Prime suspect: the TCF7L2 gene and type 2 diabetes risk

Abstract

Transcription factor-7-like 2 (TCF7L2) is the most important type 2 diabetes susceptibility gene identified to date, with common intronic variants strongly associated with diabetes in all major racial groups. This ubiquitous transcription factor in the Wnt signaling pathway was not previously known to be involved in glucose homeostasis, so defining the underlying mechanism(s) will provide new insights into diabetes. In this issue of the JCI, Lyssenko and colleagues report on their human and isolated islet studies and suggest that the risk allele increases TCF7L2 expression in the pancreatic beta cell, reducing insulin secretion and hence predisposing the individual to diabetes (see the related article beginning on page 2155).

Figure 1. From genetic association to pathophysiology in TCF7L2 genotypes predisposing to type 2 diabetes.

Diagram of proposed pathophysiological pathway explaining how TCF7L2 risk genotypes predispose to type 2 diabetes. The risk genotype results in overexpression of TCF7L2 in pancreatic β cells, which in turn results in reduced insulin secretion. Reduced insulin secretion results in a predisposition to type 2 diabetes directly and also indirectly by increasing hepatic glucose output. Dotted arrows represent previous genetic associations. Solid arrows show observations reported by Lyssenko and colleagues in the current issue of the JCI (1).