Impaired expression and insulin-stimulated phosphorylation of Akt-2 in muscle of obese patients with atypical diabetes.
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 -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 after a hyperglycemic crisis and again after 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 microU/ml (0.6 nM) insulin increased insulin receptor phosphorylation threefold and Akt-1 phosphorylation on Ser(473) twofold, whereas Akt-2 phosphorylation was not stimulated. After 10-wk intensive insulin therapy that led to near-normoglycemic remission and discontinuation of insulin therapy, both Akt-2 expression and insulin-stimulated Akt-2 Ser(474) phosphorylation doubled. Hyperglycemic crisis did not affect insulin-stimulated threonine 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.
Gosmanov
Aidar R
AR
Dept. of Physiology, College of Medicine, Univ. of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163, USA.
Umpierrez
Guillermo E
GE
Karabell
Ana H
AH
Cuervo
Ruben
R
Thomason
Donald B
DB
D000328:Adult; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D051275:Glucose Transporter Type 4; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity; D010766:Phosphorylation / Q000187:drug effects
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human