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J Exp Med. 2017 Sep 4;214(9):2591-2610. doi: 10.1084/jem.20161134. Epub 2017 Aug 1.

Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism.

Author information

1
Mitchell Center for Alzheimer's Disease, Department of Neurology, John P. and Kathrine G. McGovern Medical School, University of Texas Medical School at Houston, Houston, TX.
2
Facultad de Medicina, Universidad de los Andes, Las Condes, Santiago, Chile.
3
Center for Integrative Biology, Universidad Mayor, Santiago, Chile.
4
Department of Surgery, Houston Methodist Hospital, Houston, TX.
5
Mitchell Center for Alzheimer's Disease, Department of Neurology, John P. and Kathrine G. McGovern Medical School, University of Texas Medical School at Houston, Houston, TX Claudio.Soto@uth.tmc.edu.

Abstract

Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP-specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.

PMID:
28765400
PMCID:
PMC5584114
DOI:
10.1084/jem.20161134
[Indexed for MEDLINE]
Free PMC Article

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