Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

Physiological Reports

Charles A. Stuart³  Mary E. A. Howell³  Brian M. Cartwright³  Melanie P. McCurry³  Michelle L. Lee¹  Michael W. Ramsey² 

[1] Department of Allied Health, College of Clinical and Rehabilitative Health, East Tennessee State University, Johnson City, Tennessee;Department of Exercise and Sports Science, Clemmer College of Education, East Tennessee State University, Johnson City, Tennessee;Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee

关键词: Insulin receptor substrate‐1;    insulin resistance;    metabolic syndrome;    muscle;   

DOI  :  10.14814/phy2.12236

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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