Abstract
Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss.
Highlights
After decades with a stable prevalence of obesity in the United States, there has been a steady increase in adult obesity rates beginning the 1980s (Flegal et al 2010)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
Fasting serum glucose was higher in the metabolic syndrome group
Summary
After decades with a stable prevalence of obesity in the United States, there has been a steady increase in adult obesity rates beginning the 1980s (Flegal et al 2010). Strength training exerts its effect on muscle fiber hypertrophy through activation of mTOR and resultant phosphorylation of downstream targets (Frost and Lang 2011), but mTOR-mediated phosphorylation of IRS-1 Ser636 inhibits insulin action in mice (Ozes et al 2001) These studies of IRS-1 phosphorylation in mice suggest that the obesity of the metabolic syndrome might result in insulin resistance via obesity-related chronic inflammation and activation of the JNK1 pathway and the IKKNFkB cascade causing serine phosphorylation of IRS-1 at Ser307 and Ser636. The studies reported here evaluated the phosphorylation status by immunoblots of muscle IRS-1 at key serines in untrained metabolic syndrome subjects and quantified those again post training. Thirty-two volunteers (including 22 metabolic syndrome subjects) participated in increasing intensity strength training without weight loss for 8 weeks as previously described (Layne et al 2011). Statistical procedures were performed using SigmaPlot version 12.2 from Systat Software (San Jose, CA)
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