• Kjems, L. L.
• Hansen, Torben
• Pedersen, Oluf
• Vestmar, M. A.
• Grarup, Niels
• Gjesing, Anette P.
• Holst, Jens Juul
• Linneberg, Allan
• Deacon, Carolyn

Abstract

Aims/hypothesis<br/>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.<br/>Methods<br/>A meal challenge was performed in 31 glucose-tolerant men (age 54¿±¿7 years and BMI 26¿±¿3 kg/m2) 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/m2). 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.<br/>Results<br/>An elevated incremental AUC for plasma glucose was observed among TT genotype carriers (CC carriers 21.8¿±¿101.9 mmol/l¿×¿min vs TT carriers 97.9¿±¿89.2 mmol/l¿×¿min, p¿=¿0.001). TT carriers also had increased AUCs for proinsulin (CC carriers 6,030¿±¿3,001 pmol/l¿×¿min vs TT carriers 6,917¿±¿4,820 pmol/l¿×¿min, p¿=¿0.03), C-peptide (CC carriers 397.6¿±¿131.9 nmol/l¿×¿min vs TT carriers 417.1¿±¿109.3 nmol/l¿×¿min, p¿=¿0.04) and GIP (CC carriers 12,310¿±¿3,840 pmol/l¿×¿min vs TT carriers 14,590¿±¿5,910 pmol/l¿×¿min, p¿=¿0.004).<br/>Conclusions/interpretation<br/>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.<br/>

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