title: Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity.
abstract: 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.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Rivera
authors.forename: Safia
authors.initials: S
authors.lastname: Costes
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D020836:Protein Structure, Quaternary; D059748:Proteolysis; D051381:Rats; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011994:Recombinant Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse