Type 2 Diabetes and TCF7L2 - Author: Ali Torkamani, PhD, Assistant Faculty, Research, Scripps Genomic Medicine and Assistant Professor of Molecular and Experimental Medicine, Scripps Research Institute
 

TCF7L2 variants have been associated with type 2 diabetes in multiple ethnic groups.^{1,2,3,4,5,6,7} Specific associated variants increase risk of type 2 diabetes 1.5-fold in heterozygotes and 2.41-fold in homozygotes, corresponding to a population attributable risk of 21%. This makes TCF7L2 variants the strongest known genetic risk factor for type 2 diabetes.⁸

TCF7L2 is a transcription factor and key component of the Wnt signaling pathway, and is involved in the development of a wide variety of cell lineages and organs.⁹ Potential mechanisms by which TCF7L2 variants influence type 2 diabetes include its role in adipogenesis, myogenesis, and pancreatic islet development, as well transcription of the genes for proglucagon and the glucagon-like-peptides GLP-1 and GLP-2, which play a role in post-prandial insulin secretion.¹⁰ Additionally, TCF7L2 polymorphisms have been associated with impaired insulin secretion, glucose production, and glucose tolerance via direct effects on pancreatic islet beta-cells.^11,12 Thus, while the specific mechanism driving the development of type 2 diabetes remains unclear, there is sufficient evidence to demonstrate that TCF7L2 variants strongly predict the development of type 2 diabetes and/or the progression to diabetes from impaired glucose tolerance.^12,13