Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic beta-cell function.

Article Details

Citation

Copy to clipboard

Paradis R, Lazar N, Antinozzi P, Perbal B, Buteau J

Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic beta-cell function.

PLoS One. 2013 May 21;8(5):e64957. doi: 10.1371/journal.pone.0064957. Print 2013.

PubMed ID

23705021 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Insulin human	Protein NOV homolog	Protein	Humans	Unknown	Downregulator	Details