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Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell

Huei-Min Lin1, Ji-Hyeon Lee, Hariom Yadav

  • 1Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.

The Journal of Biological Chemistry
|March 7, 2009
PubMed

Insights

Transforming growth factor-beta (TGF-β) signaling, via Smad3, represses insulin gene transcription and beta-cell function. Inhibiting Smad3 improves insulin secretion and glucose tolerance, suggesting a role in diabetes.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Pathogenesis

Background:

  • Pancreatic beta-cell dysfunction is central to Type 2 diabetes.
  • The role of Transforming Growth Factor-beta (TGF-β) signaling in adult pancreatic function is largely unknown.

Purpose of the Study:

  • To investigate the role of TGF-β signaling in regulating insulin gene transcription and beta-cell function in the adult pancreas.
  • To identify specific mediators of TGF-β action on beta-cells.

Main Methods:

  • Identification of insulin as a TGF-β target gene.
  • Analysis of Smad3 binding to the insulin gene promoter.
  • Experimental manipulation of Smad3 levels in primary human and non-human primate islets.
  • Assessment of glucose tolerance and insulin secretion in Smad3-deficient mice.
  • Ex vivo perifusion assays of Smad3-deficient islets.

Main Results:

  • Smad3 directly represses insulin gene transcription by binding to its promoter.
  • Smad3 inhibition or deficiency enhances insulin levels and secretion.
  • Smad3-deficient mice show improved glucose tolerance and enhanced glucose-stimulated insulin secretion.
  • Smad3 deficiency leads to an activated insulin-receptor signaling pathway in islets.

Conclusions:

  • TGF-β/Smad3 signaling is a critical negative regulator of insulin gene transcription and beta-cell function.
  • Dysregulation of TGF-β/Smad3 pathway components may contribute to diabetes pathogenesis.
  • Targeting the TGF-β/Smad3 pathway could offer therapeutic strategies for diabetes.

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