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.
Keywords GLP-1 - Insulin secretion - Polymorphism -
TCF7L2
An erratum to this article can be found at
http://dx.doi.org/10.1007/s00125-008-1248-9