TCF7L2 is the strongest signal associated with type 2 diabetes. Its association with diabetes was first identified via a linkage signal on chromosome 10q and subsequently replicated by GWAS. Prior to this, it had been recognised as as a transcription factor on the WNT pathway. The functional effect of this allele is mediated by reduced insulin secretion, in turn apparently due to a reduced incretin effect.
Several lines of investigation support the suggestion that resistance to the actions of incretins (both GLP-1 and GIP) is responsible for the insulin secretory deficit observed with TCF7L2, and this effect appears to be amplified by hyperglycaemia, such that the gene effect becomes greater as the person affected progresses towards diabetes. This observation might potentially provide the basis for better understanding of gene-environment interactions and has potential implications in terms of response (or potentially lack of response) to DPP4 inhibitors.
^ Wagner R et al. Untangling the interplay of genetic and metabolic influences on beta cell function: examples of potential therapeutic implications involving TCF7L2 and FFAR1. Molecular Metabolism 2014;3:261-7