The DKK family of genes are known to be regulators of the Wnt signalling pathway. Defective Wnt signalling has been linked to inflammation, atherogenesis and the regulation of glucose metabolism. Studies on several cohorts suggest that Wnt signalling components contribute to T2DM susceptibility. To date, scientists have been unable to elucidate the biological pathways involved in T2DM pathogenesis. Under the aegis of the project DKK3 T2DM (Wnt agonist Dickkopf 3 (DKK3) is a type 2 diabetes susceptibility gene), researchers singled out the DKK3 gene to study its role in T2DM. More specifically, they aimed to characterise DKK3 and determine its role in Wnt signalling and function in beta cells and pancreatic islets. Experiments validated their hypothesis that DKK3 is a regulator in Wnt signalling. However, for DKK3 to act as a Wnt agonist, the presence of both Frizzled Wnt receptors and lipoprotein receptor-related protein co-receptors were required. Researchers also studied the impact of DKK3 overexpression as well as loss of expression in Wnt signalling pathways. A significant finding was that DKK3 activates Wnt pathways upstream of the switch between Wnt signalling pathways, whether beta-catenin-independent or beta-catenin-dependent. Scientific studies indicate that beta-catenin-independent Wnt signalling plays a more important role in the function of endocrine islet cells. To elucidate DKK3 function, researchers characterised Wnt signalling using a murine insulinoma beta cell line and isolated pancreatic islets from mice. T2DM has devastating complications such as loss of vision, cardiovascular and kidney disease, and sometimes limb amputation. Project activities have contributed to a better understanding of disease pathogenesis at the gene level. Applications include novel targets for gene therapy.
DKK3, diabetes, Wnt signalling, beta cells, pancreatic islets, beta-catenin