Ability of GHTD-amide and analogs to enhance insulin activity through zinc chelation and dispersal of insulin oligomers
- Paule, Sarah, Nikolovski, Biljana, Ludeman, Justin, Gray, Robyn, Spiccia, Leone, Zimmet, Paul, Myers, Mark
- Authors: Paule, Sarah , Nikolovski, Biljana , Ludeman, Justin , Gray, Robyn , Spiccia, Leone , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 6 (2009), p. 1088-1097
- Full Text:
- Reviewed:
- Description: GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free α-amino group were optimal at binding Zn2+ and adopting secondary structure in the presence of Zn2+. Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn2+ contributes to the hypoglycemic activity of these tetrapeptides. Crown Copyright © 2009.
- Authors: Paule, Sarah , Nikolovski, Biljana , Ludeman, Justin , Gray, Robyn , Spiccia, Leone , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 6 (2009), p. 1088-1097
- Full Text:
- Reviewed:
- Description: GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free α-amino group were optimal at binding Zn2+ and adopting secondary structure in the presence of Zn2+. Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn2+ contributes to the hypoglycemic activity of these tetrapeptides. Crown Copyright © 2009.
Influence of zinc on productivity and species composition in algal periphyton communities
- Atazadeh, Islam, Sharifi, Mozafar
- Authors: Atazadeh, Islam , Sharifi, Mozafar
- Date: 2012
- Type: Text , Journal article
- Relation: Algological Studies Vol. 138, no. 1 (April 2012 2012), p. 57-73
- Full Text: false
- Reviewed:
- Description: In order to evaluate the influence of zinc on biomass and species composition in algal periphyton communities, indoor artificial streams were used with differing zinc additions (0, 1 and 2 mg L–1). The effects of zinc on community biomass were assessed by measuring dry mass, ash-free dry mass (AFDM), chlorophyll a, species composition, relative abundance, biovolume and bioconcentration factor. In artificial streams with zinc, there was a significant (p < 0.05) reduction of chlorophyll a, dry mass and AFDM. Species diversity and relative abundance of periphyton species changed drastically under the influence of zinc. In an artificial stream containing the higher concentration of added zinc (2 mg L–1), the taxonomic composition of the population shifted from a cyanophyceaen dominated community to a community mainly consisting of Chlorophyceae, while changes among species within the Bacillariophyceae did not show a marked difference under the influence of zinc. Some taxa such as Oocystis crassa and Scenedesmus sp. showed a strong association with the higher concentration of zinc. These observations suggest that biomass and structure of periphyton community could serve as an indicator of zinc pollution.
- Description: C1
Electrochemical studies of organic compounds in zinc electrowinning circuits
- Authors: Vawdrey, Peter
- Date: 1986
- Type: Text , Thesis , Masters
- Full Text:
- Description: Most of Australia's zinc production is by the electrolytic zinc process, in which zinc is electrowon from an acid sulphate solution. The process is known to be exceptionally sensitive to the presence of trace impurities. At the Electrolytic Zinc plant (Risdon, Tasmania), isobenzofuranone (pthalide) has been detected in the electrowinning circuit, and found in higher concentrations during efficiency slumps. It was found that di-2-ethylhexyphthalate, (present in the liners and plastics used in the electrowinning circuit), is reduced to isobenzofuranone under the electrolysis conditions employed. In addition, an investigation involved a constant current electrolysis of a synthetic zinc electrolyte, as identified an additional pathway for the productionof isobenzofuranone. 2-Naphthol, added to the electrolysis circuit for current efficiency purposes, is also a major precursor of isobenzofuranone. 2-Napthol and possibly 1-nitroso-2-napthol can be oxidized to pthalic acid, either at a lead anode or via anode oxidation productions, and the phthalic acid produced can be reduced to isobenzofuranone at a zinc cathode. In addition, it was found that isobenzofurane is further reduced at the potential of zinc deposition to ultimately yield 2-methylbenzaldehyde. This compound, which has also been detected in Risdon plant electrolytes, is also toxic in the zince electrowinning circuit. The compound 2-methylabenzyl alcohol has also been detected via GLC examination of Risdon plant liquors. However, this compound was not detected in the present investigation, and thus no explanation can be offered for its presence in plant electrolytes. The toxicity of zinc electrolyte impurities on current efficiency was determined by a cyclic voltammetric technique. The results of this investigation indicate that the presence of isobenzofuranone and 2-methylbenzaldehyde can significantly lower current effciency, and the compounds phthalic acid and 2-methylbenzyl alcohol also lower efficiency.
- Description: Masters Degree in Applied Science
- Authors: Vawdrey, Peter
- Date: 1986
- Type: Text , Thesis , Masters
- Full Text:
- Description: Most of Australia's zinc production is by the electrolytic zinc process, in which zinc is electrowon from an acid sulphate solution. The process is known to be exceptionally sensitive to the presence of trace impurities. At the Electrolytic Zinc plant (Risdon, Tasmania), isobenzofuranone (pthalide) has been detected in the electrowinning circuit, and found in higher concentrations during efficiency slumps. It was found that di-2-ethylhexyphthalate, (present in the liners and plastics used in the electrowinning circuit), is reduced to isobenzofuranone under the electrolysis conditions employed. In addition, an investigation involved a constant current electrolysis of a synthetic zinc electrolyte, as identified an additional pathway for the productionof isobenzofuranone. 2-Naphthol, added to the electrolysis circuit for current efficiency purposes, is also a major precursor of isobenzofuranone. 2-Napthol and possibly 1-nitroso-2-napthol can be oxidized to pthalic acid, either at a lead anode or via anode oxidation productions, and the phthalic acid produced can be reduced to isobenzofuranone at a zinc cathode. In addition, it was found that isobenzofurane is further reduced at the potential of zinc deposition to ultimately yield 2-methylbenzaldehyde. This compound, which has also been detected in Risdon plant electrolytes, is also toxic in the zince electrowinning circuit. The compound 2-methylabenzyl alcohol has also been detected via GLC examination of Risdon plant liquors. However, this compound was not detected in the present investigation, and thus no explanation can be offered for its presence in plant electrolytes. The toxicity of zinc electrolyte impurities on current efficiency was determined by a cyclic voltammetric technique. The results of this investigation indicate that the presence of isobenzofuranone and 2-methylbenzaldehyde can significantly lower current effciency, and the compounds phthalic acid and 2-methylbenzyl alcohol also lower efficiency.
- Description: Masters Degree in Applied Science
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.
The role of Zn2+ in insulin signalling and muscle atrophy
- Authors: Maier, Michelle
- Date: 2019
- Type: Text , Thesis , PhD
- Full Text:
- Description: Zn2+ is a broadly utilised ion in biology that has important catalytic, structural and regulatory roles within the cell. Zn2+ distribution in cells is maintained by zinc transporters, Zips and ZnTs, and disruptions in levels of Zn2+ have been associated with insulin resistance and muscle atrophy disorders. Zn2+ and reactive oxygen species (ROS) interact through inhibition of protein tyrosine phosphatases and ROS-mediated oxidation of the metal-binding metallothioneins (Mts) causing release of bound Zn2+, however the precise mechanisms are unclear. In the first study of this thesis addition of inhibitors of ROS-generating enzymes, superoxide dismutase 1 (SOD1) and NADPH oxidase 1 (NOX1) showed that only SOD1 inhibition increased short-term insulin-mediated Zn2+ release and increased the expression of Mt1 and 2. These results may suggest that ROS, in particular O2- accumulation through inhibition of SOD1, plays a role in insulin-mediated Zn2+ release. Inhibiting SOD1 prevents the conversion of O2- to H2O2 causing an accumulation of O2- in the cell which oxidises Mts to release Zn2+, thereby increasing Zn2+ levels within the cell. Manipulation of the expression of the zinc transporter Zip-7 has previously been shown to modulate cell signalling and glucose metabolism in C2C12 skeletal muscle cells, warranting further investigation into the role of Zn2+ within insulin signalling. Reducing Zip-7 expression when NOX1 was inhibited caused a decrease in Mt2 expression in response to insulin suggesting an interaction between insulin, Zip-7 and NOX1 activity but this requires further investigation. Skeletal muscle atrophy is a clinical symptom of insulin resistance and diabetes. Muscle atrophy is associated with increases in circulating glucocorticoid levels and accumulation of Zn2+ in muscle. This study investigates if Zn2+ homeostasis is disrupted in glucocorticoid-induced atrophy using C2C12 skeletal muscle cells treated with Dexamethasone (DEX) and iv insulin. Results demonstrate DEX-induced atrophy significantly increased the gene expression of the Mt1&2 and decreased glycogen accumulation when treated with insulin. Both confocal microscopy and flow cytometry showed significant increases in free cellular Zn2+ after DEX treatment. Notably, free Zn2+ levels observed with confocal microscopy increased after insulin treatment in control cells but decreased in DEX treated cells. Total cellular Zn2+ was increased by DEX treatment. This demonstrates that DEX causes Zn2+ accumulation in muscle cells and disrupts both Zn2+ homeostasis through blocking insulin-induced Zn2+ release, and insulin-induced glycogen synthesis. This raised the question of whether the same effects of atrophy on Zn2+ homeostasis apply to other cell systems. To investigate this, we examined adipose cells given that these too are involved in insulin resistance and muscle atrophy disorders. In this study we found similar increases in mRNA abundance of Mt1 & 2. Confocal microscopy revealed that DEX treatment caused changes in the distribution of free Zn2+ within peri-nuclear and cytosolic regions of the cell upon stimulation with insulin. Furthermore, investigation into morphometric changes using Oil Red O staining and particle analysis through Coherent Anti-Stokes Ramen Spectrophotometry (CARS) microscopy showed changes in cell and lipid droplet size consistent with reduced lipid turnover in DEX treated cells. These results highlight a potential mechanistic role for Zn2+ in the development of atrophy in 3T3-L1 adipocytes where increased free Zn2+ and its redistribution in cells may inhibit lipid metabolism downstream of insulin signalling. These findings show that insulin-induced Zn2+ release is disrupted by glucocorticoids and this is associated with insulin resistance. Restoring control of Zn2+ homeostasis, possibly through controlling oxidation or manipulating Zn2+ levels directly, may prove beneficial in metabolic disease states such as diabetes.
- Description: Doctor of Philosophy
- Authors: Maier, Michelle
- Date: 2019
- Type: Text , Thesis , PhD
- Full Text:
- Description: Zn2+ is a broadly utilised ion in biology that has important catalytic, structural and regulatory roles within the cell. Zn2+ distribution in cells is maintained by zinc transporters, Zips and ZnTs, and disruptions in levels of Zn2+ have been associated with insulin resistance and muscle atrophy disorders. Zn2+ and reactive oxygen species (ROS) interact through inhibition of protein tyrosine phosphatases and ROS-mediated oxidation of the metal-binding metallothioneins (Mts) causing release of bound Zn2+, however the precise mechanisms are unclear. In the first study of this thesis addition of inhibitors of ROS-generating enzymes, superoxide dismutase 1 (SOD1) and NADPH oxidase 1 (NOX1) showed that only SOD1 inhibition increased short-term insulin-mediated Zn2+ release and increased the expression of Mt1 and 2. These results may suggest that ROS, in particular O2- accumulation through inhibition of SOD1, plays a role in insulin-mediated Zn2+ release. Inhibiting SOD1 prevents the conversion of O2- to H2O2 causing an accumulation of O2- in the cell which oxidises Mts to release Zn2+, thereby increasing Zn2+ levels within the cell. Manipulation of the expression of the zinc transporter Zip-7 has previously been shown to modulate cell signalling and glucose metabolism in C2C12 skeletal muscle cells, warranting further investigation into the role of Zn2+ within insulin signalling. Reducing Zip-7 expression when NOX1 was inhibited caused a decrease in Mt2 expression in response to insulin suggesting an interaction between insulin, Zip-7 and NOX1 activity but this requires further investigation. Skeletal muscle atrophy is a clinical symptom of insulin resistance and diabetes. Muscle atrophy is associated with increases in circulating glucocorticoid levels and accumulation of Zn2+ in muscle. This study investigates if Zn2+ homeostasis is disrupted in glucocorticoid-induced atrophy using C2C12 skeletal muscle cells treated with Dexamethasone (DEX) and iv insulin. Results demonstrate DEX-induced atrophy significantly increased the gene expression of the Mt1&2 and decreased glycogen accumulation when treated with insulin. Both confocal microscopy and flow cytometry showed significant increases in free cellular Zn2+ after DEX treatment. Notably, free Zn2+ levels observed with confocal microscopy increased after insulin treatment in control cells but decreased in DEX treated cells. Total cellular Zn2+ was increased by DEX treatment. This demonstrates that DEX causes Zn2+ accumulation in muscle cells and disrupts both Zn2+ homeostasis through blocking insulin-induced Zn2+ release, and insulin-induced glycogen synthesis. This raised the question of whether the same effects of atrophy on Zn2+ homeostasis apply to other cell systems. To investigate this, we examined adipose cells given that these too are involved in insulin resistance and muscle atrophy disorders. In this study we found similar increases in mRNA abundance of Mt1 & 2. Confocal microscopy revealed that DEX treatment caused changes in the distribution of free Zn2+ within peri-nuclear and cytosolic regions of the cell upon stimulation with insulin. Furthermore, investigation into morphometric changes using Oil Red O staining and particle analysis through Coherent Anti-Stokes Ramen Spectrophotometry (CARS) microscopy showed changes in cell and lipid droplet size consistent with reduced lipid turnover in DEX treated cells. These results highlight a potential mechanistic role for Zn2+ in the development of atrophy in 3T3-L1 adipocytes where increased free Zn2+ and its redistribution in cells may inhibit lipid metabolism downstream of insulin signalling. These findings show that insulin-induced Zn2+ release is disrupted by glucocorticoids and this is associated with insulin resistance. Restoring control of Zn2+ homeostasis, possibly through controlling oxidation or manipulating Zn2+ levels directly, may prove beneficial in metabolic disease states such as diabetes.
- Description: Doctor of Philosophy
Zinc transporters maintain longevity by influencing insulin/IGF-1 activity in Caenorhabditis elegans
- Novakovic, Stevan, Molesworth, Luke, Gourley, Taylin, Boag, Peter, Davis, Gregory
- Authors: Novakovic, Stevan , Molesworth, Luke , Gourley, Taylin , Boag, Peter , Davis, Gregory
- Date: 2020
- Type: Text , Journal article
- Relation: FEBS Letters Vol. 594, no. 9 (2020), p. 1424-1432
- Full Text:
- Reviewed:
- Description: Adequate dietary intake of essential metals such as zinc is important for maintaining homeostasis. Abnormal zinc intake in Caenorhabditis elegans has been shown to increase or decrease normal lifespan by influencing the insulin/IGF-1 pathway. Distribution of zinc is achieved by a family of highly conserved zinc transport proteins (ZIPT in C. elegans). This study investigated the role of the zipt family of genes and showed that depletion of individual zipt genes results in a decreased lifespan. Moreover, zipt-16 and zipt-17 mutants synthetically interact with the insulin/IGF cofactors daf-16 and skn-1, and cause abnormal localisation of DAF-16. This study suggests that the zipt family of genes are required for maintaining normal lifespan through influencing the insulin/IGF-1 pathway. © 2019 Federation of European Biochemical Societies
- Description: This study was supported by the resources at Federation University; no external funding was used to fund this study. We acknowledge the Caenorhabditis elegans Genetics Centre for the strains used in this study and Hannah Tatnell (Federation University) for technical assistance.
Zinc transporters maintain longevity by influencing insulin/IGF-1 activity in Caenorhabditis elegans
- Authors: Novakovic, Stevan , Molesworth, Luke , Gourley, Taylin , Boag, Peter , Davis, Gregory
- Date: 2020
- Type: Text , Journal article
- Relation: FEBS Letters Vol. 594, no. 9 (2020), p. 1424-1432
- Full Text:
- Reviewed:
- Description: Adequate dietary intake of essential metals such as zinc is important for maintaining homeostasis. Abnormal zinc intake in Caenorhabditis elegans has been shown to increase or decrease normal lifespan by influencing the insulin/IGF-1 pathway. Distribution of zinc is achieved by a family of highly conserved zinc transport proteins (ZIPT in C. elegans). This study investigated the role of the zipt family of genes and showed that depletion of individual zipt genes results in a decreased lifespan. Moreover, zipt-16 and zipt-17 mutants synthetically interact with the insulin/IGF cofactors daf-16 and skn-1, and cause abnormal localisation of DAF-16. This study suggests that the zipt family of genes are required for maintaining normal lifespan through influencing the insulin/IGF-1 pathway. © 2019 Federation of European Biochemical Societies
- Description: This study was supported by the resources at Federation University; no external funding was used to fund this study. We acknowledge the Caenorhabditis elegans Genetics Centre for the strains used in this study and Hannah Tatnell (Federation University) for technical assistance.
Dexamethasone leads to Zn2+ accumulation and increased unbound Zn2+ in C2C12 muscle and 3T3-L1 adipose cells
- Maier, Michelle, Nankervis, Scott, Wallace, Morgan, Develyn, Tamekha, Myers, Mark
- Authors: Maier, Michelle , Nankervis, Scott , Wallace, Morgan , Develyn, Tamekha , Myers, Mark
- Date: 2023
- Type: Text , Journal article
- Relation: Journal of Cellular Biochemistry Vol. 124, no. 3 (2023), p. 409-420
- Full Text:
- Reviewed:
- Description: Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted. © 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
- Authors: Maier, Michelle , Nankervis, Scott , Wallace, Morgan , Develyn, Tamekha , Myers, Mark
- Date: 2023
- Type: Text , Journal article
- Relation: Journal of Cellular Biochemistry Vol. 124, no. 3 (2023), p. 409-420
- Full Text:
- Reviewed:
- Description: Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted. © 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
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