| First Author | Rivera JF | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 8 | Pages | 3489-500 |
| PubMed ID | 25036708 | Mgi Jnum | J:215615 |
| Mgi Id | MGI:5605913 | Doi | 10.1172/JCI71981 |
| Citation | Rivera JF, et al. (2014) Autophagy defends pancreatic beta cells from human islet amyloid polypeptide-induced toxicity. J Clin Invest 124(8):3489-500 |
| abstractText | Type 2 diabetes (T2D) is characterized by a deficiency in beta cell mass, increased beta cell apoptosis, and extracellular accumulation of islet amyloid derived from islet amyloid polypeptide (IAPP), which beta 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 beta cells of patients with T2D and rodents expressing human IAPP. Here, we determined that beta cell IAPP content is regulated by autophagy through p62-dependent lysosomal degradation. Induction of high levels of human IAPP in mouse beta 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 beta cell-specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of beta cell mass. In human IAPP-expressing mice that lack beta cell autophagy, increased oxidative damage and loss of an antioxidant-protective pathway appeared to contribute to increased beta cell apoptosis. These findings indicate that autophagy/lysosomal degradation defends beta cells against proteotoxicity induced by oligomerization-prone human IAPP. |
