β cell dysfunction is a hallmark of type 2 diabetes (T2D) and is associated with extracellular accumulation of amyloid plaques comprised of islet amyloid polypeptide (IAPP). Human IAPP is potentially toxic and has been shown to accumulate within β cells of T2D patients and in transgenic rodent models. In this episode, Safia Costes and colleagues examine the role of autophagy in the degradation of human IAPP in murine models. Human IAPP aggregated within p62-positive inclusions in transgenic animals, with no apparent loss of β cell function or mass; however, human IAPP-expressing mice with a β cell-specific autophagy defect developed overt diabetes due β cell death. These results indicate that autophagy is protective against IAPP-induced toxicity in β cells and suggest the autophagy pathway as a potential theraputic target for treatment and/or prevention of T2D.
Type 2 diabetes (T2D) is characterized by a deficiency in β cell mass, increased β cell apoptosis, and extracellular accumulation of islet amyloid derived from islet amyloid polypeptide (IAPP), which β cells coexpress with insulin. IAPP expression is increased in the context of insulin resistance, the major risk factor for developing T2D. Human IAPP is potentially toxic, especially as membrane-permeant oligomers, which have been observed to accumulate within β cells of patients with T2D and rodents expressing human IAPP. Here, we determined that β cell IAPP content is regulated by autophagy through p62-dependent lysosomal degradation. Induction of high levels of human IAPP in mouse β cells resulted in accumulation of this amyloidogenic protein as relatively inert fibrils within cytosolic p62-positive inclusions, which temporarily averts formation of toxic oligomers. Mice hemizygous for transgenic expression of human IAPP did not develop diabetes; however, loss of β cell–specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of β cell mass. In human IAPP–expressing mice that lack β cell autophagy, increased oxidative damage and loss of an antioxidant-protective pathway appeared to contribute to increased β cell apoptosis. These findings indicate that autophagy/lysosomal degradation defends β cells against proteotoxicity induced by oligomerization-prone human IAPP.
Jacqueline F. Rivera, Safia Costes, Tatyana Gurlo, Charles G. Glabe, Peter C. Butler