 34 Negative correlations were between glucose and alkyl-acyl and diacyl-phosphatidylcholines, mostly of the poly-unsaturated type, lysophosphatidylcholines, mostly of the saturated type and parts of the lipoprotein sub-fractions from LDL and HDL.
- 90 Positive correlations were between glucose and several phospholipids, phosphatidylethanolamines, and lysophosphatidylcholines, aminoacids and low-molecular weight compounds, in addition to lipid side-groups, and triglycerides.
- Small (S), extra-small (XS), medium (M) and XL-VLDL particles, as well as the total VLDL components, and to a lesser extent IDL and LDL-triglycerides, XS-LDL to M-LDL particle components, and the ApoA1 and triglyceride content of S-HDL particles correlated positively with fasting glucose in the non-diabetic population.
- Among the 20 eligible metabolite-glucose/T2DM sets, genetically decreased levels of eight metabolites associated significantly with fasting glucose (false discovery rate, FDR < 0.05). These include XL-HDL-C (FDR = 0.03), XL-HDL-phospholipids (FDR = 2.76 × 10-3), XS-VLDL-phospholipids (FDR = 0.04), XL-HDL-free-C (FDR = 0.01), L-HDL-C (FDR = 0.01), L-HDL-free-C (FDR = 2.76 × 10-3), HDL-C (FDR = 0.04), and IDL-phospholipids (FDR = 0.04). A causal role for IDL-phospholipids was not supported (FDR = 0.17).
- Pathway-based sensitivity analysis showed possibly causal roles for three additional metabolic markers, including S-VLDL-triglycerides (FDR = 0.04), S-HDL-triglycerides (FDR = 0.04), and plasma-triglycerides (FDR = 0.04).
- Genetic predisposition to T2DM is associated with lower levels of phosphatidylcholine alkyl-acyl 42:5 (FDR = 0.02) and phosphatidylcholine alkyl-acyl 44:4 (FDR = 0.02), and higher levels of alanine (FDR = 0.02).
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.