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Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity
Jacqueline F. Rivera, … , Charles G. Glabe, Peter C. Butler
Jacqueline F. Rivera, … , Charles G. Glabe, Peter C. Butler
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3489-3500. https://doi.org/10.1172/JCI71981.
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Research Article

Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity

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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

Jacqueline F. Rivera, Safia Costes, Tatyana Gurlo, Charles G. Glabe, Peter C. Butler

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Figure 1

Intracellular IAPP levels are modulated by regulators of autophagy.

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Intracellular IAPP levels are modulated by regulators of autophagy.
(A) ...
(A) INS 832/13 cells were treated with rapamycin (Rapa, 10 nM) for 40 hours, lysosomal inhibitors (Lyso I) (E-64-d, 10 μg/ml and pepstatin A, 10 μg/ml) for 24 hours, or left untreated (C). Levels of IAPP were assessed by Western blot. GAPDH was used as loading control. The graph represents the quantification of the processed/mature form of IAPP (n = 4). (B) Human islets were treated with rapamycin (10 nM) for 30 hours, lysosomal inhibitors (E-64-d, 10 μg/ml and pepstatin A, 10 μg/ml) for 30 hours, or left untreated. Levels of IAPP were assessed by Western blot. GAPDH was used as loading control. The graph represents the quantification of IAPP protein levels (n = 3). Data are expressed as mean ± SEM; *P < 0.05; ***P < 0.001.

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