What Can Diabetes-Associated Genetic Variation in TCF7L2 Teach Us About the Pathogenesis of Type 2 Diabetes?

Abstract

Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disorder characterized by hyperglycemia occurring as a result of impaired insulin secretion and/or insulin resistance. Among the various genetic factors associated with T2DM, a common genetic variant within the transcription factor 7-like 2 locus (TCF7L2) confers the greatest genetic risk for development of the disease. However, the mechanism(s) by which TCF7L2 predisposes to diabetes remain uncertain. Here we review the current literature pertaining to the potential mechanisms by which TCF7L2 confers risk of T2DM, using genetic variation as a probe to understand the pathogenesis of the disease.

Effects of TCF7L2 rs7903146 variant on metformin response in patients with type 2 diabetes

“…The common TCF7L2 rs7903146 variant is the strongest genetic risk factor associated with T2D to date. Different underlying mechanisms of this association have been proposed, including the effect on β-cell proliferation, insulin synthesis, processing, and secretion, and impaired incretin response [7]. Most of the studies suggest that the rs7903146 variant affects β-cells and insulin secretion.…”

“…Thus, it is possible that different mechanisms are responsible for metformin-induced inhibition of gluconeogenesis and its effect on lipid metabolism and insulin sensitivity. The TCF7L2 rs7903146 variant also has pleiotropic effects [7]. Although the T allele is associated with decreased β-cell function and increased T2D risk, possibly through increased resistance to incretin effect, it is also associated with lower BMI [16] and lower triglyceride levels in patients with T2D [14].…”

“…In a recent study on the acute response to metformin and glipizide (Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans [SUGAR-MGH]), the rs7903146 C>T variant in the transcription factor 7-like 2 (TCF7L2) gene was associated with a greater decline in fasting glucose levels after metformin administration in individuals without diabetes [6]. This single nucleotide polymorphism (SNP) is the strongest genetic risk factor associated with T2D till date [7], although the underlying mechanism is not clear. TCF7L2 is a part of the canonical (β-catenin-dependent) Wnt signaling pathway, which regulates organogenesis.…”

“…Different mechanisms have been proposed for the increased risk of T2D associated with the rs7903146 T allele. Most of the studies suggest that TCF7L2 plays a key role in β-cell function and that progressive loss of insulin secretion might be the main mechanism by which carriers of the risk T allele are predisposed to develop T2D, although the exact molecular mechanisms are still unknown [7]. The pharmacogenetic effect of the TCF7L2 variant on a therapeutic response to hypoglycemic agents has been explored in only a few studies.…”

Genetic studies of multifactorial diseases in the concept of personalized medicine

“…Среди различных генетических факторов, связанных с СД 2-го типа, наибольший генетический риск связан с транскрипционным фактором 7 (TCF7L2). Однако механизмы, с помощью которых TCF7L2 предрасполагает к СД, остаются неизвестными [24].…”