Insulin Can Rapidly Increase Cell Surface Insulin Binding Capacity in Rat Adipocytes: A Novel Mechanism Related to Insulin Sensitivity

Eriksson, Jan W.; Lönnroth, Peter; Smith, Ulf

doi:10.2337/diab.41.6.707

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…Our data suggest that dexamethasone per se induces a decrease in insulin binding and that this was attributed to a reduction in the number of available cell-surface insulin receptors (28). This could contribute to insensitivity to insulin but probably not to the reduction in maximal insulin response in glucose uptake, since fat cells have a large proportion of spare receptors (48).…”

Section: Discussionmentioning

confidence: 89%

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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

Burén

Liu

Jensen

et al. 2002

European Journal of Endocrinology

137

110

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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 mmol/l) and insulin (10 4 mU/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 ,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 ðP , 0:05Þ compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by ,40%, P , 0:05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a ,75% decrease ðP , 0:001Þ in IRS-1 expression and an increase in IRS-2 (by ,150%, P , 0:001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by ,20%, P , 0:01) and a substantial decrease in PKB content (by ,45%, P , 0:001). Insulin-stimulated PKB phosphorylation was decreased (by ,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 (,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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Section: Discussionmentioning

confidence: 89%

“…Thereafter, the cells (lipocrit 5 -10%) were incubated with ADA (1 U/ml), PIA (1 mmol/l) and 2 mmol/l KCN for 5 min at 37 8C to deplete the cells of ATP and stop receptor internalization and recycling (28). Subsequently, cell-surface binding of 125 I-insulin (0.2 ng/ ml) was carried out for 60 min at 16 8C.…”

Section: I-insulin Binding To Intact Cellsmentioning

confidence: 99%

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

Burén

Liu

Jensen

et al. 2002

European Journal of Endocrinology

137

110

View full text Add to dashboard Cite

show abstract

“…The washing procedure will remove all insulin in the medium and it dissociates . 90% of any cell-bound insulin from the pretreatment period (16). In brief, adipocytes (lipocrit 3-5%) were incubated at 37 8C in Medium 199 without glucose for 15 min with 4% BSA, ADA (1 U/ml), PIA (1 mmol/l) and various insulin concentrations (0 -1000 mU/ml).…”

Section: Glucose Uptake Assaymentioning

confidence: 99%

“…90% of any bound insulin was removed (16). Thereafter, the cells (lipocrit 5 -10%) were incubated with ADA (1 U/ml), PIA (1 mmol/l) and 2 mmol/l KCN for 5 min at 37 8C to deplete the cells of ATP and stop receptor internalisation and recycling (16). Subsequently, cell surface binding of 125 I-insulin (0.2 ng/ml) was carried out for 60 min at 16 8C.…”

Section: I-insulin Binding To Adipocytesmentioning

confidence: 99%

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

et al. 2003

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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 mU/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 , 40%, and shifted the doseresponse 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 ,30 -50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by ,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 , 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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“…It has been also proved that, dexamethasone treatment for longer period may leads to a decrease in insulin binding and that this was attributed to a reduction in the number of available cell-surface insulin receptors[32]. This could contribute to insensitivity to insulin but probably not to the reduction in maximal insulin response in glucose uptake, since fat cells have a large proportion of spare receptors[33]. …”

Section: Discussionmentioning

confidence: 99%

Effects of combination of thiazolidinediones with melatonin in dexamethasone-induced insulin resistance in mice

et al. 2011

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In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia.

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Insulin Can Rapidly Increase Cell Surface Insulin Binding Capacity in Rat Adipocytes: A Novel Mechanism Related to Insulin Sensitivity

Cited by 14 publications

References 26 publications

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

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

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

Effects of combination of thiazolidinediones with melatonin in dexamethasone-induced insulin resistance in mice

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