Clinical and non-targeted metabolomic profiling of homozygous carriers of Transcription Factor 7-like 2 variant rs7903146

An important role of the type 2 diabetes risk variant rs7903146 in TCF7L2 in metabolic actions of various tissues, in particular of the liver, has recently been demonstrated by functional animal studies. Accordingly, the TT diabetes risk allele may lead to currently unknown alterations in human. Our study revealed no differences in the kinetics of glucose, insulin, C-peptide and non-esterified fatty acids during an OGTT in homozygous participants from a German diabetes risk cohort (n = 1832) carrying either the rs7903146 CC (n = 15) or the TT (n = 15) genotype. However, beta-cell function was impaired for TT carriers. Covering more than 4000 metabolite ions the plasma metabolome did not reveal any differences between genotypes. Our study argues against a relevant impact of TCF7L2 rs7903146 on the systemic level in humans, but confirms the role in the pathogenesis of type 2 diabetes in humans as a mechanism impairing insulin secretion.