Insulin resistance and muscle insulin receptor substrate-1 serine hyperphosphorylation
Charles A Stuart, Mary E A Howell, Brian M Cartwright, Melanie P McCurry, Michelle L Lee, Michael W Ramsey, Michael H Stone, Charles A Stuart, Mary E A Howell, Brian M Cartwright, Melanie P McCurry, Michelle L Lee, Michael W Ramsey, Michael H Stone
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.
Keywords: Insulin receptor substrate‐1; insulin resistance; metabolic syndrome; muscle.
© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
Figures
References
- Aguirre V., Werner E. D., Giraud J., Lee Y. H., Shoelson S. E., White M. F. 2002. Phosphorylation of Ser307 in insulin receptor substrate‐1 blocks interactions with the insulin receptor and inhibits insulin action. J. Biol. Chem.; 277:1531-1537.
- Boura‐Halfon S., Zick Y. 2009. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am. J. Physiol. Endocrinol. Metab.; 296:E581-E591.
- Bray G. A., Bellanger T. 2006. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine; 29:109-117.
- De F. K., Roth R. A. 1997. Protein kinase C modulation of insulin receptor substrate‐1 tyrosine phosphorylation requires serine 612. Biochemistry; 36:12939-12947.
- Flegal K. M., Carroll M. D., Ogden C. L., Curtin L. R. 2010. Prevalence and trends in obesity among US adults, 1999‐2008. JAMA; 303:235-241.
- Frost R. A., Lang C. H. 2011. mTor signaling in skeletal muscle during sepsis and inflammation: where does it all go wrong? Physiology (Bethesda); 26:83-96.
- Gao Z., Hwang D., Bataille F., Lefevre M., York D., Quon M. J. 2002. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J. Biol. Chem.; 277:48115-48121.
- Grundy S. M., Brewer H. B., Jr, Cleeman J. I., Smith S. C., Jr, Lenfant C. 2004. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation; 109:433-438.
- Hribal M. L., Federici M., Porzio O., Lauro D., Borboni P., Accili D. 2000. The Gly–>Arg972 amino acid polymorphism in insulin receptor substrate‐1 affects glucose metabolism in skeletal muscle cells. J. Clin. Endocrinol. Metab.; 85:2004-2013.
- Johnston A. M., Pirola L., Van O. E. 2003. Molecular mechanisms of insulin receptor substrate protein‐mediated modulation of insulin signalling. FEBS Lett.; 546:32-36.
- Kahn R., Buse J., Ferrannini E., Stern M. 2005. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care; 28:2289-2304.
- Laakso M., Malkki M., Kekalainen P., Kuusisto J., Deeb S. S. 1994. Insulin receptor substrate‐1 variants in non‐insulin‐dependent diabetes. J. Clin. Invest.; 94:1141-1146.
- Layne A. S., Nasrallah S., South M. A., Howell M. E., McCurry M. P., Ramsey M. W. 2011. Impaired muscle AMPK activation in the metabolic syndrome may Attenuate improved insulin action after exercise training. J. Clin. Endocrinol. Metab.; 96:1815-1826.
- LeBrasseur N. K., Walsh K., Arany Z. 2011. Metabolic benefits of resistance training and fast glycolytic skeletal muscle. Am. J. Physiol. Endocrinol. Metab.; 300:E3-E10.
- Li Y., Soos T. J., Li X., Wu J., Degennaro M., Sun X. 2004. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J. Biol. Chem.; 279:45304-45307.
- Liberman Z., Eldar‐Finkelman H. 2005. Serine 332 phosphorylation of insulin receptor substrate‐1 by glycogen synthase kinase‐3 attenuates insulin signaling. J. Biol. Chem.; 280:4422-4428.
- Luan B., Zhao J., Wu H., Duan B., Shu G., Wang X. 2009. Deficiency of a beta‐arrestin‐2 signal complex contributes to insulin resistance. Nature; 457:1146-1149.
- McCurdy C. E., Klemm D. J. 2013. Adipose tissue insulin sensitivity and macrophage recruitment: does PI3K pick the pathway? Adipocyte; 2:135-142.
- Nikoulina S. E., Ciaraldi T. P., Mudaliar S., Mohideen P., Carter L., Henry R. R. 2000. Potential role of glycogen synthase kinase‐3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes; 49:263-271.
- Ozes O. N., Akca H., Mayo L. D., Gustin J. A., Maehama T., Dixon J. E. 2001. A phosphatidylinositol 3‐kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate‐1. Proc. Natl Acad. Sci. USA; 98:4640-4645.
- Polonsky K. S. 2012. The past 200 years in diabetes. N. Engl. J. Med.; 367:1332-1340.
- Reeds D. N., Stuart C. A., Perez O., Klein S. 2006. Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans. Metabolism; 55:1658-1663.
- Saltiel A. R., Kahn C. R. 2001. Insulin signalling and the regulation of glucose and lipid metabolism. Nature; 414:799-806.
- Sigal R. J., Doria A., Warram J. H., Krolewski A. S. 1996. Codon 972 polymorphism in the insulin receptor substrate‐1 gene, obesity, and risk of noninsulin‐dependent diabetes mellitus. J. Clin. Endocrinol. Metab.; 81:1657-1659.
- Stuart C. A., Yin D., Howell M. E. A., Dykes R. J., Laffan J. J., Ferrando A. A. 2006. Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle. Am. J. Physiol. Endocrinol. Metab.; 291:E1067-E1073.
- Stuart C. A., South M. A., Lee M. L., McCurry M. P., Howell M. E., Ramsey M. W. 2013. Insulin responsiveness in metabolic syndrome after eight weeks of cycle training. Med. Sci. Sports Exerc.; 45:2021-2029.
- Wilson E. M., Rotwein P. 2007. Selective control of skeletal muscle differentiation by Akt1. J. Biol. Chem.; 282:5106-5110.
- Yi Z., Langlais P., De Filippis E. A., Luo M., Flynn C. R., Schroeder S. 2007. Global assessment of regulation of phosphorylation of insulin receptor substrate‐1 by insulin in vivo in human muscle. Diabetes; 56:1508-1516.
Source: PubMed