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Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose

Jaeseok Han1, Benbo Song2, Jiun Kim3

  • 1Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA Soonchunhyang Institute of Med-Bio Science (SIMS), Soonchunhyang University, Cheonan-si, Republic of Korea.

Diabetes
|March 22, 2015
PubMed

Insights

Defective proinsulin folding causes oxidative stress and beta-cell death, leading to diabetes. Antioxidant or chemical chaperone treatment shows promise for type 2 diabetes therapy.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Proinsulin misfolding in the endoplasmic reticulum (ER) triggers cell death, but the mechanism is unclear.
  • Beta-cell (β-cell) failure contributes to type 2 diabetes.
  • ER stress and oxidative stress are implicated in β-cell dysfunction.

Purpose of the Study:

  • To investigate the role of the ER co-chaperone P58(IPK)/DnajC3 in β-cell function and survival.
  • To elucidate the mechanisms by which protein misfolding leads to β-cell failure.
  • To explore potential therapeutic strategies for diabetes linked to ER stress.

Main Methods:

  • Analysis of P58(IPK) knockout (P58(IPK-/-)) mice exhibiting diabetic phenotypes.
  • Assessment of β-cell function, mass, oxidative stress, and apoptosis.
  • Intervention studies using chemical chaperones, Chop deletion, and antioxidant/chaperone feeding.
  • Evaluation of MafA localization and β-cell function in Akita mice with mutant proinsulin.

Main Results:

  • P58(IPK-/-) mice developed diabetes due to decreased β-cell function and mass, with increased oxidative stress and cell death.
  • Chemical chaperone treatment and Chop deletion ameliorated the diabetic phenotype in P58(IPK-/-) mice.
  • Antioxidant feeding rapidly restored β-cell function and corrected MafA localization in P58(IPK-/-) mice.
  • Antioxidant feeding preserved β-cell function in Akita mice, demonstrating a link between protein misfolding, oxidative stress, and apoptosis.

Conclusions:

  • Defective protein folding in β-cells induces oxidative stress as a key signal for apoptosis in response to ER stress.
  • Antioxidant feeding effectively restores β-cell function following ER molecular chaperone deletion.
  • Antioxidant or chemical chaperone therapies represent promising approaches for managing type 2 diabetes.

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