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

Abstract

Aims/hypothesis 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 lowrisk CC genotype following a meal test. Methods A meal challenge was performed in 31 glucosetolerant 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. Results 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).A. P. Gjesing and L.L. Kjems contributed equally to this study. Diabetologia (2011) 54:103-110 DOI 10.1007/s00125-010-1940 Conclusions/interpretation 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. Electronic supplementary material

Genetics of type 2 diabetes

“…TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in homozygotes and overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. These findings were replicated in several subsequent studies, indicating that TCF7L2 probably plays a role in causation of T2D by decreasing insulin secretion from beta cells, perhaps by altering the action of incretins that modulate the insulin response to meals [51,52] . Other studies indicate that alternative splicing of this gene can lead to the production of different isoforms in different tissues and the presence of specific isoforms in adipose tissue may be related to insulin sensitivity in that tissue [53,54] .…”

Glucose Metabolism in High-Risk Subjects for Type 2 Diabetes Carrying the rs7903146TCF7L2Gene Variant

“…Table 1). For instance, Gjeising et al (14) did not detect differences in insulin secretion in response to a meal between glucose tolerant subjects carrying the T of the C allele, even though T carriers had greater elevation of postprandial plasma glucose levels in spite of lower fasting plasma glucose and increased GIP secretion.…”

Clinical and non-targeted metabolomic profiling of homozygous carriers of Transcription Factor 7-like 2 variant rs7903146

“…The risk allele is associated with lower insulin production and release2 and impaired GLP-1 induced insulin secretion34. Functional studies in cell culture and animal models as well as investigation of humans elucidated an important role of TCF7L2 in β-cell function56, as well as islet morphology7.…”