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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.; Lyssenko, Valeriya LU ; Wegner, L.; Brons, C.; Vilsboll, T.; Hansen, T.; Madsbad, S. and Holst, J. J., et al. (2009) In Diabetologia 52(7). p.1298-1307
Abstract
We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. 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. Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose... (More)
We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. 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. 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. 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. (Less)
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Contribution to journal
publication status
published
subject
keywords
Type 2 diabetes, TCF7L2, Insulin secretion, Incretin hormones, Hepatic glucose production, Genetics, Glucagon
in
Diabetologia
volume
52
issue
7
pages
1298 - 1307
publisher
Springer Verlag
external identifiers
  • wos:000266496000011
  • scopus:67349102328
ISSN
1432-0428
DOI
10.1007/s00125-009-1307-x
language
English
LU publication?
yes
id
76a06989-83e1-4b46-87ae-dac8d4b463fe (old id 1443969)
date added to LUP
2009-07-17 12:24:17
date last changed
2017-10-22 03:57:32
@article{76a06989-83e1-4b46-87ae-dac8d4b463fe,
  abstract     = {We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. 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. Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p &lt; 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p &lt; 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 &lt; 0.02) suggesting altered alpha cell function. 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.},
  author       = {Pilgaard, K. and Jensen, C. B. and Schou, J. H. and Lyssenko, Valeriya and Wegner, L. and Brons, C. and Vilsboll, T. and Hansen, T. and Madsbad, S. and Holst, J. J. and Volund, A. and Poulsen, P. and Groop, Leif and Pedersen, O. and Vaag, A. A.},
  issn         = {1432-0428},
  keyword      = {Type 2 diabetes,TCF7L2,Insulin secretion,Incretin hormones,Hepatic glucose production,Genetics,Glucagon},
  language     = {eng},
  number       = {7},
  pages        = {1298--1307},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  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},
  url          = {http://dx.doi.org/10.1007/s00125-009-1307-x},
  volume       = {52},
  year         = {2009},
}