Effect of glucocorticoid receptor antagonist RU 38486 on acute glucocorticoid-induced insulin resistance in rat adipocytes.
We examined the mechanism of acute glucocorticoid-induced insulin resistance in rat adipocytes using the glucocorticoid receptor antagonist RU 38486. Pretreatment with dexamethasone (DEX) and prednisolone for 60 minutes resulted in 50% inhibition of insulin-induced [3H]2-deoxyglucose (DOG) uptake at 10(-8) and 10(-7) mol/L, respectively, in rat adipocytes and 20% and 25% inhibition of insulin-induced [3H]2-DOG uptake, respectively, in soleus muscles. Our previous experiments indicated that DEX and prednisolone alone stimulate protein kinase C (PKC) in rat adipocytes. Accordingly, we examined [3H]DEX binding to PKC from MonoQ column-purified rat brain cytosol. Specific [3H]DEX binding to MonoQ column-purified PKC was observed (kd, 56.8 nmol/L; Bmax, 725 fmol/mg protein). Thus, insulin-induced PKC translocation from the cytosol to the membrane was suppressed by pretreatment with 10(-7) mol/L DEX and 10(-6) mol/L prednisolone for 80 minutes. During treatment with RU 38486 for 60 minutes, there was no change in the glucocorticoid-induced inhibitory effect on insulin-induced [3H]2-DOG uptake and PKC translocation from the cytosol to the membrane. Moreover, pretreatment with RU 38486 for 120 minutes slightly prevented the DEX-mediated inhibition of insulin-induced glucose uptake. These results suggest that acute glucocorticoid-induced insulin resistance may be mainly mediated through the other non-glucocorticoid receptor pathway.
Ishizuka
T
T
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
Nagashima
T
T
Kajita
K
K
Miura
A
A
Yamamoto
M
M
Itaya
S
S
Kanoh
Y
Y
Ishizawa
M
M
Murase
H
H
Yasuda
K
K
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects; D011239:Prednisolone / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013997:Time Factors
D005938:Glucocorticoids; D006727:Hormone Antagonists; D007328:Insulin; D007527:Isoenzymes; D009124:Muscle Proteins; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D003847:Deoxyglucose; D011239:Prednisolone; D011493:Protein Kinase C