Type 2 Diabetes Susceptibility Gene TCF7L2 and Its Role in β-Cell Function

Type 2 diabetes is associated with impaired insulin secretion. Both 1st- and 2nd-phase insulin secretion are reduced, but the effect is particularly pronounced for the 1st phase. The processes culminating in impaired insulin secretion are not fully understood, but both genetic and environmental factors are thought to play a role. Over the past 2 years, genome-wide association scans have transformed the genetic landscape of type 2 diabetes susceptibility, with the current gene count close to 20 (1). A couple of common themes have emerged from these studies. First, the majority of the genes identified thus far seem to affect diabetes susceptibility through β-cell dysfunction (2). Second, the risk alleles tend to be common in the population, but their effect on diabetes risk is relatively small (3,4).

TCF7L2, the susceptibility gene with the largest effect on disease susceptibility discovered to date, was identified pre–genome-wide association by Grant et al. in 2006, with rapid replication of its consequence on diabetes susceptibility in multiple populations (5–9). TCF7L2 was a positional candidate gene that mapped to a region of genetic linkage to type 2 diabetes in the Icelandic population on chromosome 10. However, the identified TCF7L2 risk allele, which was present in ∼28% of control subjects and ∼36% of type 2 diabetic individuals, could not explain this linkage, so the finding was actually serendipitous (5). The precise genetic defect that causes the association of TCF7L2 with type 2 diabetes remains unclear. There is a large number of highly correlated variants, none of which are obvious functional candidates, that show association with diabetes (5). The most likely candidate is the …