Glucocorticoid-Induced Changes in β-Adrenergic Modulation of Insulin Action in 3T3-L1 Adipocytes
Gross, Jason P.
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In vitro cell models of the insulin resistance that is central to non-insulin-dependent diabetes mellitus are important in defining the molecular mechanisms that may be potential targets for new drugs. Surprisingly, the β-adrenergic agonist isoproterenol induces insulin resistance in primary adipocytes yet potentiates insulin action in 3T3-L1 adipocytes. Pretreatment of 3T3-L1 adipocytes with a glucocorticoid, dexamethasone, converted the insulin potentiating effect of isoproterenol to an attenuation. The objective of this investigation was to define dexamethasone-induced changes in cell signalling that rendered 3T3-L1 adipocytes susceptible to the insulin-attenuating actions of isoproterenol. Dexamethasone-treatment of 3T3-L1 adipocytes did not change either the cell surface abundance and affinity of insulin receptors or the ability of insulin to stimulate receptor autophosphorylation. In contrast, tyrosine phosphorylation of insulin receptor substrate-1 ([RS-1) was severely inhibited in dexamethasone-treated cells. Tyrosine phosphorylated IRS-1 interacts with a variety of signalling molecules, including phophatidylinisotol 3-kinase (P I 3-kinase). Isoproterenol partially inhibited insulindependent activation o fPI 3-kinase in control cells but gave a nearly complete inhibition in dexamethasone-treated cells. Experiments that utilized ~adrenergic antagonists have led us to conclude that isoproterenol responses in control and dexamethasone-treated 3T3-L1 adipocytes are mediated by different β-adrenergic receptor subtypes and involve different post-receptor mechanisms, including increased levels of cyclic AMP and increased activity of protein kinase A (PKA). The attenuation by isoproterenol of insulin signalling in dexamethasone-treated cells occurs at a post-insulin receptor level involving disruption of tyrosine phosphorylation of IRS-1, perhaps as a consequence of phosphorylation of serine/threonine residues in IRS-1 by a cAMP-dependent protein kinase.With honors.