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Influence of Dexamethasone on Insulin Action: Inhibition of Basal and Insulin-Stimulated Hexose Transport is Dependent on Length of Exposure in Vitro^*

DIANA M. MALCHOFF, BRUCE L. MALOFF, JAMES N. LIVINGSTON and DEAN H. LOCKWOOD

University of Rochester School of Medicine and Dentistry, Department of Medicine, Endocrine- Metabolism Unit, Rochester, New York 14642

Abstract

Rat adipose tissue was exposed to 0.1 µ M dexamethasone in a biochemically defined environment for up to 48 h in order to characterize the cellular alterations in insulin action resulting from long term glucocorticoid treatment. After treatment, adipocytes were isolated by collagenase digestion, and insulin action was determined by acute experiments that examined insulin binding, hexose transport, and glucose metabolism. Neither 2-h nor longer 10- to 48-h exposures to dexamethasone influenced insulin receptor number or affinity. Conversely, steroid treatment directly reduced both hexose transport and glucose metabolism, and the extent of the effects was dependent on the length of exposure. Two-hour treatment with dexamethasone reduced glucose transport and metabolism in the absence but not the presence of insulin. However, after 10- to 48-h exposures to dexamethasone, both basal and insulin-stimulated hexose uptake and glucose metabolism were significantly inhibited. For example, after 24-h treatment, -deoxyglucose transport was reduced by approximately 40%, and significant reductions were also apparent for glucose oxidation and glucose incorporation into lipids. Although the maximal responsiveness to insulin was decreased, the shape of the insulin dose-response curve was not altered by the glucocorticoid treatment; halfmaximal stimulation of treated cells was produced by an insulin concentration of 36 ± 3 µU/ml in comparison to a concentration of 38 ± 3 µU/ml for the control cells. These results indicate that in this in vitro system, dexamethasone exerts significant insulinantagonistic effects on postbinding cellular processes only. Furthermore, this phenomenon follows a step-wise progression, requiring longer periods to influence the insulin-stimulated response when compared to the acute effect of the steroid on basal transport activity. These findings also suggest a difference in the processes that control the activities of basal and insulin-stimulated hexose transport.

Footnotes

^* This work was supported by USPHS Grant AM-20129 and grants from the Juvenile Diabetes Foundation, the Weight Watchers Foundation, Inc., and the Upjohn Company.

Present address: Department of Biochemistry, University of Virginia School of Medicine, Charlottesville, Virginia 22908.

Recipient of NIH Research Career Development Award AM- 00470.

To whom requests for reprints should be addressed

Received June 29, 1981.

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