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Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.

Lyssenko, Valeriya LU ; Lupi, Roberto; Marchetti, Piero; Del Guerra, Silvia; Orho-Melander, Marju LU ; Almgren, Peter LU ; Sjögren, Marketa LU ; Ling, Charlotte LU ; Eriksson, Karl-Fredrik LU and Lethagen, ÅsaLinda LU , et al. (2007) In Journal of Clinical Investigation 117(8). p.2155-2163
Abstract
Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish).... (More)
Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion. (Less)
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Journal of Clinical Investigation
volume
117
issue
8
pages
2155 - 2163
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000248478100023
  • scopus:34547702501
ISSN
0021-9738
DOI
10.1172/JCI30706
language
English
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yes
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3b442326-7a71-43db-8137-6dcef2ac84f0 (old id 607116)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17671651&dopt=Abstract
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2007-12-17 16:10:26
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2017-10-22 04:45:59
@article{3b442326-7a71-43db-8137-6dcef2ac84f0,
  abstract     = {Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.},
  author       = {Lyssenko, Valeriya and Lupi, Roberto and Marchetti, Piero and Del Guerra, Silvia and Orho-Melander, Marju and Almgren, Peter and Sjögren, Marketa and Ling, Charlotte and Eriksson, Karl-Fredrik and Lethagen, ÅsaLinda and Mancarella, Rita and Berglund, Göran and Tuomi, Tiinamaija and Nilsson, Peter and Del Prato, Stefano and Groop, Leif},
  issn         = {0021-9738},
  language     = {eng},
  number       = {8},
  pages        = {2155--2163},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.},
  url          = {http://dx.doi.org/10.1172/JCI30706},
  volume       = {117},
  year         = {2007},
}