COMMENTARY

Understanding the Elusive Mechanism of Action of

TCF7L2 in Metabolism
Struan F.A. Grant

ommon intronic variation within the gene

encoding transcription factor 7-like 2 (TCF7L2)
is now considered to be denitively associated
with type 2 diabetes (T2D). Since our rst report of this association in 2006 (1), independent investigators have readily replicated this nding in all the main
ethnic groups; in addition, from the rst genome-wide association study (GWAS) of T2D in Caucasians (2) onwards, the strongest association has been consistently
with the TCF7L2 locus. Indeed, a meta-analysis of published studies worldwide as early as 2007 estimated
a pooled odds ratio of 1.46 (with an impressive P = 5.4 3
102140) (3), making it one of the most statistically signicant genetic ndings in T2D to date.
Despite knowing that this association has been beyond
doubt for over 6 years, the mechanism through which
TCF7L2 exerts its effect on T2D is still very unclear, thus
making the work by Kaminska et al. (4) in this current
issue of Diabetes so timely.
TCF7L2 is a high-mobility group box-containing transcription factor and operates at the last key stage of the
canonical Wnt signaling transduction cascade, regulating the
expression of a set of target genes. Moreover, tissue-specic
isoforms have been reported (5,6), with the transcript being
heavily alternatively spliced at the 39 terminus, with the 59
end being the most stable region among isoforms.
Following the discovery of this genetic association, it was
initially speculated that TCF7L2 operated in tandem with
insulin to inuence blood glucose homeostasis through
the alteration of levels of glucagon-like peptide 1 in the gut
(1). However, other studies have shown that the TCF7L2
genetic variation is associated with increased TCF7L2 expression and decreased insulin secretion, possibly implicating the pancreatic b-cell (7,8), although an indirect effect
on insulin secretion by TCF7L2 action in another tissue
cannot be ruled out. Indeed, from one of our previous
studies of alternative splicing of TCF7L2 in metabolically relevant tissues and cell lines, we suggested that
variants in TCF7L2 correlate with an insulin-suppressed
isoform retaining exon 13 and 13a in subcutaneous adipose (5).
Following on from this latter observation, Kaminska
et al. elected to investigate the mRNA expression pattern

From the Division of Human Genetics and Center for Applied Genomics, The
Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania; and the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Corresponding author: Struan F.A. Grant, grants@chop.edu.
DOI: 10.2337/db12-0891
2012 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for prot,
and the work is not altered. See http://creativecommons.org/licenses/by-nc
-nd/3.0/ for details.

See accompanying original article, p. 2807.

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of alternative splicing in the context of weight loss following Roux-en-Y gastric bypass surgery. Interestingly,
they observed that expression levels of a specic spliced
isoform, which they termed a short mRNA variant i.e.,
lacking exons 12, 13, and 13a, was reduced both in subcutaneous fat and in liver following surgery. In addition,
this short isoform was more common among T2D cases
than in normal glucose obese subjects or in the general
population. Moreover, there was a positive correlation
with this isoform and fasting glucose levels in nondiabetic
subjects, which is in line with individuals with both impaired glucose tolerance and harboring the at-risk TCF7L2
variant being at a greater risk of T2D (7); in addition there
was also association with high levels of free fatty acids in
serum during hyperinsulinemia. This nal point is in
agreement with our observation (5) in that the short form
in suppressed by insulin, suggesting impaired insulin action at this site.
What is most intriguing is that TCF7L2 genotype status
is not correlated with these isoform observations. This is
not entirely surprising, as it is clear that genetic variation
at this locus is not associated with obesity. After all there
have been many GWASs of BMI and obesity in both adults
and children, and they have never detected an association
with this locus. That said, the fact that more than one
study shows there is an isoform correlation with various
metrics of metabolic activity in adipose suggests that this
is a key gene for insulin action within this tissue, but its
mechanism of action appears not to be dictated to any
great degree by genetic variants harbored within the gene.
Thus, it is conceivable that the TCF7L2 locus exerts its
effect on both insulin production (based on genetic association studies of T2D) and on insulin action (based on
isoform studies in key tissues).
Although many genetic associations have been robustly
uncovered with GWAS for various complex traits over
recent years using proxy single nucleotide polymorphisms,
only in a handful of instances has the actual underlying
causal variant been determined. This is where the T2D
TCF7L2 association has an advantage, as the causal variant is widely thought to be identied i.e., the work with
multiple ethnicities has distilled down the association to
a single variant, rs7903146, in intron 3. It is still far from
clear if rs7903146 impacts alternative splicing directly,
with existing studiesincluding the current onebeing
underpowered statistically to elucidate this possible connection. What is also sorely lacking is a comparable study
in pancreatic islets, but of course obtaining sufcient sample size in this context is highly challenging. Therefore, as it
is still far from clear where the primary sites of action are
with respect to the observed genetic association, the ideal
scenario would be to conduct relatively large-scale parallel
studies of isoform distributions in at least adipose tissue,
the gut, and pancreatic islets obtained from individuals of
both known TCF7L2 genotype and known disease status.
DIABETES, VOL. 61, NOVEMBER 2012

2657

COMMENTARY

The case for a TCF7L2 role in metabolism only continues

to strengthen, with our own chromatin immunoprecipitation sequencing work suggesting the genes bound by
TCF7L2 are strongly enriched in pathway categories related
to metabolism (9). The case is further strengthened by an
emerging metabolic role in cancer; for instance, the key
8q24 locus associated with a number of cancers likely exerts
its effect through mutation of an upstream TCF7L2-binding
element driving the transcription of the MYC gene (10,11).
Although many more studies are required beyond that of
Kaminska et al., TCF7L2 remains a key and intriguing
factor in the arena of metabolic traits. Given the important
need for effective translational research in T2D to enable
potentially more specic and individualized treatments to
be used for the disease, it is clear that there is great
promise in understanding the mechanism of action of this
key gene product.
ACKNOWLEDGMENTS

No potential conicts of interest relevant to this article

were reported.
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