| First Author | Paradis R | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 5 | Pages | e64957 |
| PubMed ID | 23705021 | Mgi Jnum | J:202162 |
| Mgi Id | MGI:5517610 | Doi | 10.1371/journal.pone.0064957 |
| Citation | Paradis R, et al. (2013) Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic beta-cell function. PLoS One 8(5):e64957 |
| abstractText | Type 2 diabetes is characterized by both insulin resistance and progressive deterioration of beta-cell function. The forkhead transcription factor FoxO1 is a prominent mediator of insulin signaling in beta-cells. We reasoned that identification of FoxO1 target genes in beta-cells could reveal mechanisms linking beta-cell dysfunction to insulin resistance. In this study, we report the characterization of Nov/Ccn3 as a novel transcriptional target of FoxO1 in pancreatic beta-cells. FoxO1 binds to an evolutionarily conserved response element in the Ccn3 promoter to regulate its expression. Accordingly, CCN3 levels are elevated in pancreatic islets of mice with overexpression of a constitutively active form of FoxO1 or insulin resistance. Our functional studies reveal that CCN3 impairs beta-cell proliferation concomitantly with a reduction in cAMP levels. Moreover, CCN3 decreases glucose oxidation, which translates into inhibition of glucose-stimulated Ca(2+) entry and insulin secretion. Our results identify CCN3, a novel transcriptional target of FoxO1 in pancreatic beta-cells, as a potential target for therapeutic intervention in the treatment of diabetes. |
