Glucocorticoid-Induced Changes in β-Adrenergic Modulation of Insulin Action in 3T3-L1 Adipocytes
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Authors
Gross, Jason P.
Issue Date
1996
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
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.
With honors.
Description
vi, 68 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.