Brief Report TCF7L2 Polymorphisms Modulate Proinsulin Levels and -Cell Function in a British Europid Population

Rapidly accumulating evidence shows that common T-cell transcription factor (TCF)7L2 polymorphisms confer risk of type 2 diabetes through unknown mechanisms. We examined the association between four TCF7L2 single nucleotide polymorphisms (SNPs), including rs7903146, and measures of insulin sensitivity and insulin secretion in 1,697 Europid men and women of the population-based MRC (Medical Research Council)-Ely study. The T-(minor) allele of rs7903146 was strongly and positively associated with fasting proinsulin (P 4.55 10 ) and 32,33 split proinsulin (P 1.72 10 ) relative to total insulin levels; i.e., differences between T/T and C/C homozygotes amounted to 21.9 and 18.4% respectively. Notably, the insulin-to-glucose ratio (IGR) at 30-min oral glucose tolerance test (OGTT), a frequently used surrogate of firstphase insulin secretion, was not associated with the TCF7L2 SNP (P > 0.7). However, the insulin response (IGR) at 60-min OGTT was significantly lower in T-allele carriers (P 3.5 10 ). The T-allele was also associated with higher A1C concentrations (P 1.2 10 ) and reduced -cell function, assessed by homeostasis model assessment of -cell function (P 2.8 10 ). Similar results were obtained for the other TCF7L2 SNPs. Of note, both major genes involved in proinsulin processing (PC1, PC2) contain TCF-binding sites in their promoters. Our findings suggest that the TCF7L2 risk allele may predispose to type 2 diabetes by impairing -cell proinsulin processing. The risk allele increases proinsulin levels and diminishes the 60-min but not 30-min insulin response during OGTT. The strong association between the TCF7L2 risk allele and fasting proinsulin but not insulin levels is notable, as, in this unselected and largely normoglycemic population, external influences on -cell stress are unlikely to be major factors influencing the efficiency of proinsulin processing. Diabetes 56:1943–1947, 2007 A common variant in the TCF7L2 gene was found to increase the risk of type 2 diabetes by 1.41 in heterozygotes and by 2.27 in homozygotes in an Icelandic population, a finding that was replicated in a Danish and a European-American population (1). The association is robust and has been consistently reproduced in geographically and ethnically diverse populations (2–12). The mechanisms through which TCF7L2 affects the susceptibility to type 2 diabetes remain to be elucidated. It is known that TCF7L2 serves as a nuclear receptor for -catenin, which mediates the Wnt signaling pathway (13). The bipartite transcription factor, cat/TCF7L2, activates many genes downstream of the Wnt signaling cascade (14). One of the genes transcriptionally regulated by cat/TCF7L2 is proglucagon, which encodes the insulinotropic hormone glucagon-like peptide 1 (GLP-1) (13). Because GLP1, in concert with insulin, plays a critical role in blood glucose homeostasis, it has been postulated that TCF7L2 gene variants may affect the susceptibility to type 2 diabetes by indirectly altering GLP-1 levels (13). Since the Wnt signaling pathway is involved in a variety of biological events and TCF7L2 transcriptionally regulates many genes, other mechanisms cannot be excluded. Case-control studies have been instrumental in confirming the association between TCF7L2 variants and type 2 diabetes. However, by design, these studies provide limited insight into the biological pathways through which TCF7L2 exerts its effect because the biochemical profile in case subjects is likely to have been altered by the disease status or by treatment. Cohort studies with detailed phenotypic characterization can provide new insights to further elucidate the mechanisms that underlie the robust association. The present study examines the association between four TCF7L2 polymorphisms and measures of fasting insulin sensitivity, -cell function, and insulin secretion during a 120-min oral glucose tolerance test (OGTT) in 1,697 Europid men and women of the population-based Ely study.