- Nield, Alex, Quarrell, Sean, Myers, Stephen
- Authors: Nield, Alex , Quarrell, Sean , Myers, Stephen
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Diabetes and Metabolism Vol. 4, no. 6 (2013), p. 1-6
- Full Text: false
- Reviewed:
- Description: Type 2 diabetes (T2D) is a chronic metabolic disorder that is predominately associated with lifestyle changes including reduced physical activity, poor nutrition and obesity. Despite major medical advances in the treatment of T2D, its prevalence is still increasing at an alarming rate. Accordingly, better management and prevention strategies are urgently needed to prevent the development and progression of this disease. In the last decade there have been considerable efforts to improve public health through alternative research paradigms. Community-Based Participatory Research (CBPR) is one such process by which researchers form an equal and transparent partnership with the community with the final goal of creating empowerment and societal change to facilitate action and provide solutions to promote health and well-being. One CBPR program, the Kahnawake Schools Diabetes Prevention Project (KSDPP), was initiated to promote increased physical activity and healthier eating habits among school children based on the Mohawk’s “Living in Balance” philosophy. Utilizing CBPR principles, KSDPP engaged researchers and the community in all stages of the research processes. This project was community driven from the beginning and was independent of any external institutional change agent to facilitate community action and the implementation of strategies to find solutions. Although the project has been instrumental in community empowerment and societal change, several challenges remain. Accordingly, understanding the unique social, environmental and historical context that shapes lifestyle and risk factors for T2D in Native populations will help to understand the unique nature of this disease in these groups.
Renal denervation promotes atherosclerosis in hypertensive apolipoprotein E-Deficient mice infused with angiotensin II
- Wang, Yutang, Dinh, Tam, Nield, Alex, Krishna, Smriti, Denton, Kate, Golledge, Jonathan
- Authors: Wang, Yutang , Dinh, Tam , Nield, Alex , Krishna, Smriti , Denton, Kate , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Frontiers in Physiology Vol. 8, no. (2017), p. 1-9
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice. Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR. Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5-7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = -0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2). Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients. © 2017 Wang, Dinh, Nield, Krishna, Denton and Golledge.
- Authors: Wang, Yutang , Dinh, Tam , Nield, Alex , Krishna, Smriti , Denton, Kate , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Frontiers in Physiology Vol. 8, no. (2017), p. 1-9
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice. Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR. Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5-7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = -0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2). Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients. © 2017 Wang, Dinh, Nield, Krishna, Denton and Golledge.
The role of Zinc Transporters in modulating Insulin signalling
- Authors: Nield, Alex
- Date: 2015
- Type: Text , Thesis , PhD
- Full Text:
- Description: Zinc is a cell impermeable transition metal with a large number of biological functions, and is an essential component of the insulin signalling pathway. Cellular free zinc increases insulin sensitivity though it is also toxic at high levels, making it essential for cells to tightly regulate bioavailable levels. This homeostasis is maintained by three groups of proteins known as Zips, ZnTs and metallothioneins (MTs). Zips and ZnTs are zinc transporters with Zips increasing cytosolic zinc by pumping it outside the cell or from organelle stores, while the ZnTs decrease cytosolic zinc. The MTs bind to free zinc in the cytosol, reducing its bioavailability. The rapid release of zinc mediated by these proteins has been implicated as a mechanism of signal pathway activation, through zinc activating and deactivating various signalling proteins. This thesis investigated one zinc transporter in particular, known as Zip7. Zip7 is a novel Zip transporter localised to the endoplasmic reticulum and has been implicated in cell signalling in breast cancer cells through release of zinc from cellular stores in response to extracellular stimuli. The aim of this thesis was to investigate the potential role of this zinc transporter in modulating the insulin signalling pathway. The human Zip7 protein sequence was analysed using various bioinformatics tools to identify regions that may contribute to the proposed novel function of this transporter. The loop regions of Zip7 were found to be poorly conserved between species with the exception of histidine rich regions, which showed a high level of conservation when compared to a diverse series of species and so are suspected to have an essential role in modulating the transport function of Zip7 by binding to zinc. These findings implicate histidine residues as an important functional component of Zip7. In order to identify whether Zip7 expression is essential for a normal insulin response, Zip7 mRNA was reduced via transfection of siRNA in mouse skeletal muscle cells and measurement of markers of insulin signalling. When Zip7 expression was reduced there was a subsequent decrease in the expression of several markers of insulin signalling including Glut4 protein levels, Akt phosphorylation and insulin-mediated glycogen synthesis, indicating that the cells were insulin resistant compared to the control. It was hypothesised that given the proposed role for Zip7 in mediating rapid zinc release and that Zip7 expression is important for normal insulin signalling, Zip7 activation is stimulated by insulin treatment to temporarily increase cytosolic zinc bioavailability as a positive feedback mechanism for prolonging pathway activation. To test this, live cell imaging of zinc flux in cells was performed in cells with reduced Zip7 expression compared to controls. Insulin was shown to cause an increase in cytosolic zinc in C2C12 cells. However when Zip7 expression was reduced, even though the cells showed signs of insulin resistance, there was still an increase in zinc levels mediated by insulin. Insulin treatment is known to induce cellular ROS production and hydrogen peroxide has been suggested to cause a release of zinc due to oxidation of MTs leading to a release of bound zinc. These findings indicate that insulin-stimulated zinc flux is the result of MT oxidation rather than Zip7 activation. Taken together, these results highlight an important role for Zip7 in the insulin signalling pathway and show a previously undescribed positive feedback loop whereby insulin mediates a release of zinc to potentially inhibit PTP1B and other phosphatases to prolong insulin signalling activation. Further work is needed to fully elucidate the role of Zip7 in this pathway.
- Description: Doctor of Philosophy
- Authors: Nield, Alex
- Date: 2015
- Type: Text , Thesis , PhD
- Full Text:
- Description: Zinc is a cell impermeable transition metal with a large number of biological functions, and is an essential component of the insulin signalling pathway. Cellular free zinc increases insulin sensitivity though it is also toxic at high levels, making it essential for cells to tightly regulate bioavailable levels. This homeostasis is maintained by three groups of proteins known as Zips, ZnTs and metallothioneins (MTs). Zips and ZnTs are zinc transporters with Zips increasing cytosolic zinc by pumping it outside the cell or from organelle stores, while the ZnTs decrease cytosolic zinc. The MTs bind to free zinc in the cytosol, reducing its bioavailability. The rapid release of zinc mediated by these proteins has been implicated as a mechanism of signal pathway activation, through zinc activating and deactivating various signalling proteins. This thesis investigated one zinc transporter in particular, known as Zip7. Zip7 is a novel Zip transporter localised to the endoplasmic reticulum and has been implicated in cell signalling in breast cancer cells through release of zinc from cellular stores in response to extracellular stimuli. The aim of this thesis was to investigate the potential role of this zinc transporter in modulating the insulin signalling pathway. The human Zip7 protein sequence was analysed using various bioinformatics tools to identify regions that may contribute to the proposed novel function of this transporter. The loop regions of Zip7 were found to be poorly conserved between species with the exception of histidine rich regions, which showed a high level of conservation when compared to a diverse series of species and so are suspected to have an essential role in modulating the transport function of Zip7 by binding to zinc. These findings implicate histidine residues as an important functional component of Zip7. In order to identify whether Zip7 expression is essential for a normal insulin response, Zip7 mRNA was reduced via transfection of siRNA in mouse skeletal muscle cells and measurement of markers of insulin signalling. When Zip7 expression was reduced there was a subsequent decrease in the expression of several markers of insulin signalling including Glut4 protein levels, Akt phosphorylation and insulin-mediated glycogen synthesis, indicating that the cells were insulin resistant compared to the control. It was hypothesised that given the proposed role for Zip7 in mediating rapid zinc release and that Zip7 expression is important for normal insulin signalling, Zip7 activation is stimulated by insulin treatment to temporarily increase cytosolic zinc bioavailability as a positive feedback mechanism for prolonging pathway activation. To test this, live cell imaging of zinc flux in cells was performed in cells with reduced Zip7 expression compared to controls. Insulin was shown to cause an increase in cytosolic zinc in C2C12 cells. However when Zip7 expression was reduced, even though the cells showed signs of insulin resistance, there was still an increase in zinc levels mediated by insulin. Insulin treatment is known to induce cellular ROS production and hydrogen peroxide has been suggested to cause a release of zinc due to oxidation of MTs leading to a release of bound zinc. These findings indicate that insulin-stimulated zinc flux is the result of MT oxidation rather than Zip7 activation. Taken together, these results highlight an important role for Zip7 in the insulin signalling pathway and show a previously undescribed positive feedback loop whereby insulin mediates a release of zinc to potentially inhibit PTP1B and other phosphatases to prolong insulin signalling activation. Further work is needed to fully elucidate the role of Zip7 in this pathway.
- Description: Doctor of Philosophy
The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells
- Myers, Stephen, Nield, Alex, Chew, Guatsiew, Myers, Mark
- Authors: Myers, Stephen , Nield, Alex , Chew, Guatsiew , Myers, Mark
- Date: 2013
- Type: Text , Journal article
- Relation: Plos One Vol. 8, no. 11 (November 2013 2013), p. 15
- Full Text:
- Reviewed:
- Description: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
- Authors: Myers, Stephen , Nield, Alex , Chew, Guatsiew , Myers, Mark
- Date: 2013
- Type: Text , Journal article
- Relation: Plos One Vol. 8, no. 11 (November 2013 2013), p. 15
- Full Text:
- Reviewed:
- Description: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
Zinc transporters, mechanisms of action and therapeutic utility : Implications for type 2 diabetes mellitus
- Myers, Stephen, Nield, Alex, Myers, Mark
- Authors: Myers, Stephen , Nield, Alex , Myers, Mark
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Nutrition and Metabolism Vol. 2012, no. (2012), p. 1-13
- Full Text:
- Reviewed:
- Description: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy. © 2012 Stephen A. Myers et al.
- Description: 2003010692
- Authors: Myers, Stephen , Nield, Alex , Myers, Mark
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Nutrition and Metabolism Vol. 2012, no. (2012), p. 1-13
- Full Text:
- Reviewed:
- Description: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy. © 2012 Stephen A. Myers et al.
- Description: 2003010692
Zinc, zinc transporters and Type 2 Diabetes
- Authors: Myers, Stephen , Nield, Alex
- Date: 2014
- Type: Text , Book chapter
- Relation: Endocrine diseases Chapter 2 p.
- Full Text: false
- Reviewed:
- Description: Insulin resistance is an important characteristic of Type 2 Diabetes (T2D) and is commonly associated with obesity, hypertension and cardiovascular disease (Carsten, 2000; Hulver and Lynis, 2004). Insulin resistance reduces insulin-stimulated glucose disposal due to multiple post-recepter intracellular defects in insulin signaling with subsequent reductions in glucose transport, glucose oxidation and incorporation of glucose into glycogen (Abdul-Ghani and DeFronzo, 2010; Peppa et al., 2010). The intracellular post-receptor regulatory effects of insulin include the regulation of the cellular glucose transport system, adaptive changes in gene expression and subsequent biosynthesis and action of the enzymes involved in the preservation of metabolism, and the modulation of genes that contribute to increased pro-mitotic, proliferative and anti-apoptotic activity of cells (Taton et al., 2010). Accordingly, the reduced activity of insulin action in any, or all of these post-receptor regulatory actions is insulin resistance. Given that insulin resistance usually precedes the development of T2D and is a major component of the progressive nature of this disease (Pagel-Langenickel et al., 2010), understanding the pathophysiology of insulin resistance will enable the development of therapeutic strategies to prevent or manage disease progression. Although many theories have been forthcoming, the primary mechanism of insulin resistance remains largely elusive.
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