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Åsalinda Lethagen

Physician

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

Author

  • Valeriya Lyssenko
  • Roberto Lupi
  • Piero Marchetti
  • Silvia Del Guerra
  • Marju Orho-Melander
  • Peter Almgren
  • Marketa Sjögren
  • Charlotte Ling
  • Karl-Fredrik Eriksson
  • ÅsaLinda Lethagen
  • Rita Mancarella
  • Göran Berglund
  • Tiinamaija Tuomi
  • Peter Nilsson
  • Stefano Del Prato
  • Leif Groop

Summary, in English

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Cardiovascular Disease
  • Cardiovascular Research - Hypertension
  • Diabetes - Epigenetics
  • Vascular Diseases - Clinical Research
  • Department of Clinical Sciences, Malmö
  • Internal Medicine - Epidemiology

Publishing year

2007

Language

English

Pages

2155-2163

Publication/Series

Journal of Clinical Investigation

Volume

117

Issue

8

Document type

Journal article

Publisher

Am Soc Clin Investig

Topic

  • Clinical Medicine

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Cardiovascular Disease
  • Cardiovascular Research - Hypertension
  • Diabetes - Epigenetics
  • Vascular Diseases - Clinical Research
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 0021-9738