Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Regulation of Hepatic Glucose Uptake

Roy Taylor, Gerald I. Shulman

10.1002/cphy.cp070226

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Homeostatic Mechanisms
1.1 Overview
1.2 Insulin
1.3 Glucagon
1.4 Noninsulin/Glucagon Regulation of Hepatic Glucose Production
2 Metabolism in the Postprandial State
2.1 Overview
2.2 Hepatic Glycogen Storage after Eating
2.3 Source of Glucose Carbon for Glycogen Synthesis
2.4 Modulation of Hepatic Glucose Uptake by a Portal Signal
2.5 Turnover of Liver Glycogen Stores
2.6 Normal Diurnal Fluctuation in Hepatic Glycogen Content
2.7 Effect of Eating on Hepatic Glucose Production
3 Metabolism in the Postabsorptive State
3.1 Overview
3.2 Gluconeogenesis
3.3 Glycogenolysis
3.4 Early Adaptation to Starvation
4 Nature's Experiments
4.1 Glycogen Storage Disease
4.2 Diabetes
4.3 Cirrhosis
4.4 Pregnancy
Figure 1. Figure 1.

Insulin dose–response curve for glycogen synthesis, as measured by MRS. Data were obtained under conditions of glucagon suppression and intravenous glucose. Solid symbols represent data from Roden et al. 104, open circles represent data from Cline et al. 15, and open triangles represent data from Magnusson et al. 69.

[From Roden et al. 104 with permission.]
Figure 2. Figure 2.

Separate effects of high glucose (10 mmol/l) and high insulin (400 pmol/l) in regulating glycogen synthase and glycogen phosphorylase under conditions of glucagon suppression. Glycogen synthase flux, glycogen phosphorylase flux, and hepatic glycogen cycling are expressed as millimoles per liter of liver per minute. HGP is expressed as percentage suppression from the preinfusion basal state. The effect of glucose in inhibiting glycogen phosphorylase flux and the effect of insulin in stimulating glycogen synthase flux are clearly seen.

[Data plotted from Petersen et al. 90.]
Figure 3. Figure 3.

In a group of healthy subjects, plasma insulin was maintained at ˜60 pM while plasma glucagon was elevated as shown (bottom panel). HGP increased from ˜12 to ˜28 μmol per kilogram of body weight per minute within 30 min, causing a rise in plasma glucose (middle panel). The change in HGP was almost entirely accounted for by glycogenolysis (93% of HGP during the first 120 min).

[From Magnussen et al. 68 with permission.]
Figure 4. Figure 4.

Physiological changes in a group of eight young healthy subjects following ingestion of a mixed meal (824 kcal; 67.3% carbohydrate as glucose, 18.5% fat, 14.2% protein). Concurrent changes in the liver glycogen concentration were measured by 13C‐NMR spectroscopy (upper panel), hepatic glucose output (middle panel), and the plasma glucagon/insulin ratio after the standard mixed meal. Note that both plasma insulin and glucagon rose sharply to peak 30 min after eating but that the much greater rise in insulin concentration brought about the change in molar ratio (lower panel).

[From Taylor et al. 118 with permission.]
Figure 5. Figure 5.

The relationship between net hepatic glucose uptake and the hepatic sinusoidal insulin concentration with (▪) or without (□) portal glucose delivery in 42 h fasted conscious dogs. The plasma glucagon concentration was kept constant, and the insulin concentration was varied during somatostatin infusion. The load of glucose reaching the liver was twofold basal and was equal in the two protocols.

[Data taken from Myers et al. 79.]
Figure 6. Figure 6.

The concentration of liver glycogen is subject to a degree of autoregulation. This is demonstrated by the relationship between liver glycogen concentration and net hepatic glycogenolysis.

[Data taken from references 70 and 106; figure from Magnussen et al. 69 with permission.]
Figure 7. Figure 7.

Time course of change in liver glycogen concentration during a day in which three isocaloric meals (60% carbohydrate, 20% protein, 20% fat; total 35 kcal/kg/day) were taken by healthy adult subjects.

[From Taylor and Shulman 121 with permission).]
Figure 8. Figure 8.

Changes in endogenous and exogenous glucose following ingestion of a mixed meal (824 kcal; 67.3% carbohydrate as glucose, 18.5% fat, 14.2% protein). Exogenous glucose was traced by inclusion of 3 g of [2‐2H]glucose in the meal. By stepwise variation in the rate of infusion of [3‐3H]glucose, endogenous specific activity was maintained constant. Upper panel: Time course of change in the endogenous (open circle) and exogenous (solid circle) components of total plasma glucose concentration. Middle panel: Time course of endogenous glucose (open circle) and [3‐3H]glucose radiotracer (triangle) concentration expressed as a percentage of the respective basal levels. Lower panel: Relative constancy of endogenous glucose specific activity.

[From Taylor et al. 118 with permission.]
Figure 9. Figure 9.

Diagrammatic representation of whole body fuel metabolism in the overnight fasted state. Even though no significant glucose uptake is occurring under the influence of insulin in any tissue, maintenance of basal plasma insulin level is crucial to restrain adipose tissue lipolysis, maintain muscle glycogen in storage, and restrain ketogenesis.

[From Shulman et al. 110 with permission.]
Figure 10. Figure 10.

Change in contribution to HGP of glycogenolysis and gluconeogenesis in normal subjects during a prolonged fast. Plasma glucose levels averaged 5.1, 4.7, 3.7, and 3.5 mmol/l at each time point. The rate of gluconeogenesis was derived from isotopic measurement of HGP and MRS measurement of the rate of decline in liver glycogen concentration. In the lower panel, the absolute rate of gluconeogenesis is shown as a solid bar.

[Data taken from Rothman et al. 106 and Petersen et al. 91.]


Figure 1.

Insulin dose–response curve for glycogen synthesis, as measured by MRS. Data were obtained under conditions of glucagon suppression and intravenous glucose. Solid symbols represent data from Roden et al. 104, open circles represent data from Cline et al. 15, and open triangles represent data from Magnusson et al. 69.

[From Roden et al. 104 with permission.]


Figure 2.

Separate effects of high glucose (10 mmol/l) and high insulin (400 pmol/l) in regulating glycogen synthase and glycogen phosphorylase under conditions of glucagon suppression. Glycogen synthase flux, glycogen phosphorylase flux, and hepatic glycogen cycling are expressed as millimoles per liter of liver per minute. HGP is expressed as percentage suppression from the preinfusion basal state. The effect of glucose in inhibiting glycogen phosphorylase flux and the effect of insulin in stimulating glycogen synthase flux are clearly seen.

[Data plotted from Petersen et al. 90.]


Figure 3.

In a group of healthy subjects, plasma insulin was maintained at ˜60 pM while plasma glucagon was elevated as shown (bottom panel). HGP increased from ˜12 to ˜28 μmol per kilogram of body weight per minute within 30 min, causing a rise in plasma glucose (middle panel). The change in HGP was almost entirely accounted for by glycogenolysis (93% of HGP during the first 120 min).

[From Magnussen et al. 68 with permission.]


Figure 4.

Physiological changes in a group of eight young healthy subjects following ingestion of a mixed meal (824 kcal; 67.3% carbohydrate as glucose, 18.5% fat, 14.2% protein). Concurrent changes in the liver glycogen concentration were measured by 13C‐NMR spectroscopy (upper panel), hepatic glucose output (middle panel), and the plasma glucagon/insulin ratio after the standard mixed meal. Note that both plasma insulin and glucagon rose sharply to peak 30 min after eating but that the much greater rise in insulin concentration brought about the change in molar ratio (lower panel).

[From Taylor et al. 118 with permission.]


Figure 5.

The relationship between net hepatic glucose uptake and the hepatic sinusoidal insulin concentration with (▪) or without (□) portal glucose delivery in 42 h fasted conscious dogs. The plasma glucagon concentration was kept constant, and the insulin concentration was varied during somatostatin infusion. The load of glucose reaching the liver was twofold basal and was equal in the two protocols.

[Data taken from Myers et al. 79.]


Figure 6.

The concentration of liver glycogen is subject to a degree of autoregulation. This is demonstrated by the relationship between liver glycogen concentration and net hepatic glycogenolysis.

[Data taken from references 70 and 106; figure from Magnussen et al. 69 with permission.]


Figure 7.

Time course of change in liver glycogen concentration during a day in which three isocaloric meals (60% carbohydrate, 20% protein, 20% fat; total 35 kcal/kg/day) were taken by healthy adult subjects.

[From Taylor and Shulman 121 with permission).]


Figure 8.

Changes in endogenous and exogenous glucose following ingestion of a mixed meal (824 kcal; 67.3% carbohydrate as glucose, 18.5% fat, 14.2% protein). Exogenous glucose was traced by inclusion of 3 g of [2‐2H]glucose in the meal. By stepwise variation in the rate of infusion of [3‐3H]glucose, endogenous specific activity was maintained constant. Upper panel: Time course of change in the endogenous (open circle) and exogenous (solid circle) components of total plasma glucose concentration. Middle panel: Time course of endogenous glucose (open circle) and [3‐3H]glucose radiotracer (triangle) concentration expressed as a percentage of the respective basal levels. Lower panel: Relative constancy of endogenous glucose specific activity.

[From Taylor et al. 118 with permission.]


Figure 9.

Diagrammatic representation of whole body fuel metabolism in the overnight fasted state. Even though no significant glucose uptake is occurring under the influence of insulin in any tissue, maintenance of basal plasma insulin level is crucial to restrain adipose tissue lipolysis, maintain muscle glycogen in storage, and restrain ketogenesis.

[From Shulman et al. 110 with permission.]


Figure 10.

Change in contribution to HGP of glycogenolysis and gluconeogenesis in normal subjects during a prolonged fast. Plasma glucose levels averaged 5.1, 4.7, 3.7, and 3.5 mmol/l at each time point. The rate of gluconeogenesis was derived from isotopic measurement of HGP and MRS measurement of the rate of decline in liver glycogen concentration. In the lower panel, the absolute rate of gluconeogenesis is shown as a solid bar.

[Data taken from Rothman et al. 106 and Petersen et al. 91.]
References
 1. Adkins, B. A., S. R. Myers, G. K. Hendrick, P. E. Williams, R. W. Stevenson, and A. D. Cherrington. Importance of the route of intravenous glucose delivery on hepatic glucose balance in the conscious dog. J. Clin. Invest. 79: 557–565, 1987.
 2. Adkins‐Marshall, B. A., S. R. Myers, G. K. Hendrick, P. E. Williams, K. Triebwasser, B. Flyod, and A. D. Cherrington. Interaction between insulin and glucose delivery route in regulation of net hepatic glucose uptake in conscious dogs. Diabetes 39: 87–95, 1990.
 3. Adkins‐Marshall, B., M. J. Pagliassotti, J. R. Asher, C. C. Connolly, D. W. Neal, P. E. Williams, S. R. Myers, G. K. Hendrick, R. B. Adkins, and A. D. Cherrington. Role of hepatic nerves in response of liver to intraportal glucose delivery in dogs. Am. J. Physiol. 262: E679–E686, 1992.
 4. Agius, L., M. Peak, and K. G. M. M. Alberti. Regulation of glycogen synthesis from glucose and gluconeogenic precursors by insulin in periportal and perivenous rat hepatocytes. Biochem. J. 266: 91–102, 1990.
 5. Agius, L., D. Tosh, and M. Peak. The contribution of pyruvate cycling to loss of [6–3H]glucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes. Biochem. J. 289: 255–262, 1993.
 6. Argyraki, M., P. D. Wright, C. W. Venables, G. Proud, and R. Taylor. Study of human skeletal muscle in vitro: effect of NEFA supply on glucose storage. Metabolism 38: 1183–1187, 1989.
 7. Assel, B., K. Rossi, and S. Kalhan. Glucose metabolism during fasting through human pregnancy: comparison of tracer method with respiratory calorimetry. Am. J. Physiol. 265: E351–E356, 1993.
 8. Bergman, R. N., J. R. Beir, and P. M. Hourigan. Intraportal glucose infusion matched to oral glucose absorption: lack of evidence for “gut factor” involvement in hepatic glucose storage. Diabetes 31: 27–35, 1982.
 9. Boden, G., X. Chen, J. Ruiz, J. V. White, and L. Rossetti. Mechanism of fatty acid induced inhibition of glucose uptake. J. Clin. Invest. 93: 2438–2446, 1994.
 10. Byrne, B. M., M. D. Gillmer, R. C. Turner, and A. Aynsley‐Green. Glucose homeostasis in adulthood and in pregnancy in a patient with hepatic glycogen synthetase deficiency. Br. J. Obstet. Gynecol. 102: 931–933, 1995.
 11. Cahill, G. F. J.. Physiology of insulin in man. Diabetes 20: 785–799, 1971.
 12. Cherrington, A. D., D. Edgerton, and D. K. Sindelar. The direct and indirect effects of insulin on hepatic glucose production in vivo. Diabetologia 41: 987–996, 1998.
 13. Cherrington, A. D., P. Williams, G. I. Shulman, and W. W. Lacy. Differential time course of glucagon's effect on glycogenolysis and glycogenolysis in the concious dog. Diabetes 30: 180–187, 1981.
 14. Chiasson, J. L., W. W. Liljenquist, W. W. Lacy, A. S. Jennings, and A. D. Cherrington. Gluconeogenesis: methodological approaches in vivo. Federation Proc. 36: 229–235, 1977.
 15. Cline, G. W., D. L. Rothman, I. Magnusson, L. D. Katz, and G. I. Shulman. GI. 13C‐nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin‐dependent diabetes mellitus. J. Clin. Invest. 94: 2369–2376, 1994.
 16. Clore, J. N., P. S. Glickman, J. E. Nestler, and W. G. Blackard. In vivo evidence for hepatic autoregulation during FFA‐stimulated gluconeogenesis in normal humans. Am. J. Physiol. 261: E425–E429, 1991.
 17. Cobelli, C., A. Mari, and E. Ferrannini. Non‐steady state: error analysis of Steel's model and developments for glucose kinetics. Am. J. Physiol. 252: E679–E689, 1987.
 18. Collins, P. J., M. Horowitz, and B. E. Chatterton. Proximal, distal and total stomach emptying of a digestible solid meal in normal subjects. Br. J. Radiol. 61: 12–18, 1988.
 19. Consoli, A., F. Kennedy, J. Miles, and J. Gerich. Determination of Krebs cycle metabolic carbon exchange in vivo and its use to estimate the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output in man. J. Clin. Invest. 80: 1303–1310, 1987.
 20. Consoli, A., N. Nurjhan, F. Capani, and J. Gerich. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38: 550–557, 1989.
 21. Curnow, R. T., E. J. Rayfield, D. T. George, T. V. Zenzer, and F. de Rubertis. Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration. Am. J. Physiol. 228: 80–87, 1975.
 22. De Fronzo, R. A.. The triumvirate: b‐cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37: 667–687, 1988.
 23. De Fronzo, R. A., E. Ferrannini, R. Hendler, J. Wahren, and P. Felig. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc. Natl. Acad. Sci. USA 75: 5173–5177, 1978.
 24. De Fronzo, R. A., E. Ferrannini, and D. C. Simonson. Fasting hyperglycaemia in non‐insulin dependent diabetews mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387–395, 1989.
 25. De Fronzo, R. A., D. Simonson, and E. Ferrannini. Hepatic and peripheral insulin resistance: a common feature of type 2 (non‐insulin dependent) and type 1 (insulin dependent) diabetes mellitus. Diabetologia 23: 313–319, 1982.
 26. Elia, M., P. Folmer, P. A. Schlatmann, A. Goren, and S. Austin. Carbohydrate, fat and protein metabolism in muscle and in the whole body after mixed meal ingestion. Metabolism 37: 542–551, 1988.
 27. Felig, P., E. Marliss, O. E. Owen, and C. F. J. Cahill. Role of substrate in the regulation of hepatic gluconeogenesis in fasting man. Adv. Enzyme Regul. 7: 41–46, 1969.
 28. Felig, P., J. Wahren, and R. Hendler. Influence of oral glucose ingestion on splanchnic glucose and gluconeogenic substrate metabolism in man. Diabetes 24: 468–475, 1975.
 29. Ferrannini, E., O. Bjorkman, G. A. Reichard, A. Pilo, M. Olsson, and J. Wahren. The disposal of an oral glucose load in healthy subjects: A quantitative study. Diabetes 34: 580–588, 1985.
 30. Ferrannini, E., R. A. de Fronzo, and R. S. Sherwin. Transient hepatic response to glucagon in man: the role of insulin and hyperglycemia. Am. J. Physiol. 242: E72–E81, 1982.
 31. Ferrannini, E., J. Wahren, P. Felig, and R. De Fronzo. The role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man. Metabolism 29: 28–35, 1980.
 32. Finegood, D. T., R. N. Bergman, and M. Vranic. Estimation of endogenous glucose production during hyperinsulinemic‐euglycemic glucose clamps: comparison of unlabelled and labelled exogenous glucose infusates. Diabetes 36: 914–924, 1987.
 33. Fraze, E., C. C. Donner, A. L. M. Swislocki, Y.‐A. M. Chiou, Y.‐D. I. Chen, and G. M. Reaven. Ambient plasma free fatty acid concentrations in non‐insulin dependent diabetes mellitus: evidence for insulin resistance. J. Clin. Endocrinol. Metab. 61: 807–811, 1985.
 34. Friedman, J. E., J. F. Caro, W. J. Pories, J. L. Azevedo, Jr., and G. L. Dohm. Glucose metabolism in incubated human muscle: effect of obesity and non‐insulin‐dependent diabetes mellitus. Metabolism 43: 1047–1054, 1994.
 35. Froguel, P., H. Zouali, N. Vionnet, G. Velho, M. Vaxillaire, F. Sun, S. Lesage, M. Stoffel, J. Takeda, and P. Passa. Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. New Engl. J. Med. 328: 697–702 1993.
 36. Fryburg, D. A., E. J. Barrett, R. J. Louard, and R. A. Gelfand. Effect of starvation on human muscle protein metabolism and its response to insulin. Am. J. Physiol. 259: E477–E482, 1990.
 37. Fulcher, G. R., M. Walker, C. Catalano, L. Agius, and K. G. M. M. Alberti. Metabolic effects of suppressions of non‐esterified fatty acid levels with acipimox in obese NIDDM subjects. Diabetes 41: 1400–1408, 1992.
 38. Gillmer, M. D. G., S. M. Holmes, and M. Moore. Diabetes in pregnancy: obstetric management. In: Carbohydrate Metabolism in Pregnancy and the Newborn, 3rd ed., edited by H. W. Sutherland and J. M. Stowers. Edinburgh: Churchill Livingstone, p. 102–118, 1984.
 39. Halimi, S., F. Assimacopoulos‐Jeannet, J. Terrettaz, and B. Jeanrenaud. Differential effect of steady‐state hyperinsulinaemia and hyperglycaemia on hepatic glycogenolysis and glycolysis in rats. Diabetologia 30: 268–272, 1987.
 40. Hauguel, S., M. Gilbert, and Girard, J.. Pregnancy induced insulin resistance in liver and skeletal muscles of the conscious rabbit. Am. J. Physiol. 252: E165–E169, 1987.
 41. Havel, R. J., E. O. Balasse, H. E. Williams, J. B. Kane, and N. Segel. Splanchnic metabolism in von Gierke's disease (glycogenosis type 1). Trans. Am. Assoc. Physicians 82: 305–323, 1969.
 42. Hems, D. A., and P. D. Whitton. Control of hepatic glycogenolysis. Physiol. Rev. 60: 1–50, 1980.
 43. Hers, H. G., H. De Wulf, W. Stalmans, and G. van den Berghe. The control of glycogen synthesis in the liver. Adv. Enzyme Regul. 8: 171–190, 1970.
 44. Hetenyi, G. J., B. Lussier, C. Ferrarotto, and J. Radziuk. Calculation of the rate of gluconeogenesis from the incorporation of 14C atoms from labelled bicarbonate or acetate. Can. J. Physiol. Pharmacol. 60: 1603–1609, 1982.
 45. Horowitz, M., A. Maddox, M. Bochner, J. Wishart, R. Bratasiuk, P. Collins, and D. Shearman. Relationships between gastric emptying of solid and caloric liquid meals and alcohol absorption. Am. J. Physiol. 257: G291–G298, 1989.
 46. Hsieh, P.‐P., M. C. Moore, D. W. Neal, and A. D. Cherrington. Hepatic glucose uptake rapidly decreases after removal of the portal signal in conscious dogs. Am. J. Physiol. 275: E987–E992, 1998.
 47. Hue, L., F. Bontemps, and H. Hers. The effects of glucose and of potassium ions on the interconversion of the two forms of glycogen phosphorylase and of glycogen synthetase in isolated rat liver preparations. Biochem. J. 152: 105–114, 1975.
 48. Hwang, J.‐H., G. Perseghin, D. L. Rothman, G. W. Cline, I. Magnusson, K. Falk‐Petersen, and G. I. Shulman. Impaired net hepatic glycogen synthesis in insulin‐dependent diabetic subjects during mixed meal ingestion. J. Clin. Invest. 95: 783–787, 1995.
 49. Ishida, T., J. Chou, R. Lewis, R. Hartley, M. Entman, and J. B. Field. Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs. J. Clin. Invest. 72: 590–600, 1983.
 50. Jackson, R. A., R. D. Roshania, M. I. Hawa, B. M. Sim, and L. Di Sivio. Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J. Clin. Endocrinol. Metab. 63: 541–549, 1986.
 51. Jacquez, J. A.. Theory of production rate calculations in steady and non‐steady states and its application to glucose metabolism. Am. J. Physiol. 262: E779–E790, 1992.
 52. Jones, I. R., D. R. Owens, S. Luzio, S. Williams, and T. M. Hayes. The gastrointestinal inhibitory peptide response to oral glucose and mixed meals is increased in patients with type 2 (NIDDM) diabetes mellitus. Diabetologia 32: 668–677, 1989.
 53. Jue, T., D. L. Rothman, B. A. Tavitian, and R. G. Shulman. Natural abundance 13C NMR study of glycogen repletion in human liver and muscle. Proc. Natl. Acad. Sci. USA 86: 1439–1442, 1989.
 54. Kalderon, M., S. H. Korman, A. Gutman, and A. Lapidot. Estimation of glucose carbon recycling in children with glycogen storage disease: a 13C NMR study using [U‐13C] glucose. Proc. Natl. Acad. Sci. USA 86: 4690–4694, 1989.
 55. Kalderon, M., S. H. Korman, A. Gutman, and A. Lapidot. Glucose recycling and production in glycogenosis type 1 and 111: stable isotope techique study. Am. J. Physiol. 257: E346–E353, 1989.
 56. Kalhan, S., K. Rossi, L. Gruca, E. Burkett, and A. O'Brien. Glucose turnover and gluconeogenesis in human pregnancy. J. Clin. Invest. 100: 1775–1781, 1997.
 57. Katz, J., S. Golden, and P. Wals. Glycogen synthesis by rat hepatocytes. Biochem. J. 180: 389–402, 1979.
 58. Katz, J., and J. D. McGarry. The glucose paradox. Is glucose a substrate for liver metabolism? J. Clin. Invest. 74: 1901–1909, 1984.
 59. Katz, L. D., M. G. Glickman, S. Rapoport, E. Ferranninni, and R. A. De Fronzo. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32: 675–679, 1983.
 60. Kelley, D., A. Mitrakou, F. Schwenk, J. Benn, G. Sonnenberg, M. Arcangell, T. Aoki, J. Sorensen, M. Berger, P. Sonksen, and J. Gerich. Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J. Clin. Invest. 81: 1563–1571, 1988.
 61. Landau, B. R., J. Wahren, V. Chandramouli, W. C. Schumann, K. Ekberg, and S. C. Kalhan. Contributions to glucose production in the fasted state. J. Clin. Invest. 98: 378–385, 1996.
 62. Large, V., M. Soloviev, H. Brunengraber, and M. Beylot. Lactate and pyruvate isotopic enrichments in plasma and tissues of postabsorptive and starved rats. Am. J. Physiol. 268: E880–E888, 1995.
 63. Lautt, W. W.. Afferent and efferent neural roles in liver function. Prog. Neurobiol. 21: 323–348, 1983.
 64. Leturque, A., S. Hauguel, P. Ferre, and J. Girard. Glucose metabolism in pregnancy. Biol. Neonate 51: 64–69, 1987.
 65. Liu, Z., L. B. Gardner, and E. J. Barrett. Insulin and glucose suppress hepatic glycogenolysis by distinct enzymatic mechanisms. Metabolism 42: 1546–1551, 1993.
 66. Luzi, L., and R. A. De Fronzo. Effect of loss of first phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am. J. Physiol. 257: E241–E246, 1989.
 67. Magnusson, I., V. Chandramouli, W. C. Schumann, K. Kumaran, J. Wahren, and B. R. Landau. Pathways of hepatic glycogen formation in humans following ingestion of a glucose load in the fed state. Metabolism 38: 583–585, 1989.
 68. Magnussen, I., D. L. Rothman, D. P. Gerard, L. D. Katz, and G. I. Shulman. Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration. Diabetes 44: 185–189, 1995.
 69. Magnussen, I., D. L. Rothman, B. Jucker, G. W. Cline, R. G. Shulman, and G. I. Shulman. Liver glycogen turnover in fed and fasted humans. Am. J. Physiol. 266: E796–E803, 1994.
 70. Magnusson, I., D. L. Rothman, L. D. Katz, R. G. Shulman, and G. I. Shulman. Increased rate of gluconeogenesis in type‐II diabetes mellitus—a C‐13 nuclear‐magnetic‐resonance study. J. Clin. Invest. 90: 1323–1327, 1992.
 71. Marliss, E. B., T. T. Aoki, R. H. Unger, and J. S. Soeldner, and G. F. Cahill. Glucagon effects and metabolic effects in fasting man. J. Clin. Invest. 49: 2256–2270, 1970.
 72. McMahon, M., H. Marsh, and R. A. Rizza. Comparison of the pattern of postprandial carbohydrate metabolism after ingestion of a glucose drink or a mixed meal. J. Clin. Endocrinol. Metab. 68: 647–653, 1989.
 73. Merli, M., L. S. Eriksson, and L. Hagenfeldt. Splanchnic and leg exchange of free fatty acids in patients with liver cirrhosis. J. Hepatol. 3: 348–355, 1986.
 74. Miyoshi, H., G. I. Shulman, E. J. Peters, M. M. Wolfe, D. Elahi, and R. R. Wolfe. Hormonal control of substrate cycling in humans. J. Clin. Invest. 81: 1545–1555, 1988.
 75. Moore, M. C., A. D. Cherrington, G. W. Cline, M. J. Pagliassotti, E. M. Jones, D. W. Neal, C. Badet, and G. I. Shulman. Sources of carbon for hepatic glycogen synthesis in the concious dog. J. Clin. Invest. 88: 578–587, 1991.
 76. Moore, M. C., P. J. Flakoll, P.‐S. Hsieh, M. J. Pagliassotti, D. W. Neal, M. T. Monohan, C. Venable, and A. D. Cherrington. Hepatic glucose disposition during concomitant portal glucose and amino acid infusions in the dog. Am. J. Physiol. 274: E893–E902, 1998.
 77. Muller, M. I., J. Moring, and H. J. Seitz. Regulation of hepatic glucose output by glucose in vivo. Metabolism 37: 55–60, 1988.
 78. Myers, J. D.. Net splanchnic glucose production in normal man and in various disease states. J. Clin. Invest. 29: 1421–1429, 1950.
 79. Myers, S. R., D. W. Biggers, D. W. Neal, and A. D. Cherrington. Intraportal glucose delivery enhances the effects of hepatic glucose load on net glucose uptake in vivo. J. Clin. Invest. 88: 158–167, 1991.
 80. Niijima, A.. Nervous regulation of metabolism. Prog. Neurobiol. 33: 135–147, 1989.
 81. Nilsson, L., and E. Hultman. Liver glycogen in man: the effect of total starvation or a carbohydrate poor diet followed by carbohydrate refeeding. Scand. J. Clin. Lab. Invest. 32: 325–330, 1973.
 82. Norwich, K. N.. Molecular dynamics. In: The Kinetics of Tracers in the Intact Organism. Oxford: Pergamon Press, p. 1977.
 83. O'Connell, R. C., A. P. Morgan, T. T. Aoki, M. R. Ball, and F. D. Moore. Nitrogen conservation in starvation: graded responses to intravenous glucose. J. Clin. Endocrinol. Metab. 39: 555–562, 1974.
 84. Owens, O. E., A. Reichle, and A. Mozzoli. Hepatic and renal substrate flux rates in patients with hepatic cirrhosis. J. Clin. Invest. 68: 240–252, 1981.
 85. Pagliassotti, M. J., L. C. Holste, M. C. Moore, D. W. Neal, and A. D. Cherrington. Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. J. Clin. Invest. 97: 81–91, 1996.
 86. Pagliassotti, M. J., M. C. Moore, D. W. Neal, and A. D. Cherrington. Insulin is required for the liver to respond to intraportal glucose delivery in the conscious dog. Diabetes 41: 1247–1256, 1992.
 87. Pagliassotti, M. J., S. R. Myers, M. C. Moore, D. W. Neal, and A. D. Cherrington. Magnitude of negative arterial‐portal glucose gradient alters net glucose balance in conscious dogs. Diabetes 40: 1659–1668, 1991.
 88. Petersen, K. F., and N. Grunnet. Gluconeogenesis in rat hepatocytes determined with [2–13]acetate and quantitative 13C NMR spectroscopy. Int. J. Biochem. 25: 1–5, 1993.
 89. Petersen, K. F., M. Krssak, V. Navarro, V. Chandramouli, R. Hundal, W. C. Schumann, B. R. Landau, and G. I. Shulman. Contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in normal and cirrhotic subjects. Am. J. Physiol. 276: E529–535, 1998.
 90. Petersen, K. F., D. Laurent, D. Rothman, G. W. Cline, and G. I. Shulman. Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J. Clin. Invest. 101: 1203–1209, 1998.
 91. Petersen, K. F., T. Price, G. W. Cline, D. L. Rothman, and G. I. Shulman. Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period. Am. J. Physiol. 270( 1 Pt 1): E186–E191, 1996.
 92. Pimenta, W., N. Nurjhan, P.‐A. Jansson, M. Stumvoll, J. Gerich, and M. Korytkowski. Glycogen: its mode of formation and contribution to hepatic glucose output in postabsorptive humans. Diabetologia 37: 697–702, 1994.
 93. Powell, R. C., S. M. Wentworth, and I. K. Brandt. Endogenous glucose production in type 1 glycogen storage disease. Metabolism 30: 443–450, 1981.
 94. Prager, R., P. Wallace, and J. M. Olefsky. Direct and indirect effects of insulin to inhibit hepatic glucose output in obese subjects. Diabetes 36: 607–611, 1987.
 95. Price, T. B., R. Taylor, G. F. Mason, D. L. Rothman, G. I. Shulman, and R. G. Shulman. Turnover of human muscle glycogen with low‐intensity exercise. Med. Sci. Sports Exer. 26: 983–991, 1994.
 96. Proietto, J., F. B. Alford, and F. J. Dudley. The mechanism of carbohydrate intolerance in cirrhosis. J. Clin. Endocrinol. Metab. 51: 1030–1036, 1980.
 97. Puhakainen, I., and H. Yki‐Jarvinen. Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose procduction in NIDDM. Diabetes 42: 1694–1699, 1993.
 98. Radziuk, J., and R. Inculet. The effects of ingested and intravenous glucose and glucogenic substrate in normal man. Diabetes 32: 977–981, 1983.
 99. Radziuk, J., K. H. Norwich, and M. Vranic. Experimental validation of measurements of glucose turnover in nonsteady state. Am. J. Physiol. 234: E84–E93, 1978.
 100. Rasmussen, H., K. C. Zawalich, S. Ganesan, R. Calle, and W. S. Zawalich. Physiology and pathophysiology of insulin secretion. Diabetes Care 13: 655–666, 1990.
 101. Rebrin, K., G. M. Steil, L. Getty, and R. Bergman. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 44: 1038–1045, 1995.
 102. Reece, E. A., and D. R. Coustan, eds. Diabetes Mellitus in Pregnancy: Principles and Practice. New York: Churchill Livingstone, 1988: 286.
 103. Rizza, R. A., L. J. Mandarino, and J. E. Gerich. Dose‐response characteristics for effects of insulin on production and utilisation of glucose in man. Am. J. Physiol. 240: E630–E639, 1981.
 104. Roden, M., G. Perseghin, K. F. Petersen, J. H. Hwang, G. W. Cline, K. Gerow, D. L. Rothman, and G. I. Shulman. The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans. J. Clin. Invest. 97: 642–648, 1996.
 105. Roser, W., N. Beckman, U. Weisman, and J. Seelig. Absolute quantification of the hepatic glycogen content in a patient with glycogen storage disease by 13C magnetic resonance spectroscopy. Mag. Res. Imaging 14: 1217–1220, 1996.
 106. Rothman, D. L., I. Magnusson, L. D. Katz, R. G. Shulman, and G. I. Shulman. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 254: 573–576, 1991.
 107. Sacca, L., R. Hendler, and R. S. Sherwin. Hyperglycemia inhibits glucose production in man independent of changes in glucoregulatory hormones. J. Clin. Endocrinol. Metab. 47: 1160–1163, 1978.
 108. Saloranta, C., M. R. Taskinen, E. Widen, M. Harkonen, A. Melander, and L. Groop. Metabolic consequences of sustained suppression of free fatty acids by acipimox in patients with NIDDM. Diabetes 42: 1559–1566, 1993.
 109. Schumann, W. C., I. Magnusson, V. Chandramouli, K. Kumaran, J. Wahren, and B. R. Landau. Metabolism of [2–14C]acetate and its use in assessing hepatic Krebs cycle activity and gluconeogenesis. J. Biol. Chem. 266: 6985–6990, 1991.
 110. Shulman, G. I., E. J. Barrett, and R. S. Sherwin. Integrated fuel metabolism. In: Ellenberg and Rifkin's Diabetes Mellitus in Theory and Practice, 5th ed., edited by D. Porte and R. S. Sherwin. New York: Elsevier, p. 1–37, 1996.
 111. Shulman, G. I., G. Cline, W. C. Schumann, V. Chandramouli, K. Kumaran, and B. R. Landau. Quantitative comparison of pathways of hepatic glycogen repletion in fed and fasted humans. Am. J. Physiol. 260: E335–E341, 1990.
 112. Shulman, G. I., W. W. Lacy, J. E. Liljenquist, U. Keller, P. E. Williams, and A. D. Cherrington. Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog. J. Clin. Invest. 65: 496–505, 1980.
 113. Shulman, G. I., J. E. Liljenquist, P. E. Williams, W. W. Lacy, and A. D. Cherrington. Glucose disposal during insulinopenia in somatostatin‐treated dogs: the roles of glucose and glucagon. J. Clin. Invest. 62: 487–491, 1978.
 114. Shulman, G. I., and L. Rossetti. Influence of the route of glucose administration on hepatic glycogen repletion. Am. J. Physiol. 257: E681–E685, 1989.
 115. Shulman, G. I., D. L. Rothman, T. Jue, P. Stein, R. A. De Fronzo, and R. G. Shulman. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non‐insulin dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med. 322: 223–228, 1990.
 116. Stewart, A., D. G. Johnston, and K. G. M. M. Alberti Hormone. and metabolic profiles in alcholic liver disease. Eur. J. Clin. Invest. 13: 397–403, 1983.
 117. Stumpel, F., and K. Jungermann. Sensing by intrahepatic muscarinic nerves of a portal‐arterial glucose concentration gradient as a signal for insulin‐dependent uptake in the perfused rat liver. FEBS Lett. 406: 119–122, 1997.
 118. Taylor, R., I. Magnussen, D. L. Rothman, G. W. Cline, A. Caumo, C. Cobelli, and G. I. Shulman. Direct assessment of liver glycogen storage by 13C‐nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J. Clin. Invest. 97: 126–132, 1996.
 119. Taylor, R., T. B. Price, D. R. Rothman, R. G. Shulman, and G. I. Shulman. Validation of 13C‐NMR measurement of human muscle glycogen by comparison with biopsy and direct biochemical measurement. Mag. Res. Med. 27: 13–20, 1992.
 120. Taylor, R., and G. I. Shulman. New insights into human carbohydrate metabolism using nuclear magnetic resonance spectroscopy. In: The Diabetes Annual, vol. 8, edited by S. M. Marshall and P. D. Home. Amsterdam: Elsevier, p. 157–175, 1994.
 121. Taylor, R., and G. I. Shulman. Regulation of carbohydrate metabolism. In: Clinical Research in Diabetes and Obesity, Part 1: Methods, Assessment and Metabolic Regulation, edited by B. Draznin and R. Rizza. Humana Press, Totowa, NJ, p. 287–303, 1997.
 122. Terrettaz, J., F. Assimacopoulos‐Jeannet, and B. Jeanrenaud. Inhibition of hepatic glucose production by insulin in vivo in rats: contribution of glycolysis. Am. J. Physiol. 250: E346–E351, 1986.
 123. Tillil, H., E. T. Shapiro, M. A. Miller, T. Karrison, B. H. Frank, J. A. Galloway, A. H. Rubinstein, and K. S. Polonsky. Dose‐dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am. J. Physiol. 254: E349–E357, 1988.
 124. Tosh, D., G. Beresford, and L. Agius. Glycogen synthesis from glucose by direct and indirect pathways in hepatocyte cultures from different nutritional states. Biochem. Biophys. Acta 1224: 205–212, 1994.
 125. van de Werve, G., L. Hue, and H. G. Hers. Hormonal and ionic control of the glycogenolytic cascade in rat liver. Biochem. J. 162: 135–142, 1977.
 126. Velho, G., K. F. Petersen, G. Perseghin, J. H. Hwang, D. L. Rothman, M. E. Pueyo, G. W. Cline, P. Froguel, and G. I. Shulman. Impaired hepatic glycogen synthesis in glucokinase‐deficient (MODY‐2) subjects. J. Clin. Invest. 98: 1755–1761, 1996.
 127. Wahren, J., P. Felig, E. Cerasi, and R. Luft. Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J. Clin. Invest. 51: 1870–1878, 1972.
 128. Waldhausl, W. K., S. Gasic, P. Bratusch‐Marrain, and P. Nowotny. The 75‐g oral glucose tolerance test: effect on splanchnic metabolism of substrates and pancreatic hormone release in healthy man. Diabetologia 25: 489–495, 1983.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Regulation of Hepatic Glucose Uptake
 

How to Cite

Roy Taylor, Gerald I. Shulman. Regulation of Hepatic Glucose Uptake. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 787-802. First published in print 2001. doi: 10.1002/cphy.cp070226