The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in β-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in β-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and β-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in β-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by β-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.
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Original Articles|
May 01 1994
Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans
Eelco J P de Koning;
Eelco J P de Koning
Diabetes Research Laboratories, Radcliffe Infirmary
Oxford, United Kingdom
Department of Human Anatomy, University of Oxford
Oxford, United Kingdom
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Jo W M Höppener;
Jo W M Höppener
Laboratory for Physiological Chemistry, University of Utrecht
Utrecht, The Netherlands
Departments of Internal Medicine, University Hospital Utrecht
Utrecht, The Netherlands
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J Sjef Verbeek;
J Sjef Verbeek
Experimental Immunology, University Hospital Utrecht
Utrecht, The Netherlands
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Cor Oosterwijk;
Cor Oosterwijk
Departments of Internal Medicine, University Hospital Utrecht
Utrecht, The Netherlands
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Karen L van Hulst;
Karen L van Hulst
Departments of Internal Medicine, University Hospital Utrecht
Utrecht, The Netherlands
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Catherine A Baker;
Catherine A Baker
Department of Biochemistry, University of Nottingham
Nottingham, United Kingdom
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Cees J M Lips;
Cees J M Lips
Departments of Internal Medicine, University Hospital Utrecht
Utrecht, The Netherlands
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John F Morris;
John F Morris
Department of Human Anatomy, University of Oxford
Oxford, United Kingdom
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Anne Clark
Anne Clark
Department of Human Anatomy, University of Oxford
Oxford, United Kingdom
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Address correspondence and reprint requests to Dr. Eelco J.P. de Koning, Diabetes Research Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford 0X2 6HE, United Kingdom.
Diabetes 1994;43(5):640–644
Article history
Received:
December 07 1993
Revision Received:
January 05 1994
Accepted:
January 05 1994
PubMed:
8168639
Citation
Eelco J P de Koning, Jo W M Höppener, J Sjef Verbeek, Cor Oosterwijk, Karen L van Hulst, Catherine A Baker, Cees J M Lips, John F Morris, Anne Clark; Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans. Diabetes 1 May 1994; 43 (5): 640–644. https://doi.org/10.2337/diab.43.5.640
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