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1 Department of Physiology, University of Tennessee Health Science Center, Collegeof Medicine, Memphis, TN, USA
2 Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
3 Department of Medicine, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: thomason{at}physio1.utmem.edu.
Although a pharmacological dose of insulin produces a dramatic increase in phosphorylation and activity of Akt isoforms 1 and 2 in mammalian skeletal muscle, few studies have examined the effect of physiological concentrations of insulin on the phosphorylation of Akt-1 and Akt-2 in normal and diabetic tissue. This study examined the patterns of insulin-stimulated Akt isoform phosphorylation and protein expression in muscle biopsies obtained from obese patients with atypical diabetes immediately following a hyperglycemic crisis and again following near-normoglycemic remission. In obese patients with new onset diabetes mellitus presenting with hyperglycemic crisis (plasma glucose 30.5±4.8 mM), in vitro stimulation of vastus lateralis muscle biopsies with 100 µU/ml (0.6 nM) insulin increased insulin receptor phosphorylation 3-fold and Akt-1 phosphorylation on Ser473 2-fold, whereas Akt-2 phosphorylation was not stimulated. Following 10-week intensive insulin therapy that led to near-normoglycemic remission and discontinuation of insulin therapy, both Akt-2 expression and insulinstimulated Akt-2 Ser474 phosphorylation doubled. Hyperglycemic crisis did not affect insulin-stimulated Thr phosphorylation of either Akt-1 or Akt-2. The decreased Akt-2 expression at presentation was accompanied by reduced GLUT4 protein expression and increased expression of enzymes counterregulatory to insulin action. Thus, a physiological concentration of insulin stimulated Akt-1 and Akt-2 phosphorylation in human skeletal muscle in the absence of hyperglycemia, but Akt-2 expression and stimulation appeared to be impaired in muscle of obese patients with atypical diabetes presenting with severe hyperglycemia.
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