Please use this identifier to cite or link to this item:
Type: Theses
Title: Investigations into the role of zinc and zinc transporters in the pathogenesis of type 2 diabetes in db/db mice
Author: Bosco, Mariea Dencey
Issue Date: 2015
School/Discipline: School of Medicine
Abstract: Zn is critical for the synthesis, storage and release of insulin and abnormalities in Zn and Zn transporters occur in type 1 and 2 diabetes. However, the mechanism by which Zn is regulated in islet cells is still poorly understood. The major goal of this thesis was to investigate the role of Zn and Zn transporters in the pathogenesis of normal and type two diabetic pancreatic islets, using the type 2 db/db mouse model. There is limited information available on the physiological role of Zn and Zn transporters in these mice. The following hypotheses were tested. 1) There is an early loss of Zn in the development of type 2 diabetes which contributes to the transition to established diabetes; 2) The loss of Zn causes a block in insulin maturation resulting in impaired glucose responsiveness, hyperglycemia and decline in beta cell function; 3) This loss of Zn is due to alterations in Zn transporter proteins and metallothionein at the gene and protein level. Specifically changes in the organelle Zn transporters ZnT7 and ZnT8 result in the block in insulin maturation, while dysregulation of the inflammation related plasma membrane Zn transporter protein ZIP14 contributes to inflammation that results in further beta cell dysfunction. The major aims of the project were to determine whether in early and late diabetes there are changes in 1) total and labile Zn and metallothionein, 2) Zn transporter gene expression; and 3) Zn transporter proteins. Whole pancreata from the db/db mice and age matched controls at various ages were used to investigate Zn, metallothionein protein, gene expression and subcellular distribution of Zn transporters and Zn related proteins. Immunofluorescence, immunoperoxidase and western blotting were used to investigate the Zn transporter protein expression and distribution. The major findings in this study were in early diabetes 1) loss of Zn occurred in the labile islet beta cells Zn pools without decrease in systemic Zn ; 2) There were no changes at the gene level of Zn transporters ZnT1-10 and ZIP1-14 or metallothionein; 3)There was a significant increase in islet ZnT7 protein with a golgi like appearance; 4) ZnT8 protein was downregulated in islet beta cells but not alpha cells; 5) ZIP4 was expressed almost exclusively in the somatostatin producing delta cells; 6) ZIP14 staining was signficantly increased and coincided with islet macrophages. Changes in ZnT7, ZnT8 and ZIP14 expression may be factors leading to the loss of islet beta granule Zn. ZIP4 may be the major influx transporter for Zn in delta cells, ZnT8 is the transporter regulating Zn in insulin secretory granules and ZIP14 may be a novel marker of macrophage infiltration in diabetic islets. There are two potential clinical implications. The first is in understanding better the early events in development of type 2 diabetes, how these are influenced by Zn status and whether Zn supplements have a role to play in slowing down the transition from pre-diabetes to established diabetes. The second is a better understanding of islet Zn homeostasis with potential benefits for outcomes of islet transplantation.
Advisor: Coates, Patrick Toby Hewlett
Zalewski, Peter Ernest
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2015.
Keywords: zinc
type 2 diabetes
zinc transporter
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
Appears in Collections:Research Theses

Files in This Item:
File Description SizeFormat 
01front.pdf579.93 kBAdobe PDFView/Open
02whole.pdf9.02 MBAdobe PDFView/Open
  Restricted Access
Library staff access only527.99 kBAdobe PDFView/Open
  Restricted Access
Library staff access only20.46 MBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.