The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Donald F. Steiner - One of the best experts on this subject based on the ideXlab platform.
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Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide
Molecular Medicine, 1995Co-Authors: Gunilla Westermark, Michelle Benig Arora, Niles Fox, Raymond Carroll, Shu Jin Chan, Per Westermark, Donald F. SteinerAbstract:Background Human, but not mouse, islet amyloid polypeptide (IAPP) is amyloidogenic. Transgenic mice overexpressing human IAPP in the β cells of the islets of Langerhans should be useful in identifying factors important for the deposition of IAPP as insoluble amyloid fibrils. Materials and Methods Transgenic mice expressing human IAPP were examined using several experimental models for the production of persistent hyperglycemia, as well as for the overstimulation and/or inhibition of β cell secretion. Obesity was induced by aurothioglucose. Persistent hyperglycemia was produced by long-term administration of glucocorticosteroids or by partial pancreatectomy. Inhibition of normal β cell exocytosis by diazoxide administration, with or without concurrent dexamethasone injections, was carried out to increase Crinophagy of secretory granules. The human IAPP gene was also introduced into the db and ob mouse models for diabetes. Finally, isolated islets cultivated in vitro at high glucose concentration were also examined. Results No amyloid deposits were found in the pancreata of any of the animals, either by light microscopy after Congo red staining or by electron microscopy after immunogold labeling with antibodies specific for human IAPP. Aurothioglucose treatment resulted in increased numbers of granules in the β cell and the appearance of large lysosomal bodies without amyloid. However, islets from db and ob mice expressing human IAPP cultivated in vitro in the presence of glucocorticosteroid and/or growth hormone, were found to contain extracellular amyloid deposits reacting with antibodies to human IAPP. Conclusions Oversecretion of human IAPP or increased Crinophagy are not sufficient for amyloid formation. This indicates that other factors must influence amyloid deposition; one such factor may be the local clearance of IAPP.
Ulf T. Brunk - One of the best experts on this subject based on the ideXlab platform.
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β-Cells, Oxidative Stress, Lysosomal Stability, and Apoptotic/Necrotic Cell Death
Antioxidants & redox signaling, 1999Co-Authors: Beata T. Olejnicka, Arne Andersson, Björn Tyrberg, Helge Dalen, Ulf T. BrunkAbstract:ABSTRACTReactive oxygen intermediates (ROI) may be involved in the destruction of pancreatic β-cells during the development of insulin-dependent diabetes mellitus (IDDM). To investigate the possible role of lysosomes in this process, normal mouse β-cells were cultured as monolayers at d-glucose concentrations of 1.6 (pronounced Crinophagy), 11 or 28 mM (minimal Crinophagy), subjected to a low level of oxidative stress and returned to standard culture conditions. Some cultures were exposed to desferrioxamine (Des) before the oxidative stress. As a result of such stress, many of the cells' lysosomes ruptured with consequent apoptosis or necrosis. Cells kept at 1.6 mM glucose were rich in secretory granules, showed Crinophagy/autophagy, were very sensitive to oxidative stress, and had the least stable lysosomes. Cells kept at 28 mM glucose did not show Crinophagy, contained fewer secretory granules, were less sensitive to oxidative stress, and had more stable lysosomes. Des-treated cells behaved almost as ce...
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A short exposure to a high-glucose milieu stabilizes the acidic vacuolar apparatus of insulinoma cells in culture to ensuing oxidative stress.
APMIS : acta pathologica microbiologica et immunologica Scandinavica, 1997Co-Authors: Beata T. Olejnicka, Karin Öllinger, Ulf T. BrunkAbstract:It was recently suggested that extracellular hydrogen peroxide, after diffusing into and throughout adjacent cells - which may be the case if they have only a weak capacity to degrade hydrogen peroxide - labilizes their lysosomal compartment due to its content of low-molecular-weight iron in redox-active form. The iron would be present as a consequence of normal autophagocytotic degradation of various iron-containing metalloproteins. Beta- and insulinoma cells are especially vulnerable to oxidative stress, since they possess only low capacity to degrade hydrogen peroxide, and, perhaps, since they normally have a certain degree of autophagocytotic degradation of secretory granules with some iron content - Crinophagy. The toxicity to beta cells of oxidative stress, such as an exposure to alloxan, that results in extracellular formation of hydrogen peroxide, is considerably reduced if animals are initially given an intravenous bolus dose of glucose, temporarily bringing up the blood level to about 20 mM. In this study it was demonstrated that already as short an exposure as 30 min to 20 mM D-glucose reduces the sensitivity of HIT and NIT insulinoma cells in culture to a subsequent exposure to hydrogen peroxide. In parallel, exposure to such a high-glucose medium also reduces their desferrioxamine-available amount of iron and, moreover, stabilizes their lysosomal membranes against oxidative stress - thus preventing diffusion to the cytosol of damaging lysosomal contents following iron-catalyzed, Fenton-type, intralysosomal reactions. We suggest that both general autophagocytotic turnover and, in particular, Crinophagy of secretory granules are decreased by an increased glucose concentration of the surrounding milieu, with attendant reduced amounts of intralysosomal low-molecular-weight iron and, thus, diminished sensitivity to oxidative stress.
L. A. Håkan Borg - One of the best experts on this subject based on the ideXlab platform.
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Steroid effects on intracellular degradation of insulin and Crinophagy in isolated pancreatic islets.
Molecular and cellular endocrinology, 2007Co-Authors: Monica Sandberg, L. A. Håkan BorgAbstract:Under physiological conditions substantial amounts of hormone may be degraded within endocrine cells by a crinophagic process comprising fusions of secretory granules with lysosomes. Glucocorticoids may stabilise and progesterone destabilise lysosomal membranes. The effects of corticosterone and progesterone on intracellular degradation of insulin and Crinophagy were determined in pancreatic beta-cells, and possible pathways mediating these effects were evaluated. Pancreatic islets were isolated from mice, intracellular degradation of insulin was measured by a pulse-chase method, and Crinophagy was studied by electron microscopy. The islets were exposed to 3.3, 5.5 or 28 mM glucose with or without corticosterone, progesterone or the receptor ligands A-224817.0 and WAY-161358. Mifepristone was used to block steroid receptors and indomethacin to inhibit prostaglandin synthesis. Corticosterone caused a concentration-dependent decrease of insulin degradation at the lower glucose concentrations. Progesterone effected a concentration-dependent stimulation of insulin degradation. These results were paralleled with changes of the crinophagic activity in the beta-cells. Corticosterone decreased and progesterone increased islet production of prostaglandin E(2). Mifepristone abolished the steroid actions on insulin degradation and prostaglandin production. The effects of corticosterone were mimicked by the selective glucocorticoid receptor modulator A-224817.0, but in contrast to progesterone, the selective progesterone receptor agonist WAY-161358 had no effect on insulin degradation or prostaglandin production. Inhibition of cyclooxygenase blocked insulin degradation. The findings indicate that both corticosterone and progesterone could affect intracellular insulin degradation and Crinophagy solely via the glucocorticoid receptor, and that prostaglandins may have a regulatory role in intracellular turnover of secretory material in pancreatic islet beta-cells.
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Steroid effects on intracellular degradation of insulin and Crinophagy in isolated pancreatic islets.
Molecular and Cellular Endocrinology, 2007Co-Authors: Monica Sandberg, L. A. Håkan BorgAbstract:Abstract Under physiological conditions substantial amounts of hormone may be degraded within endocrine cells by a crinophagic process comprising fusions of secretory granules with lysosomes. Glucocorticoids may stabilise and progesterone destabilise lysosomal membranes. The effects of corticosterone and progesterone on intracellular degradation of insulin and Crinophagy were determined in pancreatic β-cells, and possible pathways mediating these effects were evaluated. Pancreatic islets were isolated from mice, intracellular degradation of insulin was measured by a pulse-chase method, and Crinophagy was studied by electron microscopy. The islets were exposed to 3.3, 5.5 or 28 mM glucose with or without corticosterone, progesterone or the receptor ligands A-224817.0 and WAY-161358. Mifepristone was used to block steroid receptors and indomethacin to inhibit prostaglandin synthesis. Corticosterone caused a concentration-dependent decrease of insulin degradation at the lower glucose concentrations. Progesterone effected a concentration-dependent stimulation of insulin degradation. These results were paralleled with changes of the crinophagic activity in the β-cells. Corticosterone decreased and progesterone increased islet production of prostaglandin E 2 . Mifepristone abolished the steroid actions on insulin degradation and prostaglandin production. The effects of corticosterone were mimicked by the selective glucocorticoid receptor modulator A-224817.0, but in contrast to progesterone, the selective progesterone receptor agonist WAY-161358 had no effect on insulin degradation or prostaglandin production. Inhibition of cyclooxygenase blocked insulin degradation. The findings indicate that both corticosterone and progesterone could affect intracellular insulin degradation and Crinophagy solely via the glucocorticoid receptor, and that prostaglandins may have a regulatory role in intracellular turnover of secretory material in pancreatic islet β-cells.
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Intracellular degradation of insulin and Crinophagy are maintained by nitric oxide and cyclo‐oxygenase 2 activity in isolated pancreatic islets
Biology of the cell, 2006Co-Authors: Monica Sandberg, L. A. Håkan BorgAbstract:Intracellular degradation of insulin and Crinophagy are maintained by nitric oxide and cyclooxygenase-2 activity in isolated pancreatic islets
Gunilla Westermark - One of the best experts on this subject based on the ideXlab platform.
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Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide
Molecular Medicine, 1995Co-Authors: Gunilla Westermark, Michelle Benig Arora, Niles Fox, Raymond Carroll, Shu Jin Chan, Per Westermark, Donald F. SteinerAbstract:Background Human, but not mouse, islet amyloid polypeptide (IAPP) is amyloidogenic. Transgenic mice overexpressing human IAPP in the β cells of the islets of Langerhans should be useful in identifying factors important for the deposition of IAPP as insoluble amyloid fibrils. Materials and Methods Transgenic mice expressing human IAPP were examined using several experimental models for the production of persistent hyperglycemia, as well as for the overstimulation and/or inhibition of β cell secretion. Obesity was induced by aurothioglucose. Persistent hyperglycemia was produced by long-term administration of glucocorticosteroids or by partial pancreatectomy. Inhibition of normal β cell exocytosis by diazoxide administration, with or without concurrent dexamethasone injections, was carried out to increase Crinophagy of secretory granules. The human IAPP gene was also introduced into the db and ob mouse models for diabetes. Finally, isolated islets cultivated in vitro at high glucose concentration were also examined. Results No amyloid deposits were found in the pancreata of any of the animals, either by light microscopy after Congo red staining or by electron microscopy after immunogold labeling with antibodies specific for human IAPP. Aurothioglucose treatment resulted in increased numbers of granules in the β cell and the appearance of large lysosomal bodies without amyloid. However, islets from db and ob mice expressing human IAPP cultivated in vitro in the presence of glucocorticosteroid and/or growth hormone, were found to contain extracellular amyloid deposits reacting with antibodies to human IAPP. Conclusions Oversecretion of human IAPP or increased Crinophagy are not sufficient for amyloid formation. This indicates that other factors must influence amyloid deposition; one such factor may be the local clearance of IAPP.
Beata T. Olejnicka - One of the best experts on this subject based on the ideXlab platform.
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β-Cells, Oxidative Stress, Lysosomal Stability, and Apoptotic/Necrotic Cell Death
Antioxidants & redox signaling, 1999Co-Authors: Beata T. Olejnicka, Arne Andersson, Björn Tyrberg, Helge Dalen, Ulf T. BrunkAbstract:ABSTRACTReactive oxygen intermediates (ROI) may be involved in the destruction of pancreatic β-cells during the development of insulin-dependent diabetes mellitus (IDDM). To investigate the possible role of lysosomes in this process, normal mouse β-cells were cultured as monolayers at d-glucose concentrations of 1.6 (pronounced Crinophagy), 11 or 28 mM (minimal Crinophagy), subjected to a low level of oxidative stress and returned to standard culture conditions. Some cultures were exposed to desferrioxamine (Des) before the oxidative stress. As a result of such stress, many of the cells' lysosomes ruptured with consequent apoptosis or necrosis. Cells kept at 1.6 mM glucose were rich in secretory granules, showed Crinophagy/autophagy, were very sensitive to oxidative stress, and had the least stable lysosomes. Cells kept at 28 mM glucose did not show Crinophagy, contained fewer secretory granules, were less sensitive to oxidative stress, and had more stable lysosomes. Des-treated cells behaved almost as ce...
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A short exposure to a high-glucose milieu stabilizes the acidic vacuolar apparatus of insulinoma cells in culture to ensuing oxidative stress.
APMIS : acta pathologica microbiologica et immunologica Scandinavica, 1997Co-Authors: Beata T. Olejnicka, Karin Öllinger, Ulf T. BrunkAbstract:It was recently suggested that extracellular hydrogen peroxide, after diffusing into and throughout adjacent cells - which may be the case if they have only a weak capacity to degrade hydrogen peroxide - labilizes their lysosomal compartment due to its content of low-molecular-weight iron in redox-active form. The iron would be present as a consequence of normal autophagocytotic degradation of various iron-containing metalloproteins. Beta- and insulinoma cells are especially vulnerable to oxidative stress, since they possess only low capacity to degrade hydrogen peroxide, and, perhaps, since they normally have a certain degree of autophagocytotic degradation of secretory granules with some iron content - Crinophagy. The toxicity to beta cells of oxidative stress, such as an exposure to alloxan, that results in extracellular formation of hydrogen peroxide, is considerably reduced if animals are initially given an intravenous bolus dose of glucose, temporarily bringing up the blood level to about 20 mM. In this study it was demonstrated that already as short an exposure as 30 min to 20 mM D-glucose reduces the sensitivity of HIT and NIT insulinoma cells in culture to a subsequent exposure to hydrogen peroxide. In parallel, exposure to such a high-glucose medium also reduces their desferrioxamine-available amount of iron and, moreover, stabilizes their lysosomal membranes against oxidative stress - thus preventing diffusion to the cytosol of damaging lysosomal contents following iron-catalyzed, Fenton-type, intralysosomal reactions. We suggest that both general autophagocytotic turnover and, in particular, Crinophagy of secretory granules are decreased by an increased glucose concentration of the surrounding milieu, with attendant reduced amounts of intralysosomal low-molecular-weight iron and, thus, diminished sensitivity to oxidative stress.