Improvement of ER stress-induced diabetes by stimulating autophagy

Etty Bachar-Wikstrom, Jakob D. Wikstrom, Nurit Kaiser, Erol Cerasi, Gil Leibowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Pancreatic β-cell dysfunction is central in diabetes. The diabetic milieu may impair proinsulin folding, leading to β-cell endoplasmic reticulum (ER) stress and apoptosis, and thus a worsening of the diabetes. Autophagy is crucial for the well-being of the β-cell; however, the impact of stimulating autophagy on β-cell adaptation to ER stress is unknown. We studied the crosstalk between ER stress and autophagy in a rodent model of diabetes, called Akita, in which proinsulin gene mutation leads to protein misfolding and β-cell demise. We found that proinsulin misfolding stimulates autophagy and, in symmetry, inhibition of autophagy induces β-cell stress and apoptosis. Under conditions of excessive proinsulin misfolding, stimulation of autophagy by inhibiting MTORC1 alleviates stress and prevents apoptosis. Moreover, treatment of diabetic Akita mice with the MTORC1 inhibitor rapamycin improves diabetes and prevents β-cell apoptosis. Thus, autophagy is a central adaptive mechanism in β-cell stress. Stimulation of autophagy may become a novel therapeutic strategy in diabetes.

Original languageAmerican English
Pages (from-to)626-628
Number of pages3
Issue number4
StatePublished - Apr 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grant from the Israel Science Foundation to G.L. J.W. is supported by an EFSD post-doctoral fellowship grant and by fund from the Golda Meir foundation.


  • Autophagy Abbreviations
  • Beta-cell
  • Diabetes
  • ER
  • ER stress
  • ERAD
  • Endoplasmic reticulum
  • Endoplasmic reticulum-associated degradation
  • IAPP
  • Islet amyloid polypeptide
  • MIDY
  • MTOR
  • MTORC1
  • Mechanistic target of rapamycin complex 1
  • Mutant INS gene-induced diabetes of youth syndrome
  • Rapamycin


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