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Wnt agonist Dickkopf 3 (DKK3) is a type 2 diabetes susceptibility gene

Objective

Type 2 diabetes mellitus (T2DM) is a complex genetic disorder of largely obscure etiology where alleles at numerous loci are thought to interact with environmental and stochastic cues to induce the phenotype. We have recently identified a T2DM susceptibility allele at the DKK3 locus. Using a combination of case/control association and functional studies, we demonstrated that the minor allele of SNP rs11022111 in the DKK3 promoter is significantly associated with T2DM in two Chinese and one Caucasian cohort and results in the disruption of a conserved SP1 binding site, leading to reduced DKK3 expression. We also showed that, in contrast to other members of the DKK family, DKK3 is a likely agonist of Wnt signaling (both canonical and non-canonical), in a Fz- and LRP6-dependent manner and regulates the expression of TCF7L2, another T2DM susceptibility gene. Our preliminary data implicate the regulation of Wnt signaling in the pathogenesis of T2DM. In this proposal, we hypothesize that aberrant Wnt signaling in the adult pancreas can lead to impaired glucose tolerance, insulin secretion and other diabetic phenotypes. To address how Dickkopf 3 influences Wnt signaling in β-cells and pancreatic islets as well as pancreatic islet functions, I propose to identify the subset of Wnt signaling components that are active in MIN6 cells and islets, to characterize the effect of impaired Wnt signaling on islet function and formation, and finally, to investigate the metabolic state of Dkk3-/- mice when challenged with a high fat diet.

Field of science

  • /medical and health sciences/clinical medicine/endocrinology/diabetes

Call for proposal

FP7-PEOPLE-2010-RG
See other projects for this call

Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
17177 Stockholm
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 75 000
Administrative Contact
Per-Olof Berggren (Prof.)