Transcription Factor 7-like 2 (TCFL2) - A Novel Factor Involved in Pathogenesis of Type 2 Diabetes

 

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Type 2 diabetes is a heterogeneous disease characterized by hyperglycemia. This disease results from impaired secretion of insulin from pancreatic β-cells, decreased β-cell mass, insulin resistance in peripheral tissues and hepatic overproduction of glucose. The development of type 2 diabetes is a complex result of lifestyle and genetic components and their interaction.

A number of studies have focused on the identification of genetic markers with significant association with the pathogenesis of this disorder [1]. These studies indicate multiple genetic marker involvement, whereas the occurrence of diabetes resulting from of a single mutation is a rare event. Two well-known polymorphisms found in type 2 diabetes concern a Pro12Ala mutation in the peroxisome proliferation-activated receptor-γ2 (PPAR-γ2) gene encoding a regulator of adipose cell differentiation and systemic insulin action, and an insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene. An influence on insulin sensitivity has been reported in both polymorphisms; however, the data are controversial. A significant increase of diabetic risk and a decreased insulin sensitivity was documented conferred by the Pro12Pro genotype of PPAR-γ2 in comparison to carriers of the Pro12Ala allele [2] [3]. In contrast, in a Finnish Diabetes Prevention Study the authors documented a predisposing effect of the Pro12Ala allele to the development of type 2 diabetes [4]. Concerning the ACE deletion/insertion polymorphism, some studies have postulated a positive impact of the deletion allele on insulin sensitivity [5]. However, the majority of studies have shown no effect or even an inverse effect [3] [6]. Horikawa et al. [7] identified a genetic polymorphism in the promoter region of the gene encoding phosphoenolpyruvate carboxylase (PEPCK), an enzyme crucial in gluconeogenesis and hepatic glucose production. This single nucleotide change was found to be associated with an earlier onset of type 2 diabetes. Furthermore, genetic variants in the genes encoding the cysteine protease calpain-10 and components of the ATP-sensitive potassium channel expressed on β-cell were shown to represent diabetes susceptibility alleles of modest risk [8] [9].

A novel genetic polymorphism clearly associated with type 2 diabetes has now been identified by K. Stefansson and co-workers (Grant et al. [10]) based on a previously reported evidence for the linkage of type 2 diabetes to chromosome 10 q [11]. The authors genotyped a high density of microsatellite markers with an average distance of 46 kb across a 10.5 Mb region in 1185 Icelandic individuals with type 2 diabetes and 931 control individuals in order to isolate the susceptibility locus. These extensive analyses revealed the microsatellite DG10S478, a tetranucleotide repeat emerging in six alleles, whereby protective association was observed for allele 0, and diabetes risk was conferred by the other alleles summarized as allele X. These results were reproduced in Danish and US cohorts. Combining the results from the different cohorts, the heterozygous and homozygous carriers of allele X have been estimated to have relative risks of 1.45 and 2.41, respectively, when compared with non-carriers. Therefore, the risk of developing diabetes increases by 45 % for carriers of one and to 141 % for carriers of two genetic variants. From a public health point of view, it is important to mention that heterozygous and homozygous carriers make up 38 % and 7 % of the population, respectively.

Remarkably, the newly identified susceptibility marker, DG10S478, is located within the transcription factor 7-like 2 (TCFL2) gene, a gene that has not so far been associated with diabetes development. This interesting aspect could provide the basis for new insights in mechanisms involved in the development of type 2 diabetes. The TCFL2 protein is a high-mobility group box-containing transcription factor and an element of the Wnt signaling pathway, which is known to play an important role in cell growth regulation. Stimulation of cells by Wnt glycoproteins leads to the activation of TCF transcription factors via a signal transduction cascade [12]. Interestingly, TCFL2 was recently shown to regulate the expression of the proglucagon gene in enteroendocrine cells [13]. Proglucagon is the precursor of the insulinotropic glucagon-like peptide-1 (GLP-1), which is produced by L-cells in the gut after eating, and effectively regulates the blood glucose levels by promoting insulin secretion. The insulinotropic effect of GLP-1 is markedly reduced in patients with type 2 diabetes due to the decreased secretion of GLP-1 [14]. Therefore, the study by Grant et al. has provided a new direct link between the occurrence of a genetic variant and susceptibility to type 2 diabetes.

The polymorphic microsatellite region is located in intron 3 of the TCFL2 gene, and therefore does not affect the amino acid sequence of the encoded protein. To test for the possibility that other synonymous and non-synonymous variations in exons of the TCFL2 gene account for the association with diabetes, all exons were sequenced from a high number of individuals of different population cohorts. Only three rare single nucleotide polymorphisms were observed, but these did not account for the observed association to diabetes type 2. In addition, the authors tested other distinct marker alleles in the linkage disequilibrium block for stronger association than DG10S478, but did not find any stronger link.

What could explain this possible causal influence of a polymorphism in an intronic sequence of TCFL2 on susceptibility for diabetes type 2? Non-coding sequences can influence mRNA expression both qualitatively and quantitatively. Sequence modifications in introns are known to have a direct influence on pre-mRNA splicing by changing splice donor and acceptor sites resulting in mature mRNAs with modified open reading frames or by affecting the kinetics of splicing. In addition, intronic variants can have effects on RNA stability and turnover. As a consequence, the amount or even the sequence of the TCFL2 protein might be modified in intronic variants. The exciting data provided by Grant et al. have provided a basis for new approaches towards clarifying the role of TCFL2 and its variants in the pathogenesis of type 2 diabetes.

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Dr. A. Kiessling

MTZ, B.00.002 · Department of Medicine · University of Dresden · Germany

Fetscherstr. 74 · 01307 Dresden · Germany

Phone: +49(351)4586605 ·

Email: andrea.kiessling@uniklinikum-dresden.de