Effect of alkylating and redox cycling quinones on insulin receptor autophosphorylation

Dobbelsteen, Diels J. van den; Toxopeus, Corike; Holsteijn, C.W.M. van; Nooy, H.A.; Droog, C.I.; Horbach, G. Jean; Noordhoek, J.; Blaauboer, Bas J.

doi:10.1016/0887-2333(94)90017-5

Cited by 5 publications

(6 citation statements)

References 8 publications

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“…and Van den Dobbelsteen et al . that show high doses of peroxinitrite or redox-cycling agents can inhibit InR autophosphorylation [40,41]. It is interesting to note that calorie restriction, which is known to reduce oxidative stress and oxidative damage, has also been shown to increase insulin-induced InR phosphorylation [42,43].…”

Section: Discussionmentioning

confidence: 99%

Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction

Styskal

Nwagwu

Watkins

et al. 2013

Free Radical Biology and Medicine

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Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases (Msr) reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA−/−) are prone to the development of high fat diet-induced insulin resistance and a reduced physiological insulin response compared to high fat-fed wild type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high fat-fed mice show similar reduction in insulin receptor function and the lack of MsrA further diminishes these functions. Together, these data demonstrate for the first time that MsrA plays a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.

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Section: Discussionmentioning

confidence: 99%

Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction

Styskal

Nwagwu

Watkins

et al. 2013

Free Radical Biology and Medicine

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“…On a higher level of biological organization, in situ per fused total rat livers were exposed to SH-blocking reagents (4). On lower levels of biological organization the role of SH-groups in insulin receptor configuration and functioning was studied (6,12,16,17). In addition to biochemical analysis, phasecontrast and electronmicroscopical techniques were performed (Photos.…”

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confidence: 99%

Hepatotoxic Effects of SH-reagents in Human and Rat Hepatocyte Cultures and in situ Perfused Rat Livers.

Boot

1996

Cell Struct. Funct.

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ABSTRACT.Effects organic mercurials (PCMBS, PCMB, mersalyl) an alkylating reagent (NEM), disulphide reagents (DTP, CPDS) and the dithiocarbamate agent DSF (disulfiram) were studied in hepatocyte culture. Cytotoxicity, was on a high level (organic mercurials), moderate (NEM, DTP), or none (DSF, CPDS). The organic mercurials and NEMinduced glutathione depletion. Disulphide compounds were detoxified by metalJothionein binding. Organic mercurials inhibited the cellular glucose uptake. The most prominent effect of NEM, DTPand DSFwas an inhibition of the TCA-cycle. The hepatocellular BSP metabolism was delayed by all tested compounds. Albumin synthesis was stimulated by pyruvate and blocked by PCMBand PCMBS,by inhibiting the hepatocellular amino acid uptake. Phase I and II biotransformation reactions were inhibited by PCMBS and PCMBby direct binding to Cyt. P450 cysteinyl-residues and active sites of UDP-glucuronyltransferases. DSF probably reacts by diminishing the availability of the co factor NADPH. Isolated ALDH(EC 1.2.1.3) was inhibited by all studied compounds. In cellular systems, DSF and the organomercurials inhibited ALDH,thereby reducing the cell's capacity of ethanol catabolism. All tested compounds showed, in low doses, the anabolic ability of insulin mimicking, as demonstrated in a balanced endocrine in vitro testsystem. Morphology. Exposure to NEM,DTP, CPDS, DSF did not result in any morphological alterations in the cell cultures. However, an exposure to PCMBSand PCMB, resulted in extensive bleb-formation, as a result of SHgroup blocking at the cell's outer membrane. It can be concluded, that cultured hepatocytes from human or rat origin, resist an exposure to alkylating and disulphide SH-reagents up to relatively high dose (1.0 mM). However, organic mercury compoundstriggered an extensive bleb formation, as a result of SH-blocking, thereby disturbing the osmotic balance by blocking Na+/K+carriers. Of all tested reagents, organic mercury compounds arose as the most toxic reagents.Hepatocytes in short-term and primary cultures are now being widely used in toxicological studies and offer many advantages, in studying the hepatic metabolism of endogeneous substances and xenobiotics (3-12, 14-17, 29, 33, 35). Cell membranes are intact, a relatively pure cell population can be isolated and the culture medium is in direct contact with the cells and replicate experiments can be performed, using genetically identical material. In addition to biochemical analysis, phasecontrast microcopy and electron-microscopical analysis, are interesting additional techniques. The purpose of the present study, is to describe toxicological data of SH-reagents. Effects of organic mercurials (PCMBS, PCMB, mersalyl) an alkylating reagent (NEM), disulphide reagents (DTP, CPDS) and the dithiocarbamate reagent DSF (disulfiram), were studied in vitro. Effects were compared with standard inhibitors of the physiological parameters studied. As a biological system, rat hepatocyte short term and primary cultures were used as well as humanh...

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“…Tyrosine kinase receptors are involved in mediating insulin signalling. Tyrosine kinase receptor sub-classes (I-VII) are described by Ullrich (40, 41) Spaargaren (37,38) and Van den Dobbelsteen (12,13). The insulin receptor (IR) the insulin-related receptor (IRR) and insulinlike growth factor-1 receptor (IGF-l-R) contain two a and two /3 subunits, linked by disulphide bonds into a heterotetrameric a2/52 structure.…”

Section: The Decreased Glycogen Deposition Induced By 100 Fimmentioning

confidence: 99%

“…The insulin receptor (IR) the insulin-related receptor (IRR) and insulinlike growth factor-1 receptor (IGF-l-R) contain two a and two /3 subunits, linked by disulphide bonds into a heterotetrameric a2/52 structure. The membersof these sub-classes contain two cysteine rich domainsin the extracellular part (12,42). The gene encoding for the IR is on chromosome19 (13).…”

Section: The Decreased Glycogen Deposition Induced By 100 Fimmentioning

confidence: 99%

“…The /5-subunit provides the hydrophobic 23 amino acid stretch, that crosses the cell membrane. This intracellular part contains the important enzymatic tyrosine kinase domain (12,13,37). Finally, after activation of IR's they become clustered and internalized by endocytosis until insulin is dissociated from the receptor by activation of the formed endosome.…”

Section: The Decreased Glycogen Deposition Induced By 100 Fimmentioning

confidence: 99%

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Effects of Sulphydryl Reagents on Receptor-Mediated Hormonal Responses at the Cellular Level: Insulin-mimicking Characteristics of Thiol-blocking Compounds in Rat Hepatocyte Primary Culture.

Boot¹

1996

Cell Struct. Funct.

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The interference of various SH-blocking chemicals with the insulin-controlled regulation of the hepatic carbohydrate metabolism was studied in rat hepatocyte primary cultures. The organic mercurials PCMB, PCMBS,mersalyl the disulphide agents DTP, CPDS, disulfiram and the SH-alkylating reagent NEM were used as experimental SH-blocking model compounds. All studied compounds, except for NEM,induced an increased glycogen deposition comparable with the physiological insulin-induced glycogen-deposition. PCMBSappeared to be the most effective insulin-mimicking anabolic trigger. The action of the insulin molecule itself was potentiated by PCMBSas well as demonstrated by increased glycogen deposition, induced pyruvate kinase (PK) and decreased phosphoenol-pyruvate carboxykinase (PEP-CK) activity. However, cell-exposure to insulin and PCMBSin relatively high doses was destructive, as demonstrated by decreased glycogen levels, most probably as a result of insulin-receptor overstimulation and metabolic stress. Thus, SH-blocking compounds are able to trigger insulin-dependent metabolic processes. The relatively non-permeantorganic mercurial PCMBSproved to be the most effective insulin-mimicking SH-blocking compound.

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Effect of alkylating and redox cycling quinones on insulin receptor autophosphorylation

Cited by 5 publications

References 8 publications

Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction

Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction

Hepatotoxic Effects of SH-reagents in Human and Rat Hepatocyte Cultures and in situ Perfused Rat Livers.

Effects of Sulphydryl Reagents on Receptor-Mediated Hormonal Responses at the Cellular Level: Insulin-mimicking Characteristics of Thiol-blocking Compounds in Rat Hepatocyte Primary Culture.

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