TCF7L2 and type 2 diabetes—we WNT to know
The initial report by Grant et al.  that variants in the TCF7L2 gene are strongly associated with risk of developing type 2 diabetes has now been robustly reproduced in many other populations. In fact, variants in this gene contribute more powerfully to the risk of developing type 2 diabetes than any other gene identified to date (see also ).
Since the population-attributable risk is also substantial, we need to understand whether the TCF7L2 variants are causally related to type 2 diabetes, and if so, what the pathogenetic mechanisms are.
The phenotype of individuals carrying the susceptibility variants seems to be slightly at odds with the typical individual at risk, in that the BMI is reduced relative to non-risk variants rather than increased. Virtually all reports have shown impaired insulin secretion following a glucose tolerance test, although the degree of insulin sensitivity has not been stringently defined. Using the minimal model analysis following an IVGTT in non-diabetic at-risk individuals, Damcott et al.  found both impaired insulin secretion and reduced insulin sensitivity. Additional studies characterising the phenotype in detail with sensitive techniques will enhance our understanding of the functions of TCF7L2.
Do the TCF7L2 variants have different functions?
The fundamental question of whether the genetic variants have functional consequences has not yet been answered. The identified variants are in the introns rather than in the coding regions. However, this may still lead to functional consequences in terms of protein stability and/or expression of alternatively spliced variants. This lack of information, combined with insufficient in-depth phenotypic characterisations of non-diabetic carriers of the risk variants, makes the pathogenetic mechanisms speculative. However, the well-known fundamental biological action of TCF7L2 and the available information on its role in insulin secretion, adipose tissue development (and, thus, a link to BMI) and insulin sensitivity can provide us with insight into potential mechanisms.
TCF7L2—a critical component of WNT signalling and action
TCF7L2, also known as TCF-4, is a nuclear receptor for CTNNB1 (previously known as β-catenin), which in turn mediates the canonical WNT signalling pathway. The WNT signalling pathway is critical for normal embryogenesis, cell proliferation and motility, as well as cell fate determination. Mutations in different molecules involved in WNT signalling have been identified in several cancers, and other disruptive mutations are associated with decreased bone mass [4, 5]. WNT signalling is also critical for the normal self-renewal of stem cells, as well as in regulating myogenesis and adipogenesis [6, 7]. In addition, tightly regulated WNT signalling is required for the normal development of the pancreas and islets during embryonic growth .
Figure 1 also shows the involvement of calpains in regulating the cellular β-catenin levels. Genetic variations in the CAPN10 gene (previously known as calpain 10) have previously been found to be associated with type 2 diabetes , but the mechanisms for this are unclear. Calpains are a family of intracellular proteases that are involved in the regulation of the cell cycle and apoptosis. Interestingly, it was recently reported that the calpain system plays an important role in regulating cellular β-catenin levels and, thus, is also involved in the WNT signalling pathway .
How is WNT signalling related to type 2 diabetes?
There are several known mechanisms for the involvement of WNT signalling in both insulin secretion and action, as well as in cell differentiation and maturation.
WNT signalling through the TCF7L2 nuclear receptor has been shown to be critical for glucagon-like peptide-1 (GLP-1) secretion by the intestinal endocrine L-cells . Thus, an alteration in this pathway could lead to a reduced secretion of GLP-1 which, in turn, could have consequences for both the insulin secretion following a meal and the generation of new beta cells from the ductal precursor cells. The consensus finding that the TCF7L2 risk variants are associated with a reduced insulin secretion supports such a possibility. This obviously can, and should be, tested through careful phenotyping, with GLP-1 measurements of well-matched non-diabetic individuals carrying or not carrying the risk genotypes. Mice in which the Tcf7l2 gene has been completely ablated die shortly after birth. Interestingly, however, they lack a proliferative compartment in the crypt regions between the villi in the small intestine , supporting the possibility of a defect in the development of the GLP-1-secreting L-cells.
However, the recent finding  that the TCF7L2 gene is also expressed in human pancreas, in apparent contrast to murine models , suggests direct effects on normal beta cell insulin secretion or, more likely, beta cell growth and differentiation from the precursor cells.
How is WNT signalling related to BMI?
WNT signalling plays a fundamental role in regulating adipogenesis and adipose cell differentiation . Unless WNT signalling is inhibited, committed preadipocytes will not differentiate into mature adipose cells. In contrast, loss-of-function mutations in the WNT signalling cascade leads to rapid recruitment and growth of preadipocytes. Recently, an apparent mutation of a WNT protein (WNT10B) was described in a family characterised by severe obesity , further linking this pathway to metabolic disorders. Thus, potentially increased WNT signalling in carriers of the TCF7L2 risk variants could be expected to influence adipose tissue growth and development and, thus, BMI.
Although the study by Grant et al.  provides the most convincing link between the WNT signalling pathway and type 2 diabetes, it is not the only study to make this connection. Kanazawa et al.  reported that genetic variants in WNT5B, another gene involved in the non-canonical WNT signalling pathway, were associated with type 2 diabetes in the Japanese population. Interestingly, overexpression of WNT5B in preadipocytes was also found to have a marked effect on the differentiation process .
In conclusion, the scientific community has been provided with a new opportunity to understand pathogenetic mechanisms leading to type 2 diabetes. Provided that the TCF7L2 risk variants have important functional consequences, this experiment of nature has taught us that abnormalities in WNT signalling are involved in yet another major human disease. Understanding the mechanisms could provide us with new tools for both the identification and treatment of type 2 diabetes.
- 2.Zeggini E, McCarthy MI (2006) TCF7L2: the biggest story in diabetes genetics since HLA? Diabetologia. DOI 10.1007/s00125-006-0507-x