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Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression

Hideaki Kaneto1, Gang Xu, Nobuharu Fujii

  • 1Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.

The Journal of Biological Chemistry
|May 16, 2002
PubMed

Insights

Oxidative stress impairs pancreatic beta-cell function by activating the JNK pathway, which reduces insulin gene expression. Suppressing this JNK pathway protects beta-cells and improves insulin secretion in diabetic models.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Oxidative stress is implicated in pancreatic beta-cell dysfunction during diabetes.
  • The specific signaling pathways mediating oxidative stress-induced beta-cell dysfunction are not fully understood.

Purpose of the Study:

  • To investigate the role of specific signaling pathways, particularly JNK, in oxidative stress-induced beta-cell dysfunction.
  • To determine if targeting the JNK pathway can protect beta-cells from oxidative damage and preserve insulin secretion.

Main Methods:

  • Rat islets were subjected to oxidative stress.
  • Adenovirus-mediated gene expression was used to manipulate JNK, p38 MAPK, and protein kinase C activity.
  • Inhibition and overexpression strategies were employed to assess pathway involvement.
  • Functional assays measured insulin gene expression and secretion.
  • A mouse model of diabetes (streptozotocin-induced) was used for in vivo transplantation studies.

Main Results:

  • Oxidative stress activated JNK, p38 MAPK, and protein kinase C in rat islets, preceding reduced insulin gene expression.
  • Overexpression of dominant-negative JNK (DN-JNK) protected insulin gene expression and secretion from oxidative stress.
  • Wild-type JNK overexpression suppressed insulin gene expression and secretion.
  • DN-JNK preserved the DNA binding activity of the transcription factor PDX-1 to the insulin promoter under oxidative stress.
  • Transplantation of DN-JNK-expressing islets into diabetic mice preserved insulin gene expression and ameliorated hyperglycemia.

Conclusions:

  • JNK pathway activation is a key mediator of reduced insulin gene expression by oxidative stress in pancreatic beta-cells.
  • Suppression of the JNK pathway offers a protective strategy against oxidative stress-induced beta-cell dysfunction.
  • Targeting the JNK pathway may be a therapeutic approach for managing diabetes.

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