Regulation of lipid metabolism - Insulin regulation of glycogen metabolism

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Insulin regulation of the glicogen metabolism

Insulin regulates key ferments of glucose uptake, catabolism and glycogen metabolism. Its action insulin realizes by binding to the extracellular domain of the insulin receptor. That results in the activation of the tyrosine kinase activity of the receptor. Following the autophosphorylation, the insulin receptor phosphorylates a number of intracellular substrates,such as IRS-1, IRS-2 (insulin receptor substrate-1 and -2), and Shc and this initiates the intracellular signaling pathways. The two main signaling cascades are H-Ras/ERK and PI3K/AKT pathways [1], [2], [3].

AKT is responsible for the insulin-stimulated translocation of the glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane stimulates andfor glucose uptake [4].

AKT suppresses some ferments of gluconeogenesis and stimulates key ferments if the glucogen metabolism utilizing different signaling pathways.

AKT diminishesthe activity of the transcription factor FKHR (forkhead box O1A) and thereby suppresses synthesis ferments of gluconeogenesis, such glucose-6-phosphatase (G6PT) and phosphoenolpyruvate carboxykinase 2 (PPCKM) [5], [6].

Conversely, AKT stimulates key ferments glycogen metabolism, such as GYS1 and GYS2 (glycogen synthase 1 and 2). AKT phosphorylates and inhibites GSK3beta (glycogen synthase kinase-3) and thereby abolish its inhibitory action on GYS1 and GYS2 [7], [8].

In another pathway, AKT activates PDE3B (phosphodiesterase 3B) that leads to reduce levels of cyclic adenosine monophosphate (cAMP) and to increase level of 5'-Adenosine monophosphate (AMP) [9]. The decrease of cAMP-level supresses cAMP-dependent protein kinase A (PKA) and diminishes inhibitory actions of protein phosphatase inhibitor-1 (IPP-1) on protein phosphotase-1 (PP1 cat). Protein phosphotase-1 in turn dephosphorylates and stimulates GYS1 and GYS2 [10].

The stimulation of Ras/ERK cascade also results to activation protein phosphotase-1 (PP1 cat). Activated p90RSK1 (ribosomal protein S6 kinase, 90kDa) phosphorelates and inhibites another inhibitor of protein phosphotase-1 - PP1G regulatory subunit (protein phosphatase 1, regulatory (inhibitor) subunit 3A) and thereby activates GYS1 and GYS2 [11], [12].



References

  1. Murata H, Hresko RC, Mueckler M
    Reconstitution of phosphoinositide 3-kinase-dependent insulin signaling in a cell-free system. The Journal of biological chemistry 2003 Jun 13;278(24):21607-14
  2. Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D
    Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. The Journal of clinical investigation 2000 Jan;105(2):199-205
  3. Pronk GJ, McGlade J, Pelicci G, Pawson T, Bos JL
    Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. The Journal of biological chemistry 1993 Mar 15;268(8):5748-53
  4. Watson RT, Pessin JE
    Bridging the GAP between insulin signaling and GLUT4 translocation. Trends in biochemical sciences 2006 Apr;31(4):215-22
  5. Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG
    FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. The Journal of biological chemistry 2006 Apr 14;281(15):10105-17
  6. Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M
    Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 2004 Dec 23;432(7020):1027-32
  7. Zhang W, DePaoli-Roach AA, Roach PJ
    Mechanisms of multisite phosphorylation and inactivation of rabbit muscle glycogen synthase. Archives of biochemistry and biophysics 1993 Jul;304(1):219-25
  8. Pugazhenthi S, Khandelwal RL
    Regulation of glycogen synthase activation in isolated hepatocytes. Molecular and cellular biochemistry 1995 Aug-Sep;149-150:95-101
  9. Carmen GY, Víctor SM
    Signalling mechanisms regulating lipolysis. Cellular signalling 2006 Apr;18(4):401-8
  10. Aschenbach WG, Suzuki Y, Breeden K, Prats C, Hirshman MF, Dufresne SD, Sakamoto K, Vilardo PG, Steele M, Kim JH, Jing SL, Goodyear LJ, DePaoli-Roach AA
    The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise. The Journal of biological chemistry 2001 Oct 26;276(43):39959-67
  11. Rodriguez-Viciana P, Sabatier C, McCormick F
    Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Molecular and cellular biology 2004 Jun;24(11):4943-54
  12. Eblen ST, Kumar NV, Shah K, Henderson MJ, Watts CK, Shokat KM, Weber MJ
    Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs. The Journal of biological chemistry 2003 Apr 25;278(17):14926-35

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