CXXC4 mediates glucose-induced β-cell proliferation.

Abstract

CXXC finger protein 4 (CXXC4) is an identified negative regulator of the Wnt/β-catenin pathway, and it is involved in cancer cell proliferation. In this study, we sought to clarify whether CXXC4 is involved in glucose-stimulated β-cell proliferation. We investigated the biological function of CXXC4 in glucose-induced β-cell proliferation, and we investigated the underlying mechanism of this activity. First, we analyzed CXXC4 expression in established rat models treated for 24h with a high glucose infusion and in INS-1 cells and primary rat islets treated with different concentrations of glucose. Subsequently, we used an adenovirus to overexpress CXXC4 in INS-1 cells and primary islets. The proliferation rate of β-cells was evaluated by CCK-8 and EdU incorporation methods. Cell cycle analysis was performed by flow cytometry. Finally, the Wnt signaling pathway and its downstream genes were assessed by Western blot. CXXC4 mRNA levels were significantly lower in islets isolated from glucose-infused rats than they were in those isolated from saline-infused rats. Decreased expression of CXXC4 also correlated with high glucose treatment of INS-1 cells and primary rat β-cells. Furthermore, adenovirus-mediated overexpression of CXXC4 inhibited cell proliferation induced by the high glucose treatment in vitro, which was mechanistically mediated by Wnt signaling and a decrease in cyclin D2 expression. Glucose inhibits CXXC4 expression and hence promotes pancreatic β-cell proliferation. Our findings may provide a new potential target for the treatment of diabetes.