Prime suspect: the TCF7L2 gene and type 2 diabetes risk (original) (raw)

Defining the biological functions of polygenes found through genetic approaches can be very hard. Calpain 10 was the first type 2 diabetes susceptibility gene to be defined through linkage rather than a candidate gene route (18). Calpain 10 had not been previously thought to be involved in the pathogenesis of diabetes; it showed initial association with intronic SNPs, and replication required large studies (19, 20). We now recognize that these three characteristics are typical of the majority of type 2 diabetes susceptibility genes, and this may mean that the biological function of such genes will be difficult to define. In the case of Calpain 10, it was 5 years before the gene was shown to play a role in apoptosis in pancreatic islets (21).

TCF7L2 polymorphisms are clearly guilty of predisposing to type 2 diabetes on the basis of strong, reproducible association in multiple populations and would appear to be the leader among a gang of susceptibility genes. The next challenge, as with all genome-wide scans, is to define how the polymorphism predisposes to disease. The associated TCF7L2 haplotype was in the noncoding region of the gene without obvious function in gene regulation, so it was uncertain how or even whether such variants alter TCF7L2 expression. What is the critical variant of the large number of polymorphisms that are coinherited as a haplotype? Is the risk variant altering the gene it is situated in, or does it have a distant regulatory function? What biological pathway are the altered gene or genes acting in and how does this predispose to diabetes? These are the fundamental questions that need to be answered if we are to move forward from the genetic association to gain new insights into diabetes.

It is the hypothesis-free results from genome-wide association studies that have the potential to create major breakthroughs in our understanding of disease, but there are intrinsic difficulties in working on these leads. Most polymorphisms are in genes on which there has been little previous work, and the leading scientists working in cell biology and rodent models already have funding for worthy work in other areas, so why should they risk time and money working on a gene whose role is not 100% certain?

The difficulty had been trying to place TCF7L2 at the scene of the crime, especially as there was some doubt regarding which organ and cell type(s) were involved in the pathophysiology. TCF7L2 is a transcription factor involved in the Wnt signaling pathway and is ubiquitously expressed. The studies from Lyssenko and colleagues (1) confirm earlier studies (22–25) showing that the predisposition to type 2 diabetes is the result of reduced insulin secretion rather than reduced insulin action, making the pancreatic β cell the most likely primary cell target of altered TCF7L2 activity. However, this was contrary to an initial, much-repeated hypothesis, suggesting that the risk genotype was altering insulin secretion indirectly by reducing intestinal TCF7L2 activity, which in turn reduced the secretion of incretins, glucagon intestinal peptide (GIP), and glucagon-like peptide 1 (GLP-1) (6). Lyssenko et al. (1), in their detailed studies, show that insulin secretion in subjects with the at-risk genotype was reduced in response to a variety of stimuli including i.v. glucose and arginine and not just oral glucose. In addition, GIP levels were not reduced, suggesting that even though GLP-1 levels were not measured, there was a reduced β cell response to incretin secretion rather than reduced incretin secretion.

The final question is how exactly the “crime” is performed within the β cell — and here there is a final twist in the story. Lyssenko et al. (1) show that TCF7L2 expression was increased 5-fold in type 2 diabetes islets, rather than being reduced. This vital and surprising observation came from studies of pancreatic islets carefully purified from type 2 diabetic and nondiabetic human cadavers. In addition, there was some suggestion that in the nondiabetic islets that the risk genotype was associated with increased TCF7L2 expression, but the numbers are small and caution must be exercised in interpreting these data until a greater number of islets are examined. Finally, in a reconstruction of the crime, overexpressing TCF7L2 in human islets using an adenovirus system reduced insulin secretion. As with much of science that has been reported in the study of type 2 diabetes, there are bits of the story that do not fit: insulin gene mRNA was positively correlated with TCF7L2 mRNA, out of keeping with the reduced insulin secretion observed, and the overexpression of TCF7L2 did not result in the increased glucagon secretion seen in the type 2 diabetic islets.