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

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

doi:10.1007/s00125-007-0753-6

Cited by 308Pancreatic function and diabetesDiabetes Treatment and ManagementGenetic Associations and Epidemiology

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

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Schäfer, S. A., Tschritter, O., Machicao, F., Thamer, C., Stefan, N., Gallwitz, B., Holst, J. J., Dekker, J. M. +5 more·2007·Diabetologia

DOI 10.1007/s00125-007-0753-6PMC PMC2063563

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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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There is interindividual heterogeneity in response to GLP-1.
“However, there has been some suggestion that there is interindividual heterogeneity in response to GLP-1, raising the possibility that some individuals may benefit more from such therapy than others earlier in the disease (25, 31).”
From A model of GLP-1 action on insulin secretion in nondiabetic subjects (2010) · cites this paper as [25]

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ARTICLE
Holst, J. J., T’hart, L. M., & van Haeften, T. W. (2013)
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Die GLP-1 induzierte Insulinsekretion ist bei Trägern der TCF7L2 SNPs vermindert
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TCF 7l2 Gene Variant Rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Secretion
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Diabetes Risk Allele of Transcription Factor 7-like 2 (TCF7L2) Polymorphisms is Associated with Higher Glucagon-like Peptide 1 (GLP1) and Lower Insulin Secretion
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The correlation between polymorphism of TCF7L2 gene and the incidence of type 2 Diabetes in Asian: a meta analysis
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Authors: Schäfer, S. A., Tschritter, O., Machicao, F., Thamer, C., Stefan, N., Gallwitz, B., Holst, J. J., Dekker, J. M., t’Hart, L. M., Nijpels, G., van Haeften, T. W., Häring, H. U., & Fritsche, A.
Affiliations: University of Tübingen (DE)
University of Copenhagen (DK)
Amsterdam Public Health (NL)
Corresponding author: Fritsche, A.
ORCID: Stefan, N.
Gallwitz, B.
Holst, J. J.
Nijpels, G.
Fritsche, A.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2007-07-28
Volume: 50
Issue: 12
Pages: 2443-2450
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-007-0753-6
PMC: PMC2063563
OpenAlex: W2132717133
Cited by: 308
References: 30
Citations by year: 2026: 3 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 11 · 2019: 18 · 2018: 14 · 2017: 10 · 2016: 15 · 2015: 15 · 2014: 26 · 2013: 17 · 2012: 23
FWCI: 32.85
Type: journal article
Language: en
Update notices: correction (2007-11-10)
correction (2009-01-08)
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
VU Research Portal (publishedVersion, other-oa)
Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders: Deutsche Forschungsgemeinschaft (KFO 114)
ZonMw
Centre for Medical Systems Biology
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: TCF7L2, glucagon-like peptide-1, insulin secretion, type 2 diabetes risk, single nucleotide polymorphisms, enteroinsular axis, GLP-1 secretion, GLP-1 receptor, rs7903146, rs12255372, risk alleles
MeSH terms: Insulin Secretion, Adult, Arginine, Blood Glucose, Female, Glucose Tolerance Test, Heterozygote, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Glucose Clamp Technique, Glucose Intolerance, Polymorphism, Single Nucleotide, TCF Transcription Factors, Glucagon-Like Peptide 1, Transcription Factor 7-Like 2 Protein

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

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