Glucocorticoid-induced insulin resistance associates with activation of protein kinase C isoforms
Introduction
It is well known that glucocorticoids reduce insulin effects in insulin-sensitive tissues. Despite numerous in vivo and in vitro investigations, the precise mechanism involved remains controversial. Recently, insulin-induced intracellular signalling pathways have been elucidated. Upon insulin binding to an insulin receptor α subunit, tyrosine kinase is activated in a receptor β subunit [1], which phosphorylates insulin receptor substrate-1 (IRS-1) [2]. The association of a p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with tyrosine phosphorylated IRS-1 through SH2 domains activates a catalytic subunit of PI 3-kinase [3]. However, glucocorticoid-induced insulin resistance cannot be fully explained by these insulin signalling steps. Dexamethasone increases insulin receptor protein levels, IRS-1 protein and IRS-1 phosphorylation and PI 3-kinase activity in Fao hepatoma cells [4]. We have shown that pretreatment with glucocorticoids for 60 min suppresses insulin-stimulated [3H] 2-deoxyglucose (DOG) uptake in rat adipocytes and soleus muscle [5], which is not prevented by the specific glucocorticoid antagonist, RU38486 [6], [7]. On the other hand, glucocorticoids activate protein kinase C (PKC) in rat adipocytes and soleus muscle [5]. We have also reported that dehydroepiandrosterone (DHEA) alone provoked [3H] 2-DOG uptake, and increased insulin-induced [3H] 2-DOG uptake [8]. DHEA also directly activates PKC. We could not explain the mechanisms of the opposite effects of these steroid hormones. Recently, the role of PKC in insulin signalling has been clarified. Diacylglycerol (DAG)-insensitive, atypical PKCs (ζ and λ) act as downstream effectors of PI 3-kinase, and contribute to the activation of GLUT4 translocation [9], [10]. In contrast, DAG-sensitive, conventional PKCs (α and β) and novel PKCs (δ, ε, η and θ) reduce insulin receptor tyrosine kinase activity, and impair insulin action [11]. These data suggest that the role of PKC in an insulin signalling network is alternatively regulated. In this study, we have investigated the effects of glucocorticoid on each PKC isoform to further clarify the mechanism of glucocorticoid-induced insulin resistance.
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Materials and methods
[3H] Dexamethasone, [γ-32P] ATP, and [1,2-3H] 2-DOG ([3H] 2-DOG) were purchased from New England Nuclear (Boston, MA). Dexamethasone, prednisolone, phosphatidylserine (PS), diolein, histone (type III-S), phenylmethylsulfonyl fluoride (PMSF), leupeptin, BSA and ATP were purchased from Sigma (St. Louis, MO). Anti-PKC α and β antibodies were purchased from Gibco (Grand Island, NY). Anti-PKC ζ antibody was purchased from Santa Cruz (Santa Cruz, CA). LY379196 was a kind gift from Eli Lily
Effect of various steroid hormones and inhibitors on [3H] 2-DOG uptake
As shown in Fig. 1A, 10 nM insulin and 10−6 M TPA, but not 10−6 M dexamethasone alone, increased [3H] 2-DOG uptake in rat adipocytes. Pretreatment with 10−7 M dexamethasone, 10−6 M prednisolone, 10−6 and 10−5 M corticosterone for 60 min reduced insulin-stimulated [3H] 2-DOG uptake. Although the inhibitory effects of 10−7 M dexamethasone and 10−6 M prednisolone were larger than 10−6 M corticosterone (P<.05), no difference was observed when compared with 10−5 M corticosterone. Treatment with 10−6
Discussion
The classical model in which steroid hormone actions are mediated by a regulation of gene expression has been accepted. Recently, nonclassical actions of steroids have been proposed in research on neurosteroids [14]. This evidence indicates that steroid hormones can act without gene transcription. Interestingly, Klein et al. [15] have also reported that dexamethasone directly stimulated PKC in T51B rat liver cells. Recently, Slater et al. [16] have reported that 1,25-dihydroxyvitamine D3
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