TI - Glucocorticoids differentially modulate insulin-mediated protein and glycogen synthetic signaling downstream of protein kinase B in rat myocardium . AB - Insulin and protein kinase B ( or Akt ) play critical roles in cardiomyocytic growth and survival . High concentrations of glucocorticoids antagonize insulin's action . To examine whether endogenous glucocorticoids modulate insulin's effect on Akt signaling in the protein and glycogen synthetic pathways in myocardium , we studied three groups of rats ( n = 12 each ) 4 d after either a bilateral adrenalectomy ( ADX ) , ADX with physiological stress dose dexamethasone treatment ( ADX + DEX ) , or a sham operation . Rats received either a saline infusion or a 3 mU/kg.min euglycemic insulin clamp for 3 h . ADX had no effect on myocardial Akt or GSK-3 [glycogen synthase (GS) kinase 3] phosphorylation , but it decreased the phosphorylation of eukaryotic initiation factor 4E binding protein 1 ( 4E-BP1 ) and ribosomal protein S6 kinase ( p70 ( S6K ) ) ( P &lt ; 0.003 for both ) . Insulin enhanced the phosphorylation of Akt ( P &lt ; 0.04 ) , 4E-BP1 ( P &lt ; 0.002 ) , and p70 ( S6K ) ( P &lt ; 0.0001 ) in ADX , but not in sham rats . Dexamethasone restored the levels of 4E-BP1 and p70 ( S6K ) phosphorylation and abrogated the insulin-stimulated Akt , 4E-BP1 , and p70 ( S6K ) phosphorylation . ADX rats had higher GS activity ( P = 0.058 ) and lower glycogen content ( P &lt ; 0.0001 ) than sham rats . GSK-3 phosphorylation after insulin infusion was greater in ADX rats . Insulin did not alter GS activity . Although insulin did not change the glycogen content in sham or ADX rats , it increased glycogen content by approximately 50% in ADX + DEX rats ( P &lt ; 0.02 ) . We conclude that endogenous glucocorticoids differentially modulate the regulation of Akt-4E-BP1/p70 ( S6K ) and Akt-GSK-3-GS signaling pathways in heart by physiologic hyperinsulinemia over a range from deficiency to physiological stress concentrations .