The role of atypical and conventional PKC in dehydroepiandrosterone-induced glucose uptake and dexamethasone-induced insulin resistance.
We have reported that both dehydroepiandrosterone (DHEA) and dexamethasone (Dexa) directly activate PKC. In this study, we investigated the effects of these hormones on conventional PKC (cPKC) and atypical PKC (aPKC). DHEA and Dexa directly activated PKCbeta and PKCzeta to the same degree. In rat adipocytes, DHEA and Dexa activated endogenous immunoprecitable PKCzeta to 246 and 164%, respectively, from basal level (100%). In adipocytes, 5 min treatment with DHEA increased phosphatidylinositol 3-kinase (PI 3-kinase) activity in immunoprecipitate with anti-phosphotyrotyrosine antibody to 235%. Preincubation with wortmannin, myristoylated PKCzeta pseudosubstrate, but not with Go6976, abolished DHEA-induced 2-deoxyglucose (DOG) uptake. cPKC inhibitors prevented Dexa-induced insulin resistance. Moreover, DHEA and Dexa increased DOG uptake to 330 and 220%, respectively, in adipocytes overexpressed with wild-type PKCzeta, but not in those overexpressed with dominant negative. These results indicate that DHEA and Dexa activate both cPKC and aPKC, and Dexa-induced cPKC activation may lead to insulin resistance. In contrast, DHEA may mimic or enhance insulin action via PI 3-kinase and aPKC.
Kajita
K
K
Third Department of Internal Medicine, Department of General Medicine, Gifu University School of Medicine, Tsukasa-machi 40, Gifu, 500, Japan.
Ishizuka
T
T
Miura
A
A
Ishizawa
M
M
Kanoh
Y
Y
Yasuda
K
K
D017667:Adipocytes / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000493:pharmacokinetics*; D007211:Indoles / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009227:Myristic Acids / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013997:Time Factors; D014162:Transfection; D000077191:Wortmannin; D000099221:Protein Kinase C zeta
D000276:Adjuvants, Immunologic; D000730:Androstadienes; D000963:Antimetabolites; D002227:Carbazoles; D003687:Dehydroepiandrosterone; D003847:Deoxyglucose; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D005947:Glucose; D007211:Indoles; D007329:Insulin Antagonists; D009227:Myristic Acids; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000077191:Wortmannin; D000099221:Protein Kinase C zeta; C081021:Go 6976