Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism.
Mutations in Wnt receptor LRP5/6 and polymorphism in Wnt-regulated transcription factor TCF7L2 are associated with dysregulation of glucose metabolism. However, it is not clear whether Wnt antagonist Dickkopf (Dkk) has a significant role in the regulation of glucose metabolism. Here, we identified small-molecule inhibitors of Wnt antagonist Dkk through molecular modeling, computation-based virtual screens, and biological assays. One of the Dkk inhibitors reduced basal blood-glucose concentrations and improved glucose tolerance in mice. This Dkk inhibitor appeared to act through DKK2 because the inhibitor exerted no additional effects on glucose metabolism in the Dkk2(-/-) mice. Our study of Dkk2(-/-) mice showed that DKK2 deficiency was associated with increased hepatic glycogen accumulation and decreased hepatic glucose output. DKK2 deficiency did not cause in increase in insulin production but resulted in increased Wnt activity and GLP1 production in the intestines. Given that the Dkk inhibitor improved glucose tolerance in a murine model of type 2 diabetes (db/db), we suggest that DKK2 may be a potential therapeutic target for treating type 2 diabetes.
Department of Pharmacology and Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
Xiaofeng
X
Li
Jufang
J
Shan
Woochul
W
Chang
Ingyu
I
Kim
Ju
J
Bao
Ho-Jin
HJ
Lee
Xinxin
X
Zhang
Varman T
VT
Samuel
Gerald I
GI
Shulman
Dakai
D
Liu
Jie J
JJ
Zheng
Dianqing
D
Wu
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D015398:Signal Transduction; D012984:Software; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
C405060:Dkk2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D006003:Glycogen; D005947:Glucose