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Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide

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Abstract

Background

Human, but not mouse, islet amyloid polypeptide (IAPP) is amyloidogenic. Transgenic mice overexpressing human IAPP in the β cells of the islets of Langerhans should be useful in identifying factors important for the deposition of IAPP as insoluble amyloid fibrils.

Materials and Methods

Transgenic mice expressing human IAPP were examined using several experimental models for the production of persistent hyperglycemia, as well as for the overstimulation and/or inhibition of β cell secretion. Obesity was induced by aurothioglucose. Persistent hyperglycemia was produced by long-term administration of glucocorticosteroids or by partial pancreatectomy. Inhibition of normal β cell exocytosis by diazoxide administration, with or without concurrent dexamethasone injections, was carried out to increase crinophagy of secretory granules. The human IAPP gene was also introduced into the db and ob mouse models for diabetes. Finally, isolated islets cultivated in vitro at high glucose concentration were also examined.

Results

No amyloid deposits were found in the pancreata of any of the animals, either by light microscopy after Congo red staining or by electron microscopy after immunogold labeling with antibodies specific for human IAPP. Aurothioglucose treatment resulted in increased numbers of granules in the β cell and the appearance of large lysosomal bodies without amyloid. However, islets from db and ob mice expressing human IAPP cultivated in vitro in the presence of glucocorticosteroid and/or growth hormone, were found to contain extracellular amyloid deposits reacting with antibodies to human IAPP.

Conclusions

Oversecretion of human IAPP or increased crinophagy are not sufficient for amyloid formation. This indicates that other factors must influence amyloid deposition; one such factor may be the local clearance of IAPP.

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Acknowledgments

This work was supported by the Swedish Medical Research Council (Project No. 5941), the Swedish Diabetes Association, the Novo-Nordisk Insulin Fund, National Institutes of Health Grants DK13914 and DK20595 and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Pathology, Faculty of Health Sciences, Linköping University, University Hospital, S-58185, Linköping, Sweden

    Gunilla Westermark & Per Westermark

  2. Department of Biochemistry, College of Medicine West, University of Illinois, Chicago, Illinois, USA

    Michelle Benig Arora

  3. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA

    Niles Fox

  4. Department of Biochemistry and Molecular Biology and the Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA

    Raymond Carroll, Shu Jin Chan & Donald F. Steiner

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  1. Gunilla Westermark
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Westermark, G., Arora, M.B., Fox, N. et al. Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide. Mol Med 1, 542–553 (1995). https://doi.org/10.1007/BF03401591

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