Posts in the category Publications


Autophagy. 2013 Feb 4 ; 9(4)
Improvement of ER stress-induced diabetes by stimulating autophagy.
Bachar-Wikstrom E, Wikstrom JD, Kaiser N, Cerasi E, Leibowitz G.

Endocrinology and Metabolism Service; Department of Medicine; Hadassah-Hebrew University Medical Center; Jerusalem, Israel.


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,


Diabetes. 2012 Dec 28
Stimulation of Autophagy Improves Endoplasmic Reticulum Stress-Induced Diabetes.
Bachar-Wikstrom E, Wikstrom JD, Ariav Y, Tirosh B, Kaiser N, Cerasi E, Leibowitz G.

Endocrinology and Metabolism Service, Department of Medicine, Hadassah Medical Center, Jerusalem, Israel.


Accumulation of misfolded proinsulin in the β-cell leads to dysfunction induced by endoplasmic reticulum (ER) stress, with diabetes as a consequence. Autophagy helps cellular adaptation to stress via clearance of misfolded proteins and damaged organelles. We studied the effects of proinsulin misfolding on autophagy and the impact of stimulating autophagy on diabetes progression in Akita mice, which carry a mutation in proinsulin, leading to its severe misfolding. Treatment of female diabetic Akita mice with rapamycin improved diabetes, increased pancreatic insulin content, and prevented β-cell apoptosis. In vitro, autophagic flux was increased in Akita β-cells. Treatment with rapamycin further stimulated autophagy, evidenced by increased autophagosome formation and enhancement of autophagosome-lysosome fusion. This was associated with attenuation of cellular stress and apoptosis.