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

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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

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 languageEnglish
Issue number7
Pages (from-to)1298-307
Number of pages10
Publication statusPublished - Jul 2009

    Research areas

  • 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

ID: 153104635