title: Insulin resistance and muscle insulin receptor substrate-1 serine hyperphosphorylation.
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.
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stuart
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Mary E A
authors.initials: ME
authors.lastname: Howell
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cartwright
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: McCurry
authors.affiliation: Department of Allied Health, College of Clinical and Rehabilitative Health, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lee
authors.affiliation: Department of Exercise and Sports Science, Clemmer College of Education, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ramsey
authors.affiliation: Department of Exercise and Sports Science, Clemmer College of Education, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Stone
keywords: Insulin receptor substrate‐1; insulin resistance; metabolic syndrome; muscle