Role of Glucose Transporters in Glucocorticoid-Induced Insulin Resistance: GLUT4 Isoform in Rat Skeletal Muscle is Not Decreased by Dexamethasone

Haber, Richard S.; Weinstein, S.

doi:10.2337/diab.41.6.728

Cited by 70 publications

(39 citation statements)

References 30 publications

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“…Our findings provide confirmation of previous studies demonstrating that glucocorticoids induce peripheral insulin resistance (2-4) in healthy humans, and they show a pronounced effect of steroids to decrease maximal insulin responsiveness, which was not clearly evident in a previous report (2). This reflects impaired stimulation of glucose uptake in skeletal muscle, which has been shown to result from defects in the recruitment of GLUT4 glucose transporters to the cell surface in animal (12,13) and cell (14 -17) models. Peripheral insulin resistance, together with insulin resistance at the level of the liver (2-4), leads to impaired glucose tolerance, as manifested in the current data by higher glucose and insulin concentrations after an oral glucose challenge.…”

Section: Discussionsupporting

confidence: 81%

“…Studies in animals (5-8) as well as humans (1)(2)(3)(4)9) have shown that glucocorticoid excess results in decreased insulin-stimulated glucose uptake in muscle, and this occurs in the absence of any consistent effect on insulin receptor number or ligand affinity (5,10,11). Additional studies in rodent skeletal muscle indicate that glucocorticoid administration disrupts insulin-mediated recruitment of glucose transporters to the cell surface, without affecting expression of the insulin-responsive GLUT4 transporter isoform (12,13). In cultured cells (14 -16), dexamethasone treatment acutely impairs glucose transporter translocation in response to insulin and, with more chronic exposure, reduces basal glucose transport activity associated with decreased expression of GLUT1 transporters (17).…”

mentioning

confidence: 99%

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Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans

et al. 2002

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Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 ؎ 11 years, BMI 31 ؎ 6.1 kg/m 2) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4 -6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P ‫؍‬ 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P ‫؍‬ 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be establ...

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans

et al. 2002

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“…This glucocorticoid-induced insulin resistance has been demonstrated not only in clinical cases but also in animal experiments (4,5) and in vitro experiments using isolated or cultured cells (6)(7)(8). For example, in skeletal muscle of glucocorticoid-treated rats, increases in glucose uptake induced by insulin, IGF-I, or hypoxia were found to be decreased (9,10). Similar observations were reported in primarily cultured adipocytes (11).…”

supporting

confidence: 70%

Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

et al. 2000

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Glucocorticoids reportedly induce insulin resistance. In this study, we investigated the mechanism of glucocorticoid-induced insulin resistance using 3T3-L1 adipocytes in which treatment with dexamethasone has been shown to impair the insulin-induced increase in glucose uptake. In 3T3-L1 adipocytes treated with dexamethasone, the GLUT1 protein expression level was decreased by 30%, which possibly caused decreased basal glucose uptake. On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. Dexamethasone did not alter tyrosine phosphorylation of insulin receptors, and it significantly decreased protein expression and tyrosine phosphorylation of insulin receptor substrate (IRS)-1. Interestingly, however, protein expression and tyrosine phosphorylation of IRS-2 were increased. To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[ 3 H]glucose uptake impaired by dexamethasone showed no significant improvement. Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110␣, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). Dexamethasone treatment clearly inhibited the increases in glucose uptake produced by these agents. Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation.

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“…Until this type of data are presented we have to conclude that the combined administration of GH and MP does not generally decrease peripheral insulin-stimulated glucose disposal. Such a conclusion is further supported by the fact that neither GH (Cartee & Bohn 1995, Napoli et al 1996 nor dexamethasone (Haber & Weinstein 1992, Venkatesan et al 1996, Dimitriadis et al 1997 change the abundance of the glucose transporter molecule GLUT-4 in muscle cell membranes.…”

Section: Carbohydrate Metabolismsupporting

confidence: 53%

“…The effects of glucocorticoids on glucose metabolism have been reported to be variable (Stojanovska et al 1990, Haber & Weinstein 1992, Ortoft et al 1992, Venkatesan et al 1996. This was probably to do with differences in the type of glucocorticoid used as well as dose and mode of administration.…”

Section: Carbohydrate Metabolismmentioning

confidence: 91%