Improvement of ER stress-induced diabetes by stimulating autophagy

Pancreatic beta-cell dysfunction is central in diabetes. The diabetic milieu may impair proinsulin folding, leading to beta-cell endoplasmic reticulum (ER) stress and apoptosis, and thus a worsening of the diabetes. Autophagy is crucial for the well-being of the beta-cell; however, the impact of stimulating autophagy on beta-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 beta-cell demise. We found that proinsulin misfolding stimulates autophagy and, in symmetry, inhibition of autophagy induces beta-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 beta-cell apoptosis. Thus, autophagy is a central adaptive mechanism in beta-cell stress. Stimulation of autophagy may become a novel therapeutic strategy in diabetes.