• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 1, 1998; 101(7): 1519–1529.
PMCID: PMC508730

Bidirectional modulation of insulin action by amino acids.


Amino acids have been shown to stimulate protein synthesis, inhibit proteolysis, and decrease whole-body and forearm glucose disposal. Using cultured hepatoma and myotube cells, we demonstrate that amino acids act as novel signaling elements in insulin target tissues. Exposure of cells to high physiologic concentrations of amino acids activates intermediates important in the initiation of protein synthesis, including p70 S6 kinase and PHAS-I, in synergy with insulin. This stimulatory effect is largely due to branched chain amino acids, particularly leucine, and can be reproduced by its transamination product, ketoisocaproic acid. Concurrently, amino acids inhibit early steps in insulin action critical for glucose transport and inhibition of gluconeogenesis, including decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2, decreased binding of grb 2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin-stimulated phosphatidylinositol 3-kinase. Taken together, these data support the hypothesis that amino acids act as specific positive signals for maintenance of protein stores, while inhibiting other actions of insulin at multiple levels. This bidirectional modulation of insulin action indicates crosstalk between hormonal and nutritional signals and demonstrates a novel mechanism by which nutritional factors contribute to insulin resistance.

Full Text

The Full Text of this article is available as a PDF (536K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Tessari P, Barazzoni R, Zanetti M, Kiwanuka E, Tiengo A. The role of substrates in the regulation of protein metabolism. Baillieres Clin Endocrinol Metab. 1996 Oct;10(4):511–532. [PubMed]
  • Kimball SR, Yancisin M, Horetsky RL, Jefferson LS. Translational and pretranslational regulation of protein synthesis by amino acid availability in primary cultures of rat hepatocytes. Int J Biochem Cell Biol. 1996 Mar;28(3):285–294. [PubMed]
  • Castellino P, Luzi L, Simonson DC, Haymond M, DeFronzo RA. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis. J Clin Invest. 1987 Dec;80(6):1784–1793. [PMC free article] [PubMed]
  • Bier DM. Intrinsically difficult problems: the kinetics of body proteins and amino acids in man. Diabetes Metab Rev. 1989 Mar;5(2):111–132. [PubMed]
  • May ME, Buse MG. Effects of branched-chain amino acids on protein turnover. Diabetes Metab Rev. 1989 May;5(3):227–245. [PubMed]
  • Louard RJ, Barrett EJ, Gelfand RA. Overnight branched-chain amino acid infusion causes sustained suppression of muscle proteolysis. Metabolism. 1995 Apr;44(4):424–429. [PubMed]
  • Goldberg AL, Odessey R. Oxidation of amino acids by diaphragms from fed and fasted rats. Am J Physiol. 1972 Dec;223(6):1384–1391. [PubMed]
  • Buse MG, Biggers JF, Friderici KH, Buse JF. Oxidation of branched chain amino acids by isolated hearts and diaphragms of the rat. The effect of fatty acids, glucose, and pyruvate respiration. J Biol Chem. 1972 Dec 25;247(24):8085–8096. [PubMed]
  • Flakoll PJ, Wentzel LS, Rice DE, Hill JO, Abumrad NN. Short-term regulation of insulin-mediated glucose utilization in four-day fasted human volunteers: role of amino acid availability. Diabetologia. 1992 Apr;35(4):357–366. [PubMed]
  • Buckspan R, Hoxworth B, Cersosimo E, Devlin J, Horton E, Abumrad N. alpha-Ketoisocaproate is superior to leucine in sparing glucose utilization in humans. Am J Physiol. 1986 Dec;251(6 Pt 1):E648–E653. [PubMed]
  • Tappy L, Acheson K, Normand S, Schneeberger D, Thélin A, Pachiaudi C, Riou JP, Jéquier E. Effects of infused amino acids on glucose production and utilization in healthy human subjects. Am J Physiol. 1992 Jun;262(6 Pt 1):E826–E833. [PubMed]
  • Abumrad NN, Robinson RP, Gooch BR, Lacy WW. The effect of leucine infusion on substrate flux across the human forearm. J Surg Res. 1982 May;32(5):453–463. [PubMed]
  • Pisters PW, Restifo NP, Cersosimo E, Brennan MF. The effects of euglycemic hyperinsulinemia and amino acid infusion on regional and whole body glucose disposal in man. Metabolism. 1991 Jan;40(1):59–65. [PubMed]
  • Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995 Feb 3;270(5):2320–2326. [PubMed]
  • Chen RH, Blenis J. Identification of Xenopus S6 protein kinase homologs (pp90rsk) in somatic cells: phosphorylation and activation during initiation of cell proliferation. Mol Cell Biol. 1990 Jun;10(6):3204–3215. [PMC free article] [PubMed]
  • Folli F, Saad MJ, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest. 1993 Oct;92(4):1787–1794. [PMC free article] [PubMed]
  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. [PubMed]
  • Downward J. Signal transduction. Regulating S6 kinase. Nature. 1994 Sep 29;371(6496):378–379. [PubMed]
  • Brown EJ, Schreiber SL. A signaling pathway to translational control. Cell. 1996 Aug 23;86(4):517–520. [PubMed]
  • Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature. 1994 Jul 7;370(6484):71–75. [PubMed]
  • Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC, Jr, Abraham RT. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 1996 Oct 1;15(19):5256–5267. [PMC free article] [PubMed]
  • Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995 Aug 17;376(6541):599–602. [PubMed]
  • Andjelković M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5699–5704. [PMC free article] [PubMed]
  • Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762–767. [PubMed]
  • Lin TA, Kong X, Saltiel AR, Blackshear PJ, Lawrence JC., Jr Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem. 1995 Aug 4;270(31):18531–18538. [PubMed]
  • Tessari P. Effects of insulin on whole-body and regional amino acid metabolism. Diabetes Metab Rev. 1994 Oct;10(3):253–285. [PubMed]
  • Miotto G, Venerando R, Khurana KK, Siliprandi N, Mortimore GE. Control of hepatic proteolysis by leucine and isovaleryl-L-carnitine through a common locus. Evidence for a possible mechanism of recognition at the plasma membrane. J Biol Chem. 1992 Nov 5;267(31):22066–22072. [PubMed]
  • Katagiri H, Asano T, Ishihara H, Inukai K, Shibasaki Y, Kikuchi M, Yazaki Y, Oka Y. Overexpression of catalytic subunit p110alpha of phosphatidylinositol 3-kinase increases glucose transport activity with translocation of glucose transporters in 3T3-L1 adipocytes. J Biol Chem. 1996 Jul 19;271(29):16987–16990. [PubMed]
  • Sutherland C, O'Brien RM, Granner DK. Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin. Dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression. J Biol Chem. 1995 Jun 30;270(26):15501–15506. [PubMed]
  • Yamamoto-Honda R, Tobe K, Kaburagi Y, Ueki K, Asai S, Yachi M, Shirouzu M, Yodoi J, Akanuma Y, Yokoyama S, et al. Upstream mechanisms of glycogen synthase activation by insulin and insulin-like growth factor-I. Glycogen synthase activation is antagonized by wortmannin or LY294002 but not by rapamycin or by inhibiting p21ras. J Biol Chem. 1995 Feb 10;270(6):2729–2734. [PubMed]
  • Elmendorf JS, Damrau-Abney A, Smith TR, David TS, Turinsky J. Insulin-stimulated phosphatidylinositol 3-kinase activity and 2-deoxy-D-glucose uptake in rat skeletal muscles. Biochem Biophys Res Commun. 1995 Mar 28;208(3):1147–1153. [PubMed]
  • Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem. 1994 Feb 4;269(5):3568–3573. [PubMed]
  • Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994 Jul;14(7):4902–4911. [PMC free article] [PubMed]
  • Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. [PMC free article] [PubMed]
  • Chin JE, Dickens M, Tavare JM, Roth RA. Overexpression of protein kinase C isoenzymes alpha, beta I, gamma, and epsilon in cells overexpressing the insulin receptor. Effects on receptor phosphorylation and signaling. J Biol Chem. 1993 Mar 25;268(9):6338–6347. [PubMed]
  • Traxinger RR, Marshall S. Role of amino acids in modulating glucose-induced desensitization of the glucose transport system. J Biol Chem. 1989 Dec 15;264(35):20910–20916. [PubMed]
  • Rossetti L, Hawkins M, Chen W, Gindi J, Barzilai N. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest. 1995 Jul;96(1):132–140. [PMC free article] [PubMed]
  • Garlick PJ, Grant I. Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids. Biochem J. 1988 Sep 1;254(2):579–584. [PMC free article] [PubMed]
  • Flakoll PJ, Kulaylat M, Frexes-Steed M, Hill JO, Abumrad NN. Amino acids enhance insulin resistance to exogenous glucose infusion in overnight-fasted humans. JPEN J Parenter Enteral Nutr. 1991 Mar-Apr;15(2):123–127. [PubMed]
  • Kimball SR, Jurasinski CV, Lawrence JC, Jr, Jefferson LS. Insulin stimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G. Am J Physiol. 1997 Feb;272(2 Pt 1):C754–C759. [PubMed]
  • Kimball SR, Jefferson LS, Fadden P, Haystead TA, Lawrence JC., Jr Insulin and diabetes cause reciprocal changes in the association of eIF-4E and PHAS-I in rat skeletal muscle. Am J Physiol. 1996 Feb;270(2 Pt 1):C705–C709. [PubMed]
  • Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994 Jun 30;369(6483):756–758. [PubMed]
  • Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995 Oct 5;377(6548):441–446. [PubMed]
  • Lane HA, Fernandez A, Lamb NJ, Thomas G. p70s6k function is essential for G1 progression. Nature. 1993 May 13;363(6425):170–172. [PubMed]
  • Jefferies HB, Reinhard C, Kozma SC, Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441–4445. [PMC free article] [PubMed]
  • Terada N, Patel HR, Takase K, Kohno K, Nairn AC, Gelfand EW. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477–11481. [PMC free article] [PubMed]
  • Giasson E, Meloche S. Role of p70 S6 protein kinase in angiotensin II-induced protein synthesis in vascular smooth muscle cells. J Biol Chem. 1995 Mar 10;270(10):5225–5231. [PubMed]
  • Mèndez R, Myers MG, Jr, White MF, Rhoads RE. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mol Cell Biol. 1996 Jun;16(6):2857–2864. [PMC free article] [PubMed]
  • Tsakiridis T, McDowell HE, Walker T, Downes CP, Hundal HS, Vranic M, Klip A. Multiple roles of phosphatidylinositol 3-kinase in regulation of glucose transport, amino acid transport, and glucose transporters in L6 skeletal muscle cells. Endocrinology. 1995 Oct;136(10):4315–4322. [PubMed]
  • Nakanishi S, Catt KJ, Balla T. A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5317–5321. [PMC free article] [PubMed]
  • Mortimore GE, Wert JJ, Jr, Miotto G, Venerando R, Kadowaki M. Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte. Biochem Biophys Res Commun. 1994 Aug 30;203(1):200–208. [PubMed]
  • Rossetti L, Rothman DL, DeFronzo RA, Shulman GI. Effect of dietary protein on in vivo insulin action and liver glycogen repletion. Am J Physiol. 1989 Aug;257(2 Pt 1):E212–E219. [PubMed]
  • Peret J, Foustock S, Chanez M, Bois-Joyeux B, Assan R. Plasma glucagon and insulin concentrations and hepatic phosphoenolpyruvate carboxykinase and pyruvate kinase activities during and upon adaptation of rats to a high protein diet. J Nutr. 1981 Jul;111(7):1173–1184. [PubMed]
  • Kettelhut IC, Foss MC, Migliorini RH. Glucose homeostasis in a carnivorous animal (cat) and in rats fed a high-protein diet. Am J Physiol. 1980 Nov;239(5):R437–R444. [PubMed]
  • Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994 Oct;94(4):1543–1549. [PMC free article] [PubMed]
  • Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12490–12495. [PMC free article] [PubMed]
  • Moxham CM, Malbon CC. Insulin action impaired by deficiency of the G-protein subunit G ialpha2. Nature. 1996 Feb 29;379(6568):840–844. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...