Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism

Abstract

Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors longrange enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dosedependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.[Supplemental material is available for this article.]Recent GWAS have uncovered a number of loci affecting risk of T2D (Voight et al. 2010). While some of these loci include genes known to play a role in glucose metabolism and diabetes pathogenesis (PPARG, KCNJ11) (Willson et al. 2001;Gloyn et al. 2006), others represent genomic regions with unknown functional roles in disease etiology. Among these, a set of single nucleotide polymorphisms (SNPs) on chromosome 10q25.2 shows strong and consistent association with T2D in virtually every population tested, constituting the greatest effect on risk identified to date, with a cumulative allelic odds ratio of 1.46 (Grant et al. 2006;Cauchi et al. 2007;Lyssenko 2008). These SNPs map to a 92-kb interval within TCF7L2, a gene encoding a transcription factor of the canonical Wnt signaling pathway known to have developmental roles in determining cell fate, survival, proliferation, and movement (Moon et al. 2004;Clevers 2006;MacDonald et al. 2009). Given the complexity of this pathway, establishing a definitive role for TCF7L2 in the etiology of T2D has been challenging (Pearson 2009).While the TCF7L2 T2D-associated interval spans coding sequence, exonic v...

The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

“…Several studies have demonstrated the beneficial effect of TCF7L2 on ␤-cell proliferation, insulin secretion, and the expression of incretin hormone receptors (3,33,34). These findings, however, are in contradiction with the suggestion that TCF7L2 exerts deleterious effects on ␤-cells by other investigations (22,30). It has also been demonstrated that TCF7L2 type 2 diabetes risk SNPs are associated with elevated hepatic glucose production in individuals even during a hyperinsulinemic euglycemic clamp as well as during hepatic insulin resistance (22,28,39).…”

“…However, the functional role of TCF7L2 in pancreatic islets remains unclear and controversial (3,19,22,30,33,34). Because TCF7L2 is also expressed in organs other than pancreatic islets, including liver, brain, muscle, and fat tissues, which are likewise important in metabolic homeostasis, it is necessary to define the function of TCF7L2 and further study the metabolic function of Wnt signaling in each of those organs.…”

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

“…Human carriers of the TCF7L2 rs7903146 risk allele have increased pancreatic islet size, and altered alpha:beta cell ratios and distribution within pancreatic islets [6]. DNA sequences around the TCF7L2 rs7903146 SNP contain regulatory elements that are critical in the regulation of TCF7L2 transcription, suggesting that the type 2 diabetes susceptibility conferred by this locus is related to modified TCF7L2 expression [7]. At least 20 different TCF7L2 splice variants and isoforms exist (Table 1) [8][9][10][11][12], which may also differ in their transcriptional activation properties [12][13][14].…”

Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis

“…Although several investigations suggested that TCF7L2 negatively regulates hepatic gluconeogenesis (8,10,11,17), one recent study (7) reported that liver-specific knockout of TCF7L2 reduced hepatic glucose production (HGP), while hepatic overexpression of TCF7L2 increased HGP. As a result, the controversial issues surrounding the metabolic function of TCF7L2 have been extended from pancreatic b-cells to liver and hepatocytes specifically (4)(5)(6)9,13,(18)(19)(20). TCF7L2 or other transcription factor (TCF) members can interact with b-catenin (b-cat), forming the bipartite transcription factor b-cat/TCF, which serves as the important effector of the Wnt signaling pathway.…”

“…Following pivotal studies indicating that the transcription factor 7-like 2 (TCF7L2) is an important risk gene for the development of type 2 diabetes (T2D) (1), great efforts have been made to explore its role as a Wnt signaling molecule in pancreatic b-cells and other tissues including liver (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Although several investigations suggested that TCF7L2 negatively regulates hepatic gluconeogenesis (8,10,11,17), one recent study (7) reported that liver-specific knockout of TCF7L2 reduced hepatic glucose production (HGP), while hepatic overexpression of TCF7L2 increased HGP.…”