TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population

Abstract

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 x 10(-9)) and 32,33 split proinsulin (P = 1.72 x 10(-4)) 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 first-phase 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 x 10(-3)). The T-allele was also associated with higher A1C concentrations (P = 1.2 x 10(-2)) and reduced beta-cell function, assessed by homeostasis model assessment of beta-cell function (P = 2.8 x 10(-2)). 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 beta-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 beta-cell stress are unlikely to be major factors influencing the efficiency of proinsulin processing.

FIG. 1

Percentage (means ± SEM) of fasting proinsulin and 32,33 split proinsulin of total fasting insulin concentration (intact proinsulin + 32,33 split proinsulin + insulin) by genotype in 1,697 Europids for the rs7903146 TCF7L2 gene variant.

FIG. 2

Consensus sequence (WWCAAWG) for TCF-binding sites in the PC1 (A–D) and PC2 (E) gene sequence. Four consensus sites were identified in PC1. A: Twenty-seven basepairs of the sequence upstream of start codon. The raw genomic position of the consensus site is 95795320–95795326 at −818 bp from the start codon. B: Twenty-seven basepairs of the sequence upstream of the start codon. The raw genomic position of the consensus site is 95794987–95794993 at −485 bp from the start codon. C: Twenty-seven basepairs of the sequence upstream of the start codon. The raw genomic position of the consensus site is 95794948–95794954 at −446 bp from start codon. D: Twenty-seven basepairs of the sequence between exons 7 and 8. The raw genomic position is 95772777–95772783 at 994 bp from the start of intron 7. One consensus site was identified in PC2. E: Twenty-seven basepairs of the sequence upstream of the start codon. The raw genomic position of the consensus site is 17155321–17155327 at −630 bp from the start codon. All alignments are composed of sequence taken 5′ → 3′ from the forward strand, and positions are as per the current build (NCBI 36 assembly) of the human genome (August 2006).