Abstract
The TCF7L2 rs7903146 T-allele shows the strongest association with type 2 diabetes (T2D) among common gene variants. The aim of this study was to assess circulating levels of metabolites following a meal test in individuals carrying the high risk rs790346 TT genotype (cases) and low-risk CC genotype (controls). Sixty-two men were recruited based on TCF7L2 genotype, 31 were TT carriers and 31 were age- and BMI-matched CC carriers. All participants consumed a test meal after 12 hours of fasting. Metabolites were measured using proton nuclear magnetic resonance (NMR) spectroscopy. Metabolomic profiling of TCF7L2 carriers were performed for 141 lipid estimates. TT carriers had lower fasting levels of L-VLDL-L (total lipids in large very low density lipoproteins, p = 0.045), L-VLDL-CE (cholesterol esters in large VLDL, p = 0.03), and L-VLDL-C (total cholesterol in large VLDL, p = 0.045) compared to CC carriers. Additionally, TT carriers had lower postprandial levels of total triglycerides (TG) (q = 0.03), VLDL-TG (q = 0.05, including medium, small and extra small, q = 0.048, q = 0.0009, q = 0.04, respectively), HDL-TG (triglycerides in high density lipoproteins q = 0.037) and S-HDL-TG (q = 0.00003). In conclusion, TT carriers show altered postprandial triglyceride response, mainly influencing VLDL and HDL subclasses suggesting a genotype-mediated effect on hepatic lipid regulation.
Highlights
Variants within the transcription factor 7-like 2 gene (TCF7L2) are the strongest genetic risk factors associated with development of type 2 diabetes (T2D)[1]
Norton et al demonstrated that silencing of Transcription factor 7-like 2 (TCF7L2) in hepatocytes led to changes in the expression of 406 genes including key regulators of cellular growth, differentiation, and of amino acid, lipid and glucose metabolism in hepatocytes[10], suggesting that TCF7L2 may mediate a variety of actions in hepatocytes including changes in lipid metabolism
Overall there seemed to be a trend towards lower lipid levels in TT carriers at 240 min in many lipid fractions including S-VLDLs and S-HDLs (Fig. 1)
Summary
Variants within the transcription factor 7-like 2 gene (TCF7L2) are the strongest genetic risk factors associated with development of type 2 diabetes (T2D)[1]. Thorough examination of the human metabolome following an oral glucose tolerance test in 15 high risk and 15 low risk homozygous TCF7L2 variant carriers revealed no differences among T and C allele carriers[12], whereas an intravenous glucose tolerance test revealed changes in plasma sphingomyelins, phosphatidylcholines and lysophosphatidylcholines species in T allele carriers[13]. Based on these findings, we aimed to perform a deep characterization of the changes that occur in lipid metabolites during a meal test in TCF7L2 variant carriers by using a nuclear magnetic resonance spectroscopy (NMR) platform. We hypothesized that normoglycemic homozygous T-allele carriers have alterations in their lipid profile reflecting a genotype-mediated effect on lipid metabolism, which arises prior to glucose intolerance and diabetes
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