Publication:
Pathways leading to β-cell dysfunction and death in type 1 and type 2 diabetes
Pathways leading to β-cell dysfunction and death in type 1 and type 2 diabetes
dc.contributor.advisor | Laybutt, Ross | en_US |
dc.contributor.advisor | Biden, Trevor | en_US |
dc.contributor.author | Akerfeldt, Mia | en_US |
dc.date.accessioned | 2022-03-21T10:38:43Z | |
dc.date.available | 2022-03-21T10:38:43Z | |
dc.date.issued | 2011 | en_US |
dc.description.abstract | The failure of β-cells to provide sufficient amounts of insulin to maintain blood glucose levels within a narrow physiological range is central to the development of all forms of diabetes. β-cell failure is characterised by both functional defects and loss of β-cell mass through apoptosis; however, the underlying mechanisms are not well defined. The broad aim of this thesis was to gain further insight into the mechanisms leading to β-cell dysfunction and death in type 1 and type 2 diabetes. Pro-inflammatory cytokines and saturated fatty acids are suggested mediators of β-cell apoptosis in type 1 diabetes and type 2 diabetes, respectively. Endoplasmic reticulum (ER) stress is induced by cytokines and saturated fatty acids in vitro. Studies in this thesis tested the hypothesis that ER stress provides a common mechanism for β-cell death induced by cytokines and the saturated fatty acid, palmitate. The research demonstrated for the first time that chemical chaperones are able to relieve ER stress in β-cells. This was associated with protection against death induced by palmitate, but not by cytokines. These findings indicated that ER stress activation is selectively necessary for palmitate- and not for cytokine-mediated β-cell death. The studies suggest that improving ER folding capacity is a promising therapeutic strategy for type 2 diabetes. Previous studies have found that β-cell dysfunction in animal models of diabetes is associated with increased expression of the helix-loop-helix protein Id1. Studies in this thesis investigated the role of Id1 in insulin secretion and glucose homeostasis. The research demonstrates a novel role of Id1 as a negative regulator of insulin secretion. Studies with Id1 knockout mice demonstrated that Id1 expression plays an essential role in the aetiology of glucose intolerance, insulin secretory dysfunction and β-cell dedifferentiation under conditions of insulin resistance and chronic lipid oversupply. The findings suggest that Id1 expression may provide a molecular link between chronic lipid oversupply and β-cell dedifferentiation and dysfunction. Id1 may therefore represent a new target for therapeutic interventions aimed at improving β-cell dysfunction and restoring disordered glucose homeostasis. | en_US |
dc.identifier.uri | http://hdl.handle.net/1959.4/51610 | |
dc.language | English | |
dc.language.iso | EN | en_US |
dc.publisher | UNSW, Sydney | en_US |
dc.rights | CC BY-NC-ND 3.0 | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/au/ | en_US |
dc.subject.other | Insulin secretion | en_US |
dc.subject.other | β-cell apoptosis | en_US |
dc.subject.other | Endoplasmic reticulum stress | en_US |
dc.subject.other | Helix-loop-helix transcription factor | en_US |
dc.title | Pathways leading to β-cell dysfunction and death in type 1 and type 2 diabetes | en_US |
dc.type | Thesis | en_US |
dcterms.accessRights | open access | |
dcterms.rightsHolder | Akerfeldt, Mia | |
dspace.entity.type | Publication | en_US |
unsw.accessRights.uri | https://purl.org/coar/access_right/c_abf2 | |
unsw.identifier.doi | https://doi.org/10.26190/unsworks/15232 | |
unsw.relation.faculty | Medicine & Health | |
unsw.relation.originalPublicationAffiliation | Akerfeldt, Mia, Garvan Institute of Medical Research, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Laybutt, Ross, Garvan Institute of Medical Research | en_US |
unsw.relation.originalPublicationAffiliation | Biden, Trevor, Garvan Institute of Medical Research | en_US |
unsw.relation.school | Garvan Institute | * |
unsw.thesis.degreetype | PhD Doctorate | en_US |
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