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

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2009 Mar 17

PMID 19288077

Citations 63

Authors

K Pilgaard

C B Jensen

J H Schou

V Lyssenko

L Wegner

C Brons

T Vilsboll

T Hansen

S Madsbad

J J Holst

A Volund

P Poulsen

L Groop

O Pedersen

A A Vaag

Affiliations

Soon will be listed here.

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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