Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms
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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, Jens Juul; Dekker, J M; 't Hart, L M; t'Hart, L M; Nijpels, G; van Haeften, T W; Häring, H U; Fritsche, A.
In: Diabetologia, Vol. 50, No. 12, 12.2007, p. 2443-50.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms
AU - Schäfer, S A
AU - Tschritter, O
AU - Machicao, F
AU - Thamer, C
AU - Stefan, N
AU - Gallwitz, B
AU - Holst, Jens Juul
AU - Dekker, J M
AU - 't Hart, L M
AU - t'Hart, L M
AU - Nijpels, G
AU - van Haeften, T W
AU - Häring, H U
AU - Fritsche, A
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
KW - Adult
KW - Arginine
KW - Blood Glucose
KW - Female
KW - Glucagon-Like Peptide 1
KW - Glucose Clamp Technique
KW - Glucose Intolerance
KW - Glucose Tolerance Test
KW - Heterozygote
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - TCF Transcription Factors
KW - Transcription Factor 7-Like 2 Protein
U2 - 10.1007/s00125-007-0753-6
DO - 10.1007/s00125-007-0753-6
M3 - Journal article
C2 - 17661009
VL - 50
SP - 2443
EP - 2450
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 12
ER -
ID: 132049933