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

Renée Paradis1, Noureddine Lazar, Peter Antinozzi

  • 1Department of Medicine, Université Laval, Quebec, Canada.

Plos One
|May 25, 2013
PubMed

Insights

Researchers identified Nov/Ccn3 as a novel target of FoxO1 in pancreatic beta-cells. Elevated CCN3 impairs beta-cell function, offering a potential therapeutic target for type 2 diabetes treatment.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Type 2 diabetes involves insulin resistance and pancreatic beta-cell dysfunction.
  • The transcription factor FoxO1 is crucial for insulin signaling in beta-cells.
  • Identifying FoxO1 targets may elucidate links between beta-cell dysfunction and insulin resistance.

Purpose of the Study:

  • To identify novel FoxO1 transcriptional targets in pancreatic beta-cells.
  • To characterize the role of Nov/Ccn3 (CCN3) in beta-cell function and its regulation by FoxO1.
  • To explore CCN3 as a potential therapeutic target for diabetes.

Main Methods:

  • Investigated FoxO1 binding to the Ccn3 promoter using conserved response elements.
  • Measured CCN3 levels in pancreatic islets from mice with FoxO1 overexpression or insulin resistance.
  • Performed functional studies on CCN3's effects on beta-cell proliferation, cAMP levels, glucose oxidation, and insulin secretion.

Main Results:

  • Nov/Ccn3 was identified as a novel transcriptional target of FoxO1 in pancreatic beta-cells.
  • CCN3 expression is upregulated in conditions of FoxO1 activation and insulin resistance.
  • CCN3 was found to inhibit beta-cell proliferation, reduce cAMP levels, decrease glucose oxidation, and impair glucose-stimulated insulin secretion.

Conclusions:

  • CCN3 is a novel FoxO1 target in pancreatic beta-cells.
  • CCN3 negatively impacts key beta-cell functions, including proliferation and insulin secretion.
  • CCN3 represents a potential therapeutic target for managing type 2 diabetes.

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