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Targeted metabolomics identifies elevated serotonin levels in carriers of a TCF7L2 diabetes-risk allele

Session Poster Session 5

Speaker Christoph Saely

Event : ESC Congress 2018

  • Topic : basic science
  • Sub-topic : Lipid Metabolism, Metabolic Syndrome, Diabetes
  • Session type : Poster Session

Authors : A Leiherer (Triesen,LI), A Muendlein (Feldkirch,AT), K Geiger (Feldkirch,AT), CH Saely (Bern,CH), EM Brandtner (Feldkirch,AT), J Ebner (Feldkirch,AT), B Larcher (Feldkirch,AT), A Mader (Feldkirch,AT), P Fraunberger (Feldkirch,AT), H Drexel (Philadelphia,US)

Authors:
A. Leiherer1 , A. Muendlein2 , K. Geiger2 , C.H. Saely3 , E.M. Brandtner2 , J. Ebner2 , B. Larcher4 , A. Mader4 , P. Fraunberger5 , H. Drexel6 , 1Private University of the Principality of Liechtenstein - Triesen - Liechtenstein , 2VIVIT Institute - Feldkirch - Austria , 3Bern University Hospital, Division of Angiology, Swiss Cardiovascular Center - Bern - Switzerland , 4Academic Teaching Hospital, Department of Medicine and Cardiology - Feldkirch - Austria , 5Academic Teaching Hospital, Medical Central Laboratory Feldkirch - Feldkirch - Austria , 6Drexel University College of Medicine - Philadelphia, Pennsylvania - United States of America ,

Citation:
European Heart Journal ( 2018 ) 39 ( Supplement ), 998

Background: The transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Its polymorphism rs7903146 is associated with risk for metabolic diseases, primarily diabetes.

Purpose: The purpose of this study was to investigate the molecular mechanisms explaining how TCF7L2 impacts metabolism.

Methods: We evaluated the metabolic profile of a total of 394 angiographied patients with respect to their rs7903146 genotype (C/T) using targeted metabolomics in a discovery (n=154) and a validation (n=240) study.

Results: We identified serotonin as the top ranked metabolite to be increased in carriers of the diabetes risk allele (T) in both studies. For all 394 patients fold change was 44.6% (p=2.06 e-5), and in multivariate logistic regression analyses, serotonin concentration was significantly associated with the rs7903146 genotype even after full adjustment including diabetes (stand. adj. OR 2.69 [1.23–5.87]; p=0.013). In a larger cohort of 1660 similar patients, we found that risky allele carriers had a significantly higher fasting glucose (116 vs. 109 mg/dl, p=0.007), post-challenge glucose (147 vs. 135 mg/dl, p=0.036), HbA1c (6.2 vs. 6.0%, p<0.001), and prevalence of T2DM (30.8 vs. 25.8%, p=0.022) than patients without the risky allele. Apart from rs7903146, analyzing the whole gene, we found that 9 out of 19 unlinked SNPs in TCF7L2 were significantly associated with serotonin as well. In conclusion, this study identifies a significant association between elevated serotonin concentrations and the diabetes risk allele of the TCF7L2 rs7903146 polymorphism. Recently, Wnt-signalling has been suggested to be involved in serotonin expression and serotonin has been shown to regulate glucose homeostasis, to increase the risk of diabetes, and to be elevated in diabetic subjects.

Conclusion: Together, these new findings suggest that serotonin may be, at least in part, involved in the impact of Wnt/TCF7L2-signalling on metabolic homeostasis and diabetes.

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