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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

In English

Författare

  • K. Pilgaard
  • C. B. Jensen
  • J. H. Schou
  • Valeriya Lyssenko
  • L. Wegner
  • C. Brons
  • T. Vilsboll
  • T. Hansen
  • S. Madsbad
  • J. J. Holst
  • A. Volund
  • P. Poulsen
  • Leif Groop
  • O. Pedersen
  • A. A. Vaag
Visa allt

Summary, in English

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.

Publiceringsår

2009

Språk

Engelska

Sidor

1298-1307

Publikation/Tidskrift/Serie

Diabetologia

Volym

52

Issue

7

Dokumenttyp

Artikel i tidskrift

Förlag

Springer

Ämne

  • Endocrinology and Diabetes

Nyckelord

  • Type 2 diabetes
  • TCF7L2
  • Insulin secretion
  • Incretin hormones
  • Hepatic glucose production
  • Genetics
  • Glucagon

Status

Published

Forskningsgrupp

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Övrigt

  • ISSN: 1432-0428