Glucocorticoid-induced insulin resistance in vitro: inhibition of insulin-stimulated methylaminoisobutyric acid uptake.
We have previously developed an in vitro model for the induction of insulin resistance by glucocorticoids using 3T3-L1 fat cells (Grunfeld, Baird, Van Obberghen and Kahn 1981). In this model, glucocorticoid treatment was shown to decrease insulin binding and inhibit the acute stimulation of deoxyglucose uptake by insulin. We now extend the findings in this model to examine insulin stimulated methylaminoisobutyric acid (MAIB) uptake, an event whose expression requires m-RNA and protein synthesis and takes many hours. As previously seen with insulin stimulation of deoxyglucose uptake, one day of exposure to dexamethasone had little effect on insulin stimulation of MAIB uptake. Significant inhibition of insulin-stimulated MAIB uptake was seen after 2 days of exposure, and 3 days were required for the maximum effect of the glucocorticoid. The half-maximal concentration of dexamethasone required for inhibition was 1.6 nM. Exposure to dexamethasone produced a 57% decrease in the maximal response to insulin and a small but consistant shift in the sensitivity to insulin. As seen with the acute effects of insulin, the major locus of glucocorticoid action in inhibiting insulin stimulated MAIB uptake is also after the binding of insulin to its receptor. These data indicate that the inhibitory effects of glucocorticoids on insulin action in fat cells extend to those effects of insulin which require gene expression and are not merely limited to short-term metabolic actions of insulin.
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000621:Aminoisobutyric Acids / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D007700:Kinetics; D051379:Mice
D000621:Aminoisobutyric Acids; D007328:Insulin; C017911:2-(methylamino)isobutyric acid; D003907:Dexamethasone