Glucocorticoids differentially modulate insulin-mediated protein and glycogen synthetic signaling downstream of protein kinase B in rat myocardium.
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 < 0.003 for both). Insulin enhanced the phosphorylation of Akt (P < 0.04), 4E-BP1 (P < 0.002), and p70(S6K) (P < 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 < 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 < 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.
Wu
Yangsong
Y
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Barrett
Eugene J
EJ
Long
Wen
W
Liu
Zhenqi
Z
D000315:Adrenalectomy; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000378:metabolism
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D003907:Dexamethasone; D006003:Glycogen; D006006:Glycogen Synthase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3