Final Report Summary - DKK3 T2DM (Wnt agonist Dickkopf 3 (DKK3) is a type 2 diabetes susceptibility gene) To date, Type 2 Diabetes mellitus (T2DM) poses one of the major global health threats, affecting more than 250 million people worldwide. The diabetes epidemic is spreading so rapidly that by 2030, roughly one in 9 adults of the age of 30 will suffer from diabetes worldwide. In spite of all medical efforts, T2DM remains an incurable chronic disease with devastating complications such as loss of vision or amputation of limbs because of poor circulation. Over recent years, several genome-wide association studies (GWAS) set out to identify genomic alleles that lead to increased T2DM susceptibility. In spite of considerable investments, however, these genetic studies have so far been unable to elucidate defined biological pathways that are involved in the pathogenesis of the disease. The currently best-replicated T2DM susceptibility locus, TCF7L2, is a Wnt signalling component that binds beta-catenin and acts as a co-transcription factor for Wnt target genes. Similarities between diabetic retinopathy and Familial Exudative Vitreoretinopathy (FEVR, OMIM #133780) which has been linked to mutations in Wnt receptors Frizzled 4 (FZD4) and Low density lipoprotein-related receptor 5 (LRP5) further implicate defective Wnt signaling in T2DM. Moreover, defective Wnt signaling has been demonstrated for genes implicated in Bardet-Biedl Syndrome (BBS, OMIM #209900) in mice and zebrafish. Symptoms of genetically heterogeneous BBS include diabetes, truncal obesity and hypertension. These lines of evidence suggest that a subset of Wnt signaling components contributes to T2DM susceptibility. Out of five candidate Wnt genes, we observed a significant association with a SNP in the promoter region of Dickkopf 3 (DKK3) in two Chinese, one Japanese, and one Caucasian cohort. Other members of the Dickkopf family of genes have been described as Wnt antagonists which, when overexpressed, lead to a loss of beta-catenin dependent Wnt signaling. In contrast, overexpression of DKK3 had no effect on transcriptional activity in vitro. DKK3 has been named for sequence similarity only and because of the absence of the characteristic phenotype (enlarged head region), it had been suggested that DKK3 had no role in Wnt signaling. The main objective of this study is therefore, to characterize the role of DKK3 as a T2DM susceptibility gene and a regulator of Wnt signaling in beta-cells and pancreatic islets. We subdivided the main objective into several aims:Aim 1: To characterize Wnt signaling in beta-cells and pancreatic islets under specific consideration of the role of Dickkopf3.Aim 2: To characterize the role of Dickkopf3 in beta-cell and pancreatic islet function.Aim 3: To characterize the role of Dickkopf3 in pancreas formation. Aim 4: To characterize the T2DM susceptibility of Dkk3 mutant mice.