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 Jensen; J Schou; V Lyssenko; L Wegner; C Brøns; T Vilsbøll; T Hansen; S Madsbad; J Holst; A Vølund; P Poulsen; L Groop; Oluf Pedersen; A Vaag; K Pilgaard; C B Jensen; J H Schou; V Lyssenko; L Wegner; C Brøns; Tina Vilsbøll; T Hansen; S Madsbad; Jens Møller Holst; Anders Vølund; P Poulsen; L Groop; O Pedersen; Allan 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 Jensen, J Schou, V Lyssenko, L Wegner, C Brøns, T Vilsbøll, T Hansen, S Madsbad, J Holst, A Vølund, P Poulsen, L Groop, Oluf Pedersen, A Vaag, K Pilgaard, C B Jensen, J H Schou, V Lyssenko, L WegnerC Brøns, Tina Vilsbøll, T Hansen, S Madsbad, Jens Møller Holst, Anders Vølund, P Poulsen, L Groop, O Pedersen, Allan 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 https://doi.org/10.1007/s00125-009-1307-x
Publication status	Published - 1 Jul 2009

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Pilgaard, K., Jensen, C., Schou, J., Lyssenko, V., Wegner, L., Brøns, C., Vilsbøll, T., Hansen, T., Madsbad, S., Holst, J., Vølund, A., Poulsen, P., Groop, L., Pedersen, O., Vaag, A., Pilgaard, K., Jensen, C. B., Schou, J. H., Lyssenko, V., ... Vaag, 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, 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; Schou, J et al.
In: Diabetologia, Vol. 52, No. 7, 01.07.2009, p. 1298-307.

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

Pilgaard, K, Jensen, C, Schou, J, Lyssenko, V, Wegner, L, Brøns, C, Vilsbøll, T, Hansen, T, Madsbad, S , Holst, J, Vølund, A, Poulsen, P, Groop, L, Pedersen, O , Vaag, A, Pilgaard, K, Jensen, CB, Schou, JH, Lyssenko, V, Wegner, L, Brøns, C, Vilsbøll, T, Hansen, T, Madsbad, S, Holst, JM, Vølund, A, Poulsen, P, Groop, L, Pedersen, O & Vaag, 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, vol. 52, no. 7, pp. 1298-307. https://doi.org/10.1007/s00125-009-1307-x, https://doi.org/10.1007/s00125-009-1307-x

Pilgaard K, Jensen C, Schou J, Lyssenko V, Wegner L, Brøns C et al. 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. 2009 Jul 1;52(7):1298-307. doi: 10.1007/s00125-009-1307-x, 10.1007/s00125-009-1307-x

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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.",

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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

AU - Schou, J

AU - Lyssenko, V

AU - Wegner, L

AU - Brøns, C

AU - Vilsbøll, T

AU - Hansen, T

AU - Madsbad, S

AU - Holst, J

AU - Vølund, A

AU - Poulsen, P

AU - Groop, L

AU - Pedersen, Oluf

AU - Vaag, A

AU - Pilgaard, K

AU - Jensen, C B

AU - Schou, J H

AU - Lyssenko, V

AU - Wegner, L

AU - Brøns, C

AU - Vilsbøll, Tina

AU - Hansen, T

AU - Madsbad, S

AU - Holst, Jens Møller

AU - Vølund, Anders

AU - Poulsen, P

AU - Groop, L

AU - Pedersen, O

AU - Vaag, Allan

N1 - Cited By (since 1996): 2Export Date: 4 November 2009Source: Scopus

PY - 2009/7/1

Y1 - 2009/7/1

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.

U2 - 10.1007/s00125-009-1307-x

DO - 10.1007/s00125-009-1307-x

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C2 - 19288077

SN - 0012-186X

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SP - 1298

EP - 1307

JO - Diabetologia

JF - Diabetologia

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