Comprehensive Physiology Wiley Online Library

Regulation of Hepatic Glucose Uptake

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.]
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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