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. 1993 Feb;91(2):509–513. doi: 10.1172/JCI116229

Abnormal regulation of ribosomal protein S6 kinase by insulin in skeletal muscle of insulin-resistant humans.

J Sommercorn 1, R Fields 1, I Raz 1, R Maeda 1
PMCID: PMC287969  PMID: 8432859

Abstract

Insulin resistance in Pima Indians appears to result from a post-receptor impairment of insulin signal transduction that affects only some responses to insulin. To identify the primary lesion responsible for insulin resistance, we investigated the influence of insulin on ribosomal protein S6 kinase activities in skeletal muscle of insulin-sensitive and insulin-resistant nondiabetic Pima Indians during a 2-h hyperinsulinemic, euglycemic clamp. In sensitive subjects, S6 kinase activity was transiently activated fivefold over basal activity by 45 min of insulin infusion. Although basal activities in the two groups were similar, the response to insulin was delayed and restricted to about threefold over basal in subjects resistant to insulin. Two major S6 kinase activities in extracts of human muscle were resolved by chromatography on Mono Q. Peak 1, which accounted for basal activity owes to an enzyme antigenically related to the 90-kD S6 kinase II, a member of the rsk gene family. The major insulin-stimulated S6 kinase eluted as peak 2 and is antigenically related to a 70-kD S6 kinase. Our results show that insulin resistance impairs signaling to the 70-kD S6 kinase.

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Selected References

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  1. Alcorta D. A., Crews C. M., Sweet L. J., Bankston L., Jones S. W., Erikson R. L. Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase. Mol Cell Biol. 1989 Sep;9(9):3850–3859. doi: 10.1128/mcb.9.9.3850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blenis J., Kuo C. J., Erikson R. L. Identification of a ribosomal protein S6 kinase regulated by transformation and growth-promoting stimuli. J Biol Chem. 1987 Oct 25;262(30):14373–14376. [PubMed] [Google Scholar]
  3. Bogardus C., Lillioja S., Bennett P. H. Pathogenesis of NIDDM in Pima Indians. Diabetes Care. 1991 Jul;14(7):685–690. doi: 10.2337/diacare.14.7.685. [DOI] [PubMed] [Google Scholar]
  4. Bogardus C., Lillioja S., Mott D. M., Hollenbeck C., Reaven G. Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol. 1985 Mar;248(3 Pt 1):E286–E291. doi: 10.1152/ajpendo.1985.248.3.E286. [DOI] [PubMed] [Google Scholar]
  5. Bogardus C., Lillioja S., Mott D., Reaven G. R., Kashiwagi A., Foley J. E. Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest. 1984 Mar;73(3):800–805. doi: 10.1172/JCI111274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Cama A., Patterson A. P., Kadowaki T., Kadowaki H., Siegel G., D'Ambrosio D., Lillioja S., Roth J., Taylor S. I. The amino acid sequence of the insulin receptor is normal in an insulin-resistant Pima Indian. J Clin Endocrinol Metab. 1990 Apr;70(4):1155–1161. doi: 10.1210/jcem-70-4-1155. [DOI] [PubMed] [Google Scholar]
  8. Chan C. P., McNall S. J., Krebs E. G., Fischer E. H. Stimulation of protein phosphatase activity by insulin and growth factors in 3T3 cells. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6257–6261. doi: 10.1073/pnas.85.17.6257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Czech M. P., Klarlund J. K., Yagaloff K. A., Bradford A. P., Lewis R. E. Insulin receptor signaling. Activation of multiple serine kinases. J Biol Chem. 1988 Aug 15;263(23):11017–11020. [PubMed] [Google Scholar]
  10. Debant A., Clauser E., Ponzio G., Filloux C., Auzan C., Contreres J. O., Rossi B. Replacement of insulin receptor tyrosine residues 1162 and 1163 does not alter the mitogenic effect of the hormone. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8032–8036. doi: 10.1073/pnas.85.21.8032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Defronzo R. A. Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes. 1979 Dec;28(12):1095–1101. doi: 10.2337/diab.28.12.1095. [DOI] [PubMed] [Google Scholar]
  12. Dent P., Lavoinne A., Nakielny S., Caudwell F. B., Watt P., Cohen P. The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature. 1990 Nov 22;348(6299):302–308. doi: 10.1038/348302a0. [DOI] [PubMed] [Google Scholar]
  13. Erikson E., Maller J. L. A protein kinase from Xenopus eggs specific for ribosomal protein S6. Proc Natl Acad Sci U S A. 1985 Feb;82(3):742–746. doi: 10.1073/pnas.82.3.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Erikson E., Maller J. L. Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6. J Biol Chem. 1986 Jan 5;261(1):350–355. [PubMed] [Google Scholar]
  15. Erikson R. L. Structure, expression, and regulation of protein kinases involved in the phosphorylation of ribosomal protein S6. J Biol Chem. 1991 Apr 5;266(10):6007–6010. [PubMed] [Google Scholar]
  16. Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Schalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989 Aug 10;321(6):337–343. doi: 10.1056/NEJM198908103210601. [DOI] [PubMed] [Google Scholar]
  17. Fink R. I., Kolterman O. G., Griffin J., Olefsky J. M. Mechanisms of insulin resistance in aging. J Clin Invest. 1983 Jun;71(6):1523–1535. doi: 10.1172/JCI110908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Freymond D., Bogardus C., Okubo M., Stone K., Mott D. Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest. 1988 Nov;82(5):1503–1509. doi: 10.1172/JCI113758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gregory J. S., Boulton T. G., Sang B. C., Cobb M. H. An insulin-stimulated ribosomal protein S6 kinase from rabbit liver. J Biol Chem. 1989 Nov 5;264(31):18397–18401. [PubMed] [Google Scholar]
  20. Jenö P., Ballou L. M., Novak-Hofer I., Thomas G. Identification and characterization of a mitogen-activated S6 kinase. Proc Natl Acad Sci U S A. 1988 Jan;85(2):406–410. doi: 10.1073/pnas.85.2.406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kida Y., Esposito-Del Puente A., Bogardus C., Mott D. M. Insulin resistance is associated with reduced fasting and insulin-stimulated glycogen synthase phosphatase activity in human skeletal muscle. J Clin Invest. 1990 Feb;85(2):476–481. doi: 10.1172/JCI114462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kida Y., Raz I., Maeda R., Nyomba B. L., Stone K., Bogardus C., Sommercorn J., Mott D. M. Defective insulin response of phosphorylase phosphatase in insulin-resistant humans. J Clin Invest. 1992 Feb;89(2):610–617. doi: 10.1172/JCI115627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  24. Lavoinne A., Erikson E., Maller J. L., Price D. J., Avruch J., Cohen P. Purification and characterisation of the insulin-stimulated protein kinase from rabbit skeletal muscle; close similarity to S6 kinase II. Eur J Biochem. 1991 Aug 1;199(3):723–728. doi: 10.1111/j.1432-1033.1991.tb16176.x. [DOI] [PubMed] [Google Scholar]
  25. Lillioja S., Mott D. M., Howard B. V., Bennett P. H., Yki-Järvinen H., Freymond D., Nyomba B. L., Zurlo F., Swinburn B., Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988 May 12;318(19):1217–1225. doi: 10.1056/NEJM198805123181901. [DOI] [PubMed] [Google Scholar]
  26. López-Alarcón L., Mojena M., Monge L., Felíu J. E. Stimulation of pyruvate kinase phosphatase activity by insulin in isolated rat hepatocytes. Biochem Biophys Res Commun. 1986 Jan 14;134(1):292–298. doi: 10.1016/0006-291x(86)90561-9. [DOI] [PubMed] [Google Scholar]
  27. Maeda R., Raz I., Zurlo F., Sommercorn J. Activation of skeletal muscle casein kinase II by insulin is not diminished in subjects with insulin resistance. J Clin Invest. 1991 Mar;87(3):1017–1022. doi: 10.1172/JCI115060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McGuire M. C., Fields R. M., Nyomba B. L., Raz I., Bogardus C., Tonks N. K., Sommercorn J. Abnormal regulation of protein tyrosine phosphatase activities in skeletal muscle of insulin-resistant humans. Diabetes. 1991 Jul;40(7):939–942. doi: 10.2337/diab.40.7.939. [DOI] [PubMed] [Google Scholar]
  29. Moller D. E., Yokota A., Flier J. S. Normal insulin-receptor cDNA sequence in Pima Indians with NIDDM. Diabetes. 1989 Nov;38(11):1496–1500. doi: 10.2337/diab.38.11.1496. [DOI] [PubMed] [Google Scholar]
  30. Mukhopadhyay N. K., Price D. J., Kyriakis J. M., Pelech S., Sanghera J., Avruch J. An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. J Biol Chem. 1992 Feb 15;267(5):3325–3335. [PubMed] [Google Scholar]
  31. Nyomba B. L., Ossowski V. M., Bogardus C., Mott D. M. Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E964–E974. doi: 10.1152/ajpendo.1990.258.6.E964. [DOI] [PubMed] [Google Scholar]
  32. Ponzio G., Contreres J. O., Debant A., Baron V., Gautier N., Dolais-Kitabgi J., Rossi B. Use of an anti-insulin receptor antibody to discriminate between metabolic and mitogenic effects of insulin: correlation with receptor autophosphorylation. EMBO J. 1988 Dec 20;7(13):4111–4117. doi: 10.1002/j.1460-2075.1988.tb03305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Price D. J., Mukhopadhyay N. K., Avruch J. Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor of the p70 S6 kinase. J Biol Chem. 1991 Sep 5;266(25):16281–16284. [PubMed] [Google Scholar]
  34. Price D. J., Nemenoff R. A., Avruch J. Purification of a hepatic S6 kinase from cycloheximide-treated Rats. J Biol Chem. 1989 Aug 15;264(23):13825–13833. [PubMed] [Google Scholar]
  35. Sommercorn J., Krebs E. G. Induction of casein kinase II during differentiation of 3T3-L1 cells. J Biol Chem. 1987 Mar 15;262(8):3839–3843. [PubMed] [Google Scholar]
  36. Tabarini D., Garcia de Herreros A., Heinrich J., Rosen O. M. Purification of a bovine liver S6 kinase. Biochem Biophys Res Commun. 1987 Apr 29;144(2):891–899. doi: 10.1016/s0006-291x(87)80048-7. [DOI] [PubMed] [Google Scholar]
  37. Taylor S. I., Kadowaki T., Kadowaki H., Accili D., Cama A., McKeon C. Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care. 1990 Mar;13(3):257–279. doi: 10.2337/diacare.13.3.257. [DOI] [PubMed] [Google Scholar]
  38. Terao K., Ogata K. Preparation and some properties of active subunits from rat liver ribosomes. Biochem Biophys Res Commun. 1970 Jan 6;38(1):80–85. doi: 10.1016/0006-291x(70)91086-7. [DOI] [PubMed] [Google Scholar]
  39. Thies R. S., Ullrich A., McClain D. A. Augmented mitogenesis and impaired metabolic signaling mediated by a truncated insulin receptor. J Biol Chem. 1989 Aug 5;264(22):12820–12825. [PubMed] [Google Scholar]
  40. Wilden P. A., Backer J. M., Kahn C. R., Cahill D. A., Schroeder G. J., White M. F. The insulin receptor with phenylalanine replacing tyrosine-1146 provides evidence for separate signals regulating cellular metabolism and growth. Proc Natl Acad Sci U S A. 1990 May;87(9):3358–3362. doi: 10.1073/pnas.87.9.3358. [DOI] [PMC free article] [PubMed] [Google Scholar]

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