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. 2007 Dec;50(12):2443-50.
doi: 10.1007/s00125-007-0753-6. Epub 2007 Jul 28.

Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

S A Schäfer  1 , O Tschritter, F Machicao, C Thamer, N Stefan, B Gallwitz, J J Holst, J M Dekker, L M 't Hart, G Nijpels, T W van Haeften, H U Häring, A Fritsche
Affiliations

Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

S A Schäfer et al. Diabetologia. 2007 Dec.

Erratum in

  • Diabetologia. 2008 Jan;51(1):208. t' Hart, L M [corrected to 't Hart, L M]
  • Diabetologia. 2009 Mar;52(3):557. Dosage error in article text

Abstract

Aims/hypothesis: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms.

Methods: We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155 participants. In 210 participants, an IVGTT combined with a hyperinsulinaemic-euglycaemic clamp was performed. In another 160 participants from the Netherlands and 73 from Germany, a hyperglycaemic clamp (10 mmol/l) was performed. In 73 German participants this clamp was combined with a GLP-1 infusion and an arginine bolus.

Results: The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT were not influenced by the TCF7L2 variants. However, GLP-1-infusion combined with a hyperglycaemic clamp showed a significant reduction in GLP-1-induced insulin secretion in carriers of the risk allele in two variants (rs7903146, rs12255372, p < 0.02).

Conclusions/interpretation: Variants of TCF7L2 specifically impair GLP-1-induced insulin secretion. This seems to be rather the result of a functional defect in the GLP-1 signalling in beta cells than a reduction in GLP-1 secretion. This defect might explain the impaired insulin secretion in carriers of the risk alleles and confers the increased risk of type 2 diabetes.

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Figures

Fig. 1
Fig. 1
Associations between the genotypes of rs7903146 polymorphism in the TCF7L2 gene with insulin secretion during a hyperglycaemic clamp in 73 German participants. Open circles CC; closed circles CT and TT. AIR Acute insulin response. Arrow Administration of 5 g arginine. The p values show the differences for first and second phases of glucose-induced insulin secretion, first and second phases of GLP-1-induced insulin secretion and acute insulin secretory response to arginine (AIR) (for calculation see ‘Methods’; insulin secretion is adjusted for insulin sensitivity)
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