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.
OBJECTIVE
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
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.
Pilgaard
K
K
Steno Diabetes Center, Niels Steensens Vej 1, Gentofte, Denmark. kapg@steno.dk
Jensen
C B
CB
Schou
J H
JH
Lyssenko
V
V
Wegner
L
L
Brøns
C
C
Vilsbøll
T
T
Hansen
T
T
Madsbad
S
S
Holst
J J
JJ
Vølund
A
A
Poulsen
P
P
Groop
L
L
Pedersen
O
O
Vaag
A A
AA
D000293:Adolescent; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000097:blood; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D005972:Glutaminase / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D006946:Hyperinsulinism / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D054795:Incretins / Q000097:blood*; D007328:Insulin / Q000097:blood*; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D012307:Risk Factors; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014316:Tritium; D055815:Young Adult
D001786:Blood Glucose; D054795:Incretins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C421249:TAX1BP3 protein, human; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014316:Tritium; D052216:Glucagon-Like Peptide 1; D005972:Glutaminase