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Carriers of a novel frame-shift insertion in WNT16a possess elevated pancreatic expression of TCF7L2.

Howard EW, Been LF, Lerner M, Brackett D, Lightfoot S, Bullen EC, Sanghera DK - BMC Genet. (2013)

Bottom Line: However, interpreting the resulting associations into function still remains unclear.Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1).However, further studies would be needed to mechanistically link the two definitively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

ABSTRACT

Background: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2.

Results: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003).

Conclusions: Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.

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Wnt signaling pathway in diabetes mellitus.
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Figure 1: Wnt signaling pathway in diabetes mellitus.

Mentions: Various in vitro and in vivo studies have shown that severalcomponents of the Wnt pathway are involved in β-cell proliferation [8], insulin secretion and cholesterol metabolism [9], and production of glucogon-like peptide-1 (GLP-1) [10]. Wnts are secreted glycoproteins with a well-established role in theearly stages of development through adulthood [11]. Wnts bind to frizzled and LRP receptors, which, in turn, inactivate thedegradation complex consisting of AXIN, DVL, and GSK3B (Figure 1). This prevents the phosphorylation of β-catenin by GSK3B, andleads to its binding to the nuclear transcription factors, TCF7, LEF1, TCF7L1 andTCF7L2, leading to the activation of more than 60 different genes involved in growthregulation and differentiation, as well as GLP-1 expression [12]. Since Wnt signaling has a role in regulating and stabilizingβ-catenin and its binding with TCF7L2, we hypothesized that any alternation inthe canonical Wnt pathway would have profound consequences in insulin secretion andthe generation of new β-cells, particularly given that Wnt signaling isrequired for normal development of the pancreas and islets during embryonic growth [13].


Carriers of a novel frame-shift insertion in WNT16a possess elevated pancreatic expression of TCF7L2.

Howard EW, Been LF, Lerner M, Brackett D, Lightfoot S, Bullen EC, Sanghera DK - BMC Genet. (2013)

Wnt signaling pathway in diabetes mellitus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675375&req=5

Figure 1: Wnt signaling pathway in diabetes mellitus.
Mentions: Various in vitro and in vivo studies have shown that severalcomponents of the Wnt pathway are involved in β-cell proliferation [8], insulin secretion and cholesterol metabolism [9], and production of glucogon-like peptide-1 (GLP-1) [10]. Wnts are secreted glycoproteins with a well-established role in theearly stages of development through adulthood [11]. Wnts bind to frizzled and LRP receptors, which, in turn, inactivate thedegradation complex consisting of AXIN, DVL, and GSK3B (Figure 1). This prevents the phosphorylation of β-catenin by GSK3B, andleads to its binding to the nuclear transcription factors, TCF7, LEF1, TCF7L1 andTCF7L2, leading to the activation of more than 60 different genes involved in growthregulation and differentiation, as well as GLP-1 expression [12]. Since Wnt signaling has a role in regulating and stabilizingβ-catenin and its binding with TCF7L2, we hypothesized that any alternation inthe canonical Wnt pathway would have profound consequences in insulin secretion andthe generation of new β-cells, particularly given that Wnt signaling isrequired for normal development of the pancreas and islets during embryonic growth [13].

Bottom Line: However, interpreting the resulting associations into function still remains unclear.Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1).However, further studies would be needed to mechanistically link the two definitively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

ABSTRACT

Background: The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2.

Results: Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003).

Conclusions: Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.

Show MeSH
Related in: MedlinePlus