Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele associates with type 2 diabetes in several populations, possibly mediated via decreased incretin secretion and/or action and altered beta and alpha cell function. We aimed to study circulating levels of glucose, proinsulin, insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and gastric inhibitory polypeptide (GIP) among individuals carrying the high-risk rs7903146 TT genotype and low-risk CC genotype following a meal test. A meal challenge was performed in 31 glucose-tolerant men (age 54 +/- 7 years and BMI 26 +/- 3 kg/m(2)) with rs7903146 TT genotype and 31 glucose-tolerant age- and BMI-matched men with CC genotype (age 53 +/- 6 years and BMI 26 +/- 3 kg/m(2)). Serum proinsulin, insulin, C-peptide and plasma glucose, glucagon, GLP-1, GLP-2 and GIP were obtained 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 min after ingestion of a standardised breakfast meal. An elevated incremental AUC for plasma glucose was observed among TT genotype carriers (CC carriers 21.8 +/- 101.9 mmol/l x min vs TT carriers 97.9 +/- 89.2 mmol/l x min, p = 0.001). TT carriers also had increased AUCs for proinsulin (CC carriers 6,030 +/- 3,001 pmol/l x min vs TT carriers 6,917 +/- 4,820 pmol/l x min, p = 0.03), C-peptide (CC carriers 397.6 +/- 131.9 nmol/l x min vs TT carriers 417.1 +/- 109.3 nmol/l x min, p = 0.04) and GIP (CC carriers 12,310 +/- 3,840 pmol/l x min vs TT carriers 14,590 +/- 5,910 pmol/l x min, p = 0.004). Middle-aged normoglycaemic individuals carrying the rs7903146 TCF7L2 risk TT genotype show early signs of dysregulated glucose metabolism, decreased processing of proinsulin and elevated GIP secretion following a meal challenge.