Glucose Is Always Required by the Central Nervous System and Erythrocytes
Erythrocytes lack mitochondria and hence are wholly reliant on (anaerobic) glycolysis and the pentose phosphate pathway at all times. The brain can metabolize ketone bodies to meet about 20% of its energy requirements; the remainder must be supplied by glucose. The metabolic changes that occur in the fasting state and starvation serve to preserve glucose and the body’s limited glycogen reserves for use by the brain and red blood cells, and to provide alternative metabolic fuels for other tissues. In pregnancy, the fetus requires a significant amount of glucose, as does the synthesis of lactose in lactation (Figure 14–9).
Metabolic interrelationships among adipose tissue, the liver, and extra-hepatic tissues. In tissues such as heart, metabolic fuels are oxidized in the following order of preference: ketone bodies > fatty acids > glucose. (LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; VLDL, very low density lipoproteins.)
In the Fed State, Metabolic Fuel Reserves Are Laid Down
For several hours after a meal, while the products of digestion are being absorbed, there is an abundant supply of metabolic fuels. Under these conditions, glucose is the major fuel for oxidation in most tissues; this is observed as an increase in the respiratory quotient (the ratio of carbon dioxide produced/oxygen consumed) from about 0.8 in the fasting state to near 1 (Table 14–1).
TABLE 14–1Energy Yields, Oxygen Consumption, and Carbon Dioxide Production in the Oxidation of Metabolic Fuels |Favorite Table|Download (.pdf) TABLE 14–1 Energy Yields, Oxygen Consumption, and Carbon Dioxide Production in the Oxidation of Metabolic Fuels
| ||Energy Yield (kJ/g) ||O2 Consumed (L/g) ||CO2 Produced (L/g) ||RQ (CO2 Produced/O2 Consumed) ||Energy (kJ)/L O2 |
|Carbohydrate ||16 ||0.829 ||0.829 ||1.00 ||~20 |
|Protein ||17 ||0.966 ||0.782 ||0.81 ||~20 |
|Fat ||37 ||2.016 ||1.427 ||0.71 ||~20 |
|Alcohol ||29 ||1.429 ||0.966 ||0.66 ||~20 |
Glucose uptake into muscle and adipose tissue is controlled by insulin, which is secreted by the β-islet cells of the pancreas in response to an increased concentration of glucose in the portal blood. In the fasting state, the glucose transporter of muscle and adipose tissue (GLUT-4) is in intracellular vesicles. An early response to insulin is the migration of these vesicles to the cell surface, where they fuse with the plasma membrane, exposing active glucose transporters. These insulin-sensitive tissues only take up glucose from the bloodstream to any significant extent in the presence of the hormone. As insulin secretion falls in the fasting state, so the receptors are internalized again, reducing glucose uptake. However, in skeletal muscle, the increase in cytoplasmic calcium ion concentration in response to nerve stimulation stimulates the migration of the vesicles to the cell surface and exposure of active glucose transporters whether or not there is significant insulin stimulation.
The uptake of glucose into the liver is independent of insulin, but liver has an isoenzyme of hexokinase (glucokinase) with a high Km, so that as the concentration of glucose entering the liver increases, so does the rate of synthesis of glucose-6-phosphate. This is in excess of the liver’s requirement for energy-yielding metabolism, and is used mainly for synthesis of glycogen. In both liver and skeletal muscle, insulin acts to stimulate glycogen synthetase and inhibit glycogen phosphorylase. Some of the additional glucose entering the liver may also be used for lipogenesis and hence triacylglycerol synthesis. In adipose tissue, insulin stimulates glucose uptake, its conversion to fatty acids, and their esterification to triacylglycerol. It inhibits intracellular lipolysis and the release of nonesterified fatty acids.
The products of lipid digestion enter the circulation as chylomicrons, the largest of the plasma lipoproteins, which are especially rich in triacylglycerol (see Chapter 25). In adipose tissue and skeletal muscle, extracellular lipoprotein lipase is synthesized and activated in response to insulin; the resultant nonesterified fatty acids are largely taken up by the tissue and used for synthesis of triacylglycerol, while the glycerol remains in the bloodstream and is taken up by the liver and used for either gluconeogenesis and glycogen synthesis or lipogenesis. Fatty acids remaining in the bloodstream are taken up by the liver and reesterified. The lipid-depleted chylomicron remnants are cleared by the liver, and the remaining triacylglycerol is exported, together with that synthesized in the liver, in very low density lipoprotein.
Under normal conditions, the rate of tissue protein catabolism is more or less constant throughout the day; it is only in cachexia associated with advanced cancer and other diseases that there is an increased rate of protein catabolism. There is net protein catabolism in the fasting state, when the rate of protein synthesis falls, and net protein synthesis in the fed state, when the rate of synthesis increases by 20% to 25%. The increased rate of protein synthesis in response to increased availability of amino acids and metabolic fuel is again a response to insulin action. Protein synthesis is an energy expensive process; it may account for up to 20% of resting energy expenditure after a meal, but only 9% in the fasting state.
Metabolic Fuel Reserves Are Mobilized in the Fasting State
There is a small fall in plasma glucose in the fasting state, and then little change as fasting is prolonged into starvation. Plasma nonesterified fatty acids increase in fasting, but then rise little more in starvation; as fasting is prolonged, the plasma concentration of ketone bodies (acetoacetate and 3-hydroxybutyrate) increases markedly (Table 14–2, Figure 14–10).
TABLE 14–2Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed and Fasting States |Favorite Table|Download (.pdf) TABLE 14–2 Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed and Fasting States
| ||Fed ||40 h Fasting ||7 Days Starvation |
|Glucose ||5.5 ||3.6 ||3.5 |
|Nonesterified fatty acids ||0.30 ||1.15 ||1.19 |
|Ketone bodies ||Negligible ||2.9 ||4.5 |
Relative changes in plasma hormones and metabolic fuels during the onset of starvation.
In the fasting state, as the concentration of glucose in the portal blood coming from the small intestine falls, insulin secretion decreases, and skeletal muscle and adipose tissue take up less glucose. The increase in secretion of glucagon by α cells of the pancreas inhibits glycogen synthetase, and activates glycogen phosphorylase in the liver. The resulting glucose-6-phosphate is hydrolyzed by glucose 6-phosphatase, and glucose is released into the bloodstream for use by the brain and erythrocytes.
Muscle glycogen cannot contribute directly to plasma glucose, since muscle lacks glucose-6-phosphatase, and the primary use of muscle glycogen is to provide a source of glucose-6-phosphate for energy-yielding metabolism in the muscle itself. However, acetyl-CoA formed by oxidation of fatty acids in muscle inhibits pyruvate dehydrogenase, leading to an accumulation of pyruvate. Most of this is transaminated to alanine, at the expense of amino acids arising from breakdown of muscle protein. The alanine, and much of the keto acids resulting from this transamination are exported from muscle, and taken up by the liver, where the alanine is transaminated to yield pyruvate. The resultant amino acids are largely exported back to muscle, to provide amino groups for formation of more alanine, while the pyruvate provides a substrate for gluconeogenesis in the liver.
In adipose tissue, the decrease in insulin and increase in glucagon results in inhibition of lipogenesis, inactivation and internalization of lipoprotein lipase, and activation of intracellular hormone-sensitive lipase (see Chapter 25). This leads to release from adipose tissue of increased amounts of glycerol (which is a substrate for gluconeogenesis in the liver) and nonesterified fatty acids, which are used by liver, heart, and skeletal muscle as their preferred metabolic fuel, so sparing glucose.
Although muscle preferentially takes up and metabolizes nonesterified fatty acids in the fasting state, it cannot meet all of its energy requirements by β-oxidation. By contrast, the liver has a greater capacity for β-oxidation than is required to meet its own energy needs, and as fasting becomes more prolonged, it forms more acetyl-CoA than can be oxidized. This acetyl-CoA is used to synthesize the ketone bodies (see Chapter 22), which are major metabolic fuels for skeletal and heart muscle and can meet up to 20% of the brain’s energy needs. In prolonged starvation, glucose may represent less than 10% of whole body energy-yielding metabolism.
Were there no other source of glucose, liver and muscle glycogen would be exhausted after about 18 hours fasting. As fasting becomes more prolonged, so an increasing amount of the amino acids released as a result of protein catabolism is utilized in the liver and kidneys for gluconeogenesis (Table 14–3).
TABLE 14–3Summary of the Major Metabolic Features of the Principal Organs |Favorite Table|Download (.pdf) TABLE 14–3 Summary of the Major Metabolic Features of the Principal Organs
|Organ ||Major Pathways ||Main Substrates ||Major Products Exported ||Specialist Enzymes |
|Liver ||Glycolysis, gluconeogenesis, lipogenesis, β-oxidation, citric acid cycle, ketogenesis, lipoprotein metabolism, drug metabolism, synthesis of bile salts, urea, uric acid, cholesterol, plasma proteins ||Nonesterified fatty acids, glucose (in fed state), lactate, glycerol, fructose, amino acids, alcohol ||Glucose, triacylglycerol in VLDL,a ketone bodies, urea, uric acid, bile salts, cholesterol, plasma proteins ||Glucokinase, glucose-6-phosphatase, glycerol kinase, phosphoenolpyruvate carboxykinase, fructokinase, arginase, HMG CoA synthase, HMG CoA lyase, alcohol dehydrogenase |
|Brain ||Glycolysis, citric acid cycle, amino acid metabolism, neurotransmitter synthesis ||Glucose, amino acids, ketone bodies in prolonged starvation ||Lactate, end products of neurotransmitter metabolism ||Those for synthesis and catabolism of neurotransmitters |
|Heart ||β-Oxidation and citric acid cycle ||Ketone bodies, nonesterified fatty acids, lactate, chylomicron and VLDL triacylglycerol, some glucose ||— ||Lipoprotein lipase, very active electron transport chain |
|Adipose tissue ||Lipogenesis, esterification of fatty acids, lipolysis (in fasting) ||Glucose, chylomicron and VLDL triacylglycerol ||Nonesterified fatty acids, glycerol ||Lipoprotein lipase, hormone-sensitive lipase, enzymes of the pentose phosphate pathway |
|Fast twitch muscle ||Glycolysis ||Glucose, glycogen ||Lactate, (alanine and ketoacids in fasting) ||— |
|Slow twitch muscle ||β-Oxidation and citric acid cycle ||Ketone bodies, chylomicron and VLDL triacylglycerol ||— ||Lipoprotein lipase, very active electron transport chain |
|Kidney ||Gluconeogenesis ||Nonesterified fatty acids, lactate, glycerol, glucose ||Glucose ||Glycerol kinase, phosphoenolpyruvate carboxykinase |
|Erythrocytes ||Anerobic glycolysis, pentose phosphate pathway ||Glucose ||Lactate ||Hemoglobin, enzymes of pentose phosphate pathway |