The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

K Pilgaard; C B Jensen; J H Schou; V Lyssenko; L Wegner; C Brøns; T Vilsbøll; T Hansen; S Madsbad; Jens Juul Holst; A Vølund; P Poulsen; L Groop; A A Vaag

doi:10.1007/s00125-009-1307-x

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

K Pilgaard, C B Jensen, J H Schou, V Lyssenko, L Wegner, C Brøns, T Vilsbøll, T Hansen, S Madsbad, Jens Juul Holst, A Vølund, P Poulsen, L Groop, A A Vaag

108 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.

METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.

RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.

CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

Original language	English
Journal	Diabetologia
Volume	52
Issue number	7
Pages (from-to)	1298-307
Number of pages	10
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-009-1307-x
Publication status	Published - Jul 2009

Keywords

Adolescent
Alleles
Blood Glucose
Diabetes Mellitus, Type 2
Genotype
Glucagon-Like Peptide 1
Glucose Clamp Technique
Glucose Tolerance Test
Glutaminase
Humans
Hyperinsulinism
Incretins
Insulin
Intracellular Signaling Peptides and Proteins
Liver
Male
Risk Factors
TCF Transcription Factors
Transcription Factor 7-Like 2 Protein
Tritium
Young Adult

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Pilgaard, K., Jensen, C. B., Schou, J. H., Lyssenko, V., Wegner, L., Brøns, C., Vilsbøll, T., Hansen, T., Madsbad, S., Holst, J. J., Vølund, A., Poulsen, P., Groop, L., & Vaag, A. A. (2009). The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia, 52(7), 1298-307. https://doi.org/10.1007/s00125-009-1307-x

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. / Pilgaard, K; Jensen, C B; Schou, J H et al.
In: Diabetologia, Vol. 52, No. 7, 07.2009, p. 1298-307.

Research output: Contribution to journal › Journal article › Research › peer-review

Pilgaard, K, Jensen, CB, Schou, JH, Lyssenko, V, Wegner, L, Brøns, C, Vilsbøll, T, Hansen, T , Madsbad, S , Holst, JJ, Vølund, A, Poulsen, P, Groop, L & Vaag, AA 2009, 'The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men', Diabetologia, vol. 52, no. 7, pp. 1298-307. https://doi.org/10.1007/s00125-009-1307-x

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title = "The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men",

abstract = "AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.",

keywords = "Adolescent, Alleles, Blood Glucose, Diabetes Mellitus, Type 2, Genotype, Glucagon-Like Peptide 1, Glucose Clamp Technique, Glucose Tolerance Test, Glutaminase, Humans, Hyperinsulinism, Incretins, Insulin, Intracellular Signaling Peptides and Proteins, Liver, Male, Risk Factors, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Tritium, Young Adult",

author = "K Pilgaard and Jensen, {C B} and Schou, {J H} and V Lyssenko and L Wegner and C Br{\o}ns and T Vilsb{\o}ll and T Hansen and S Madsbad and Holst, {Jens Juul} and A V{\o}lund and P Poulsen and L Groop and Vaag, {A A}",

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doi = "10.1007/s00125-009-1307-x",

language = "English",

volume = "52",

pages = "1298--307",

journal = "Diabetologia",

issn = "0012-186X",

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TY - JOUR

T1 - The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

AU - Pilgaard, K

AU - Jensen, C B

AU - Schou, J H

AU - Lyssenko, V

AU - Wegner, L

AU - Brøns, C

AU - Vilsbøll, T

AU - Hansen, T

AU - Madsbad, S

AU - Holst, Jens Juul

AU - Vølund, A

AU - Poulsen, P

AU - Groop, L

AU - Vaag, A A

PY - 2009/7

Y1 - 2009/7

N2 - AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

AB - AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

KW - Adolescent

KW - Alleles

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2

KW - Genotype

KW - Glucagon-Like Peptide 1

KW - Glucose Clamp Technique

KW - Glucose Tolerance Test

KW - Glutaminase

KW - Humans

KW - Hyperinsulinism

KW - Incretins

KW - Insulin

KW - Intracellular Signaling Peptides and Proteins

KW - Liver

KW - Male

KW - Risk Factors

KW - TCF Transcription Factors

KW - Transcription Factor 7-Like 2 Protein

KW - Tritium

KW - Young Adult

U2 - 10.1007/s00125-009-1307-x

DO - 10.1007/s00125-009-1307-x

M3 - Journal article

C2 - 19288077

SN - 0012-186X

VL - 52

SP - 1298

EP - 1307

JO - Diabetologia

JF - Diabetologia

IS - 7

ER -