We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in TCF7L2 with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production. All participants had a 3-hour oral glucose tolerance test (OGTT), an intravenous glucose tolerance test, and a euglycaemic, hyperinsulinaemic clamp. After adjustment for age and sex, risk T allele carriers had higher HbA(1c) levels (P=0.030), reduced first-phase insulin response (P=0.048), higher peripheral insulin sensitivity (P=0.050) and lower fasting GIP concentrations (P=0.003) than CC allele carriers. The latter was also reflected by lower total GIP secretion during the OGTT (P=0.018). We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon, and GLP-1 between the groups. The findings suggest that the effect of TCF7L2 on diabetes risk may include reduced secretion of GIP.