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- Burén, Jonas, et al.
(författare)
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Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes.
- 2002
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Ingår i: European Journal of Endocrinology. - : European Society of Endocrinology. - 0804-4643 .- 1479-683X. ; 146:3, s. 419-29
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Glucocorticoid excess leads to insulin resistance. This study explores the effects of glucocorticoids on the glucose transport system and insulin signalling in rat adipocytes. The interaction between glucocorticoids and high levels of insulin and glucose is also addressed.DESIGN AND METHODS: Isolated rat adipocytes were cultured for 24 h at different glucose concentrations (5 and 15 mmol/l) with or without the glucocorticoid analogue dexamethasone (0.3 micromol/l) and insulin (10(4) microU/ml). After the culture period, the cells were washed and then basal and insulin-stimulated glucose uptake, insulin binding and lipolysis as well as cellular content of insulin signalling proteins (insulin receptor substrate-1 (IRS-1), IRS-2, phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)) and glucose transporter isoform GLUT4 were measured.RESULTS: Dexamethasone in the medium markedly decreased both basal and insulin-stimulated glucose uptake at both 5 and 15 mmol/l glucose (by approximately 40-50%, P<0.001 and P<0.05 respectively). Combined long-term treatment with insulin and dexamethasone exerted additive effects in decreasing basal, and to a lesser extent insulin-stimulated, glucose uptake capacity (P<0.05) compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by approximately 40%, P<0.05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a approximately 75% decrease (P<0.001) in IRS-1 expression and an increase in IRS-2 (by approximately 150%, P<0.001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by approximately 20%, P<0.01) and a substantial decrease in PKB content (by approximately 45%, P<0.001). Insulin-stimulated PKB phosphorylation was decreased (by approximately 40%, P<0.01) in dexamethasone-treated cells. Dexamethasone did not alter the amount of total cellular membrane-associated GLUT4 protein. The effects of dexamethasone per se on glucose transport and insulin signalling proteins were mainly unaffected by the surrounding glucose and insulin levels. Dexamethasone increased the basal lipolytic rate (approximately 4-fold, P<0.05), but did not alter the antilipolytic effect of insulin.CONCLUSIONS: These results suggest that glucocorticoids, independently of the surrounding glucose and insulin concentration, impair glucose transport capacity in fat cells. This is not due to alterations in GLUT4 abundance. Instead dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 and PKB accompanied by a parallel reduction in insulin-stimulated activation of PKB.
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| 2. |
- Burén, Jonas, et al.
(författare)
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High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes : possible implications for insulin resistance in type 2 diabetes.
- 2003
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Ingår i: European Journal of Endocrinology. - : European Society of Endocrinology. - 0804-4643 .- 1479-683X. ; 148:1, s. 157-67
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins.DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed.RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration.CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.
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| 5. |
- Liu, Hui Rong, et al.
(författare)
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Relationship of myocardial remodeling to the genesis of serum autoantibodies to cardiac beta(1)-adrenoceptors and muscarinic type 2 acetylcholine receptors in rats.
- 2002
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Ingår i: Journal of the American College of Cardiology. - 0735-1097. ; 39:11, s. 1866-73
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We sought to investigate the mechanism responsible for the occurrence of anticardiac receptor autoantibodies. BACKGROUND: Increasing evidence suggests the involvement of autoimmune mechanisms in the pathogenesis of a number of cardiovascular diseases. Among them, the biologic, functional and pathogenic properties of anticardiac receptor antibodies have been extensively investigated. However, the mechanism responsible for the occurrence of anticardiac receptor autoantibodies remains poorly understood. METHODS: Two rat models (aortic banding [AB] and adriamycin [ADR] groups) were constructed. Determination of cardiac function and morphology and T-lymphocyte subtypes, enzyme-linked immunosorbent assay and cardiomyocyte cultures were performed. RESULTS: It was shown, in the AB and ADR groups, that the frequency and titer of autoantibodies to beta(1) and muscarinic type 2 receptors were increased when myocardial remodeling occurred, as evidenced by significant cardiac morphologic changes, deposition of collagen and obvious functional impairment. This suggests that cardiac remodeling itself, in two disparate models of heart failure and cardiomyopathy, was able to trigger the genesis of anticardiac receptor autoantibodies. These autoantibodies have biologic effects similar to those seen in human autoantibodies. They have also shown a characteristic self-growth, as well as a time-course decline, suggesting that a negative finding of anticardiac receptor autoantibodies in sera of patients with heart disease does not necessarily imply that there is no autoimmune reaction involved in the pathogenesis. CONCLUSIONS: Our results demonstrated that myocardial damage was able to trigger the occurrence of an autoimmune reaction, resulting in the genesis of anticardiac receptor autoantibodies with properties similar to those seen in patients with idiopathic dilated cardiomyopathy.
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| 6. |
- Yu, Miao, et al.
(författare)
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SERS study of single-walled carbon nanotubes on silver films deposited on different substrates
- 2003
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Ingår i: Chemical Journal of Chinese Universities / Gao Deng Xue Xiao Hua Xue Xue Bao. - : Chinese Electronic Periodical Services. - 0251-0790. ; 24:6, s. 1285-1288
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Tidskriftsartikel (refereegranskat)abstract
- Surface-enhanced Raman scattering of single-walled carbon nanotubes (SWNTs) on silver films deposited on various substrates, including sapphire, quartz and glass, has been studied systematically. The characteristic features of G-band and D-band have been analyzed and compared with arc discharged and laser ablation samples. D-band is much more sensitive than G-band. The position and the intensity of the G-band in SERS spectra depend on substrates. The peak shift and absolute intensity of G-band on sapphire is obviously larger than that on glass. The contribution of high frequency vibrations to the D-band is also deendent on substrates. Compared to the SWNTs samples with a high semiconducting tube concentration, the sample with high metallic tube concentration has a stronger interaction with silver films.
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