Online Purchasing Account You are logged on as Guest. LoginRegister a New AccountShopping cart (Empty)
United States 

A Wind of Change with Wnt

The diabetic population is constantly increasing. In 2010, an estimated 285 million people worldwide were affected by diabetes mellitus, 90% of whom had the type 2 form. Type 2 diabetes mellitus (or adult-onset diabetes) is characterized by hyperglycemia due to insulin resistance, inadequate insulin secretion and excessive or inappropriate glucagon production. It can become life-threatening when left untreated and is associated with environmental risk factors such as age, sex, obesity, low physical exercise, smoking, diet and stress. The latter are thought to reduce insulin release and activity in individuals with a genetic susceptibility to the disease.

The maintenance of blood glucose homeostasis relies on the coordination of several physiological systems including the sympathetic nervous system and the endocrine system. More recently, Wnt signaling has been tightly linked with diabetes following the identification of mutations in one of its major effector, the transcription factor TCF7L2, and the increase of metabolic regulators like incretin, insulin, pro-glucagon and GLP-1. In the canonical Wnt signaling pathway, Wnt binds to Frizzled and LRP5/6 co-receptors and triggers a signaling cascade that stabilizes β-catenin. The latter translocates from the cytoplasm into the nucleus and induces transcriptional activation of target genes. Several naturally occurring antagonists are capable of regulating Wnt signaling in vivo. For instance, Dickkopf (DKK) proteins can bind to the LRP5/6 co-receptors and prevent them from interacting with Wnt-Frizzled complexes. Professor Wu and colleagues from Yale School of Medicine collaborated with Enzo Therapeutics and investigated the involvement of the antagonist DKK2 in the regulation of glucose metabolism by means of computational and biological screening of small molecule inhibitors as well as murine genetic approach. Using Enzo’s LeadingLight® Wnt reporter assay kit, fifty-four compounds were screened for their ability to reverse DKK-mediated inhibition of Wnt signaling. This assay is a cell-based luciferase activity test, which uses an engineered cell line expressing the firefly luciferase reporter gene under the control of Wnt-responsive promoters (TCF/LEF). The luciferase activity from the reporter gene in this cell line is regulated in a dose-dependent manner upon the addition of exogenous Wnt or related ligands, agonists or antagonists to the cell culture medium.

The DKK inhibitor IIIC3 (gallocyanine) gave the most significant and reproducible results with efficient and potent reversal of DKK inhibition. IIIC3 and several custom-made analogs were then further characterized. Both IIIC3 and the analog IIIC3a were found to directly bind to LRP5/6 and compete with DKK-LRP5/6 interaction. Mice treated with either IIIC3 or IIIC3a showed significantly lower blood glucose concentration and improved glucose tolerance without altering insulin production or sensitivity. The same phenotype was observed in Dkk2-knockout mice suggesting that the positive effects on glucose metabolism of IIIC3 and IIIC3a were obtained by antagonizing DKK2. Finally, intra-peritoneal administration of IIIC3a to a murine model of type 2 diabetes led to a significant decrease in blood glucose concentration and a better tolerance to glucose. Altogether, these results suggest that Wnt signaling and more specifically DKK2 represents an interesting therapeutic target for treating type 2 diabetes mellitus. It remains to be seen, however, if an increase in Wnt activity, even moderate, does not pose a threat by increasing the risk of developing cancer.

Enzo Life Sciences offers a comprehensive portfolio for studying glucose metabolism and Wnt signaling including cell-based reporter assay, ELISA kits, antibodies, proteins and biochemicals; some of which are listed below:

Share this TechNote

Follow Us!

 
comments powered by Disqus

References:

  • X. Li, et al. Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism. PNAS (2012) 109: 11402.

Related Products

[pSer9]GSK-3β ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-123A 96 wells 550.00 USD
 

β-Catenin ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-135 96 wells 520.00 USD
 

GSK-3β ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-144 96 wells INQUIRE
 

IGF-1 (human), ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-150 96 wells 500.00 USD
 

Dkk-1 (human), ELISA kit 

First-to-market Dkk-1 ELISA commercially available for wnt signaling pathway research.
ELISA, Colorimetric detection | Print as PDF
 
ADI-900-151 96 wells 560.00 USD
 

Dkk-1 (rat), ELISA kit 

First-to-market rat Dkk-1 ELISA commercially available for wnt signaling pathway research.
ELISA, Colorimetric detection | Print as PDF
 
ADI-900-171 96 wells 460.00 USD
 

Dkk-1 (mouse), ELISA kit 

ELISA, Colorimetric detection | Print as PDF
 
ADI-900-172 96 wells 450.00 USD
 

Wnt-1, pAb 

IHC, WB | Print as PDF
 
ADI-905-617-1 1 ml 310.00 USD
 

[pTyr1150/Tyr1151]Insulin receptor, mAb (10C3) 

ELISA, WB | Print as PDF
 
ADI-905-645-100 100 µg 370.00 USD
 

[pTyr1322]Insulin receptor, mAb (21G12) 

ELISA, WB | Print as PDF
 
ADI-905-646-100 100 µg 390.00 USD
 

Insulin receptor, mAb (9H4) 

ELISA, IHC, WB | Print as PDF
 
ADI-905-647-100 100 µg 390.00 USD
 

IGF-I (human), (recombinant) 

Produced in E. coli. | ≥98% (SDS-PAGE; RP-HPLC) | Print as PDF
 
ADI-908-059-0100 100 µg 111.00 USD
 

β-Catenin, mAb (12F7) 

IHC, IP, WB | Print as PDF
 
ADI-KAM-ST001-E 100 µg 240.00 USD
 

GSK-3α/β, mAb (1H8) 

ICC, IHC, WB | Print as PDF
 
ADI-KAM-ST002-D 50 µg 180.00 USD
 
ADI-KAM-ST002-F 200 µg 340.00 USD
 

GSK-3β, pAb 

ICC, IHC (PS), WB | Print as PDF
 
ADI-KAP-ST002-C 25 µg 120.00 USD
 
ADI-KAP-ST002-E 100 µg 250.00 USD
 

Dkk-1 (mouse), (recombinant) (His-tag) 

Produced in E. coli. Mouse Dkk-1 is fused at the N-terminus to a His-tag. | ≥95% (SDS-PAGE; Western blot) | Print as PDF
 
ADI-KPR-CP100-D 50 µg 309.00 USD
 
ADI-KPR-CP100-F 200 µg 868.00 USD
 

Vaspin (human) ELISA Kit 

Sensitive ELISA kit for this key cell signaling molecule for metabolic syndrome, obesity and insulin resistance research.
ELISA | Print as PDF
 
ALX-850-375-KI01 96 wells 600.00 USD
 

Adiponectin (human), ELISA Kit 

Rapid, highly sensitive ELISA kit to quantify adiponectin for metabolic, diabetes, and obesity research.
ELISA, Colorimetric detection | Print as PDF
 
ALX-850-377-KI01 96 wells 550.00 USD
 

FABP4 (human), ELISA kit 

Rapid, highly sensitive ELISA kit to quantify FABP4 in a wide variety of sample types for obesity, diabetes and metabolic research.
ELISA, Colorimetric detection | Print as PDF
 
ALX-850-378-KI01 96 wells 750.00 USD
 

Screen-Well® Wnt Pathway library 

Compounds are highly relevant; many are unique
HTS | Print as PDF
 
BML-2838-0500 1 Library 500 µl/well INQUIRE
 
BML-2838-0100 1 Library 100 µl/well INQUIRE
 

Dishevelled-1, pAb 

WB | Print as PDF
 
BML-DA4170-0100 100 µl 330.00 USD
 

Dishevelled-2, pAb 

IHC, WB | Print as PDF
 
BML-DA4270-0025 25 µl 100.00 USD
 
BML-DA4270-0100 100 µl 320.00 USD
 

Glucagon like peptide 1, pAb 

IHC | Print as PDF
 
BML-GA1176-0025 25 µl 100.00 USD
 
BML-GA1176-0100 100 µl 320.00 USD
 

Glucagon like peptide 2, pAb 

IHC | Print as PDF
 
BML-GA1179-0025 25 µl 110.00 USD
 

Glucagon 

>97% | Print as PDF
 
BML-GP1432-0100 100 µg 216.00 USD
 

Glucagon like peptide 1 (human) (1-19) 

≥95% (HPLC) | Print as PDF
 
BML-GP1436-0100 100 µg 98.00 USD
 

Insulin-like growth factor-1 receptor (human), (recombinant) (GST-tag) 

Produced in baculovirus. The 46kDa cytoplasmic domain of the ß-subunit of human IGF-1 receptor kinase (IGF-1RK ) (aa 929-1337) is fused to GST. | Print as PDF
 
BML-SE232-0020 20 µg 360.00 USD
 

GSK-3β (human), (recombinant) (GST-tag) 

Produced in insect cells. Full length human glycogen synthase kinase-3ß is fused at the N-terminus to a GST-tag. | Print as PDF
 
BML-SE355-0005 5 µg 246.00 USD
 

IIIC3 

DKK1 inhibitor
1562-85-2 | ≥98% (TLC) | Print as PDF
 
BML-WN118-0500 500 mg 50.00 USD
Bulk Request
 

Wnt-3a (mouse), (recombinant) 

Modulator of embryogenesis, cell proliferation, stem cell differentation, and bone, glucose and lipid metabolism
Produced in CHO cells | ≥80% (SDS-PAGE) | Print as PDF
 
ENZ-60001-C001 1 µg 149.00 USD
 

Dkk-1 (mouse), (recombinant) (active) 

Modulator of embryogenesis and known effector of tissue development and morphogenesis
Produced in insect cells. | ≥80% (SDS-PAGE) | Print as PDF
 
ENZ-60002-C005 5 µg 195.00 USD
 

Leading Light® Wnt Reporter Assay Starter Kit 

Chemiluminescent cell-based assay for discovering Wnt pathway modulators
FUNC, Chemiluminescence, HTS | Print as PDF
 
ENZ-61001-0001 96 wells 900.00 USD
 

Leading Light® Wnt Reporter Cell Line 

Wnt reporter cell line for discovering Wnt pathway modulators
| Print as PDF
 
ENZ-61002-0001 1 ml 500.00 USD
 

Exendin-4 

GLP-1 receptor agonist
141758-74-9 | Synthetic. | ≥98% (HPLC) | Print as PDF
 
ENZ-PRT111-0500 500 µg 100.00 USD
 
ENZ-PRT111-0001 1 mg 160.00 USD
 

Recommend this page

 
Keep in touch

©2014 Enzo Life Sciences, Inc.,