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Research Article

Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation

Diana Ribeiro, Istvan Horvath, Nikki Heath, Ryan Hicks, Anna Forslöw, and View ORCID ProfilePernilla Wittung-Stafshede
PNAS October 17, 2017 114 (42) 11127-11132; first published October 2, 2017; https://doi.org/10.1073/pnas.1711389114
Diana Ribeiro
aDiscovery Biology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 43150 Mölndal, Sweden;
bDepartment of Biology and Biological Engineering, Chalmers University of Technology, 41258 Gothenburg, Sweden;
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Istvan Horvath
bDepartment of Biology and Biological Engineering, Chalmers University of Technology, 41258 Gothenburg, Sweden;
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Nikki Heath
cDiscovery Biology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Alderley Park SK10 4TG, United Kingdom
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Ryan Hicks
aDiscovery Biology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 43150 Mölndal, Sweden;
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Anna Forslöw
aDiscovery Biology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 43150 Mölndal, Sweden;
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Pernilla Wittung-Stafshede
bDepartment of Biology and Biological Engineering, Chalmers University of Technology, 41258 Gothenburg, Sweden;
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  • ORCID record for Pernilla Wittung-Stafshede
  • For correspondence: pernilla.wittung@chalmers.se
  1. Edited by Alan R. Fersht, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom, and approved September 11, 2017 (received for review June 28, 2017)

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Significance

Protein assembly into amyloid fibers underlies such neurodegenerative disorders as Alzheimer’s disease and Parkinson’s disease. Type 2 diabetes (T2D) also involves amyloid formation, although in the pancreas. Because there are no cures for amyloid diseases and T2D is on the rise due to an increasing prevalence of obesity, identifying involved mechanisms and control processes is of utmost importance. Extracellular vesicles (EVs) can mediate physiological and pathological communication both locally and at a distance. Here, we demonstrate that EVs secreted from healthy, but not from T2D, pancreatic cells slow amyloid formation of the major peptide found in amyloid deposits in T2D. We propose an EV-mediated process that tempers amyloid formation in the pancreas at normal conditions, which breaks down in T2D due to altered EV protein–lipid composition.

Abstract

Extracellular vesicles (EVs) are small vesicles released by cells to aid cell–cell communication and tissue homeostasis. Human islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in pancreatic islets of patients with type 2 diabetes (T2D). IAPP is secreted in conjunction with insulin from pancreatic β cells to regulate glucose metabolism. Here, using a combination of analytical and biophysical methods in vitro, we tested whether EVs isolated from pancreatic islets of healthy patients and patients with T2D modulate IAPP amyloid formation. We discovered that pancreatic EVs from healthy patients reduce IAPP amyloid formation by peptide scavenging, but T2D pancreatic and human serum EVs have no effect. In accordance with these differential effects, the insulin:C-peptide ratio and lipid composition differ between EVs from healthy pancreas and EVs from T2D pancreas and serum. It appears that healthy pancreatic EVs limit IAPP amyloid formation via direct binding as a tissue-specific control mechanism.

  • extracellular vesicles
  • type 2 diabetes
  • amyloid
  • atomic force microscopy
  • electron microscopy

Footnotes

  • ↵1To whom correspondence should be addressed. Email: pernilla.wittung{at}chalmers.se.
  • Author contributions: D.R., I.H., N.H., R.H., A.F., and P.W.-S. designed research; D.R. and I.H. performed research; D.R., I.H., N.H., and R.H. contributed new reagents/analytic tools; D.R., I.H., N.H., R.H., A.F., and P.W.-S. analyzed data; and P.W.-S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1711389114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Pancreatic exosomes inhibit IAPP amyloid formation
Diana Ribeiro, Istvan Horvath, Nikki Heath, Ryan Hicks, Anna Forslöw, Pernilla Wittung-Stafshede
Proceedings of the National Academy of Sciences Oct 2017, 114 (42) 11127-11132; DOI: 10.1073/pnas.1711389114

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Pancreatic exosomes inhibit IAPP amyloid formation
Diana Ribeiro, Istvan Horvath, Nikki Heath, Ryan Hicks, Anna Forslöw, Pernilla Wittung-Stafshede
Proceedings of the National Academy of Sciences Oct 2017, 114 (42) 11127-11132; DOI: 10.1073/pnas.1711389114
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