Journal of Inherited Metabolic Disease

, Volume 13, Issue 4, pp 395–410 | Cite as

Mechanisms of blood glucose homeostasis

  • H. -G. Hers
Article

Summary

The mechanisms by which glycogen metabolism, glycolysis and gluconeogenesis are controlled in the liver both by hormones and by the concentration of glucose are reviewed. The control of glycogen metabolism occurs by phosphorylation and dephosphorylation of both glycogen phosphorylase and glycogen synthase catalysed by various protein kinases and protein phosphatases. The hormonal effect is to stimulate glycogenolysis by the intermediary of cyclic AMP, which activates directly or indirectly the protein kinases. The glucose effect is to activate the protein phosphatase system; this occurs by the direct binding of glucose to glycogen phosphorylase which is then a better substrate for phosphorylase phosphatase and is inactivated. Since phosphorylasea is a strong inhibitor of synthase phosphatase, its disappearance allows the activation of glycogen synthase and the initiation of glycogen synthesis. When glycogen synthesis is intense, the concentrations of UDPG and of glucose 6-phosphate in the liver decrease, allowing a net glucose uptake by the liver. Glucose uptake is indeed the difference between the activities of glucokinase and glucose 6-phosphatase. Since the Km of the latter enzyme is far above the physiological concentration of its substrate, the decrease in glucose 6-phosphate concentration proportionally reduces its activity.

The control of glycolysis and of gluconeogenesis occurs mostly at the level of the interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate under the action of phosphofructokinase 1 and fructose 1,6-bisphosphatase. Fructose 2,6-bisphosphate is a potent stimulator of the first of these two enzymes and an inhibitor of the second. It is formed from fructose 6-phosphate and ATP by phosphofructokinase 2 and hydrolysed by a fructose 2,6-bisphosphatase. These two enzymes are part of a single bifunctional protein which is a substrate for cyclic AMP-dependent protein kinase. Its phosphorylation causes the inactivation of phosphofructokinase 2 and the activation of fructose 2,6-bisphosphatase, resulting in the disappearance of fructose 2,6-bisphosphate. The other major effector of these two enzymes is fructose 6-phosphate, which is the substrate of phosphofructokinase 2 and a potent inhibitor of fructose 2,6-bisphosphatase; these properties allow the formation of fructose 2,6-bisphosphate when the level of glycaemia and secondarily that of fructose 6-phosphate is high.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arion, W. J., Wallin, B. K., Lange, A. J. and Ballas, L. M. On the involvement of a glucose 6-phosphate transport system in the function of microsomal glucose 6-phosphatase.Mol. Cell. Biochem. 6 (1975) 75–83Google Scholar
  2. Arion, W. J., Lange, A. J., Walls, H. E. and Ballas L. M. Evidence for the participation of independent translocases for phosphate and glucose 6-phosphate in the microsomal glucose-6-phosphatase system.J. Biol. Chem. 255 (1980) 10396–10406Google Scholar
  3. Berridge, M. J. Inositol trisphosphate and diacylglycerol: two interacting second messengers.Annu. Rev. Biochem. 56 (1987) 159–193Google Scholar
  4. Hers, H. G. Le Métabolisme du Fructose.Editions Arsia, Bruxelles (1957) pp. 200Google Scholar
  5. Hers, H. G. The control of glycogen metabolism in the liver.Annu. Rev. Biochem. 45 (1976) 167–89Google Scholar
  6. Hers, H. G. and Van Schaftingen, E. Fructose 2,6-bisphosphate. Two years after its discovery.Biochem. J. 206 (1982) 1–12Google Scholar
  7. Hers, H. G. and Hue, L. Gluconeogenesis and related aspects of glycolysis.Annu. Rev. Biochem. 52 (1983) 617–653Google Scholar
  8. Hers, H. G., Van Hoof, F. and de Barsy, T. The glycogen storage diseases. In: Scriver, C. R., Beaudet, A. L., Sly W. S. and Valle, D. (eds.),The Metabolic Basis of Inherited Disease, 6th edn., McGraw-Hill, New York, Vol. 1, 1989, 425–452Google Scholar
  9. Kuwajima, M., Newgard, C., Foster, D. W. and McGarry, D. Time course and significance of changes in hepatic fructose 2,6-bisphosphate levels during refeeding of fasted rats.J. Clin. Invest. 74 (1984) 1108–1111Google Scholar
  10. Mvumbi, L., Bollen, M., and Stalmans, W. Calcium ions and glycogen act synergistically as inhibitors of hepatic glycogen-synthase phosphatase.Biochem. J. 232 (1985) 697–704Google Scholar
  11. Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion.Nature 308 (1984) 693–698Google Scholar
  12. Nordlie, R. C., Sukalski, A. and Alvarez, F. L. Responses of glucose 6-phosphate levels to varied glucose loads in the isolated perfused rat liver.J. Biol. Chem. 255 (1980) 1834–1838Google Scholar
  13. Pilkis, S. J., El-Maghrabi, M. R. and Claus, T. H. Hormonal regulation of hepatic gluconeogenesis and glycolysis.Annu. Rev. Biochem. 57 (1988) 755–783Google Scholar
  14. Roach, P. J., Warren, K. R. and Atkinson, D. E. Uridine diphosphate glucose synthase from calf liver: determinants of enzyme activityin vitro.Biochemistry 14 (1975) 544–5450Google Scholar
  15. Seglen, P. O. Autoregulation of glycolysis, respiration, gluconeogenesis and glycogen synthesis in isolated parenchymal rat liver cells under aerobic and anaerobic conditions.Biochem. Biophys. Acta 338 (1974) 317–336Google Scholar
  16. Soskin, S. The liver and carbohydate metabolism.Endocrinology 26 (1940) 297–308Google Scholar
  17. Stalmans, W., Bollen, M., and Mvumbi, L. Control of glycogen synthesis in health and disease.Diabetes/Metab. Rev. 3 (1987) 127–161Google Scholar
  18. Strickland, W. G., Imazu, M., Chrisman, T. D. and Exton, J. H. Regulation of rat liver glycogen synthase. Roles of Ca2+, phosphorylase kinase and phosphorylasea.J. Biol. Chem. 258 (1983) 5490–5497Google Scholar
  19. Tsuboi, K. K., Fukunaga, K. and Petricciani, J. C. Purification and specific kinetic properties of erythrocyte uridine diphosphate glucose pyrophosphorylase.J. Biol. Chem. 244 (1969) 1008–1015Google Scholar
  20. Van Schaftingen, E. Fructose 2,6-bisphosphate.Adv. Enzymol. Relat. Areas Mol. Biol. 59 (1987) 315–395Google Scholar
  21. Van Schaftingen, E. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and by fructose 1-phosphate.Eur. J. Biochem. 179 (1989) 179–184Google Scholar
  22. Van Schaftingen, E. and Hers, H. G. Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate.Biochemistry 78 (1981) 2861–2863Google Scholar
  23. Van Schaftingen, E. and Vandercammen, A. Stimulation of glucose phosphorylation by fructose in isolated hepatocyte.Eur. J. Biochem. 179 (1989) 173–177Google Scholar
  24. Van Schaftingen, E., Jett, M. F., Hue, L. and Hers, H. G. Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.Biochemistry 78 (1981) 3483–3486Google Scholar
  25. Youn, J. H., Youn, M. S. and Bergman, R. N. Synergism of glucose and fructose in net glycogen synthesis in perfused rat livers.J. Biol. Chem. 261 (1986) 15960–15969Google Scholar

Copyright information

© SSIEM and Kluwer Academic Publishers 1990

Authors and Affiliations

  • H. -G. Hers
    • 1
    • 2
  1. 1.Laboratoire de Chimie PhysiologiqueUniversité Catholique de LouvainBelgium
  2. 2.International Institute of Cellular and Molecular PathologyBrusselsBelgium

Personalised recommendations