Abstract
Aims/HypothesisPolymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant.MethodsSeventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry.ResultsTCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6).DiscussionPlasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.
Highlights
Type 2 diabetes mellitus (T2D) is a multifactorial disease resulting from a complex interaction between environment, adverse health behaviour and genetic risk factors, which may affect β-cell function and/or insulin resistance
A reduced GLP-1-induced insulin secretion in response to oral glucose was detected in transcription factor 7-like 2 (TCF7L2) risk allele carriers [3,5,6,7]
Using a targeted metabolomics platform, we identified alterations in sphingolipid, phosphatidylcholine and lysophosphatidylcholine metabolism in subjects at potentially increased risk for T2D defined by the presence of the rs7903146 risk genotype
Summary
Type 2 diabetes mellitus (T2D) is a multifactorial disease resulting from a complex interaction between environment, adverse health behaviour and genetic risk factors, which may affect β-cell function and/or insulin resistance. TCF7L2 SNPs primarily affect insulin secretion and hepatic insulin sensitivity [3,4]. A reduced GLP-1-induced insulin secretion in response to oral glucose was detected in TCF7L2 risk allele carriers [3,5,6,7]. TCF7L2 SNPs were shown to affect GLP-1 responsiveness of β-cells [3,7], indicating an impaired incretin effect as one of the factors contributing to decreased insulin secretion in TCF7L2 risk allele carriers. It has been shown that tissue-specific alternative splicing patterns of TCF7L2 mRNA variants determine insulin sensitivity of adipose tissue and are involved in the regulation of hepatic gluconeogenesis [9,10,11]
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