dc.contributor.advisor |
Garth Cooper |
en |
dc.contributor.author |
Bai, Ji Zhong |
en |
dc.date.accessioned |
2006-11-30T01:20:16Z |
en |
dc.date.available |
2006-11-30T01:20:16Z |
en |
dc.date.issued |
1999 |
en |
dc.identifier.citation |
Thesis (PhD--Developmental Biology and Cancer Research (Biological Sciences))--University of Auckland, 1999. |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/92 |
en |
dc.description |
Restricted Item. Print thesis available in the University of Auckland Library or may be available through Interlibrary Loan. Subscription resource available via Digital Dissertations. |
en |
dc.description.abstract |
Amylin is a 37-amino acid peptide usually cosecreted with insulin from pancreatic islet β-cells. It is implicated in the regulation of normal glucose metabolism and thought to induce pathological features of non-insulin-dependent diabetes mellitus (NIDDM). In particular, human amylin (hA) deposits as islet amyloid, and is associated with the loss of insulin-producing islet β-cells in NIDDM. The biochemical mechanism of hA-evoked death in cultured RINm5F pancreatic islet β-cells has been investigated in this thesis. Synthetic hA but not rat amylin (rA) aggregated in aqueous solution, formed fibrils, and evoked β-cell death in a time- and concentration-dependent manner. The cell death exhibited apoptotic features, including inter-nucleosomal DNA fragmentation, mitochondrial dysfunction, delayed membrane lysis, aurintricarboxylic acid suppression and cell membrane blebbling. Cytotoxicity of hA was inhibited by Congo red (an amyloid-binding dye), 8-37hA fragment (fibril-forming but non-toxic), 1-40βA or 25-35βA (Alzheimer-associated peptide), but neither by sorbitol (inhibitory to hA fibril formation), rA nor its 8-37rA peptide (non-fibril-forming and non-toxic). Preformed large amyloid deposits of hA were less potent in causing β-cell death than small aggregates. These data suggest that hA induces β-cell apoptosis via small aggregates through a possible membrane receptor pathway. Inhibitors of protein and mRNA synthesis did not inhibit hA-evoked apoptosis, but rather enhanced or directly triggered β-cell death during prolonged exposure. Likewise, Ca2+ modulators, which alter intracellular free Ca2+ concentration ([Ca2+]i), failed to prevent hA cytotoxicity and were ultimately cytotoxic themselves. Fura-2 loading and 45Ca2+ uptake studies indicated that hA did not mobilise intracellular Ca2+ during its toxicity. These results indicate a protein synthesis- and Ca2+-independent process of hA toxicity RINm5F islet β-cells. The studies reported in this thesis have established a new in vitro model of hA-evoked apoptosis using cultured RINm5F pancreatic islet β-cells. A new model of NIDDM pathogenesis is presented and discussed. |
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dc.language.iso |
en |
en |
dc.publisher |
ResearchSpace@Auckland |
en |
dc.relation.ispartof |
PhD Thesis - University of Auckland |
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dc.relation.isreferencedby |
UoA877467 |
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dc.rights |
Whole document restricted. Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
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dc.source.uri |
http://wwwlib.umi.com/dissertations/fullcit/9943763 |
en |
dc.subject.other |
BIOLOGY, CELL (0379) |
en |
dc.subject.other |
BIOPHYSICS, MEDICAL (0760) |
en |
dc.title |
The mechanism of death evoked by human amylin in pancreatic islet B cells |
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dc.type |
Thesis |
en |
thesis.degree.discipline |
Biological Sciences |
en |
thesis.degree.grantor |
The University of Auckland |
en |
thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.local.anzsrc |
1112 - Oncology and Carcinogenesis |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/ClosedAccess |
en |
pubs.org-id |
Faculty of Science |
en |
dc.identifier.wikidata |
Q112849177 |
|