Glucose Is Always Required by the Central Nervous System & Erythrocytes

Erythrocytes lack mitochondria and hence are wholly reliant on (anaerobic) glycolysis and the pentose phosphate path way at all times. The brain normally metabolizes glucose but can metabolize ketone bodies. When ketone availability is high such as prolonged fasting, they can 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 plasma glucose for use by the brain and red blood cells, and to provide alternative metabolic (lipids, amino acids) fuels for other tissues (Figure 1). In pregnancy, the fetus requires a significant amount of glucose, as does the mammary gland for synthesis of lactose during lactation.

Fig1. Metabolic interrelationships among adipose tissue, the liver, and extrahepatic tissues. In tissues such as heart, metabolic fuels are oxidized in the following order of preference: fatty acids > ketone bodies > glucose. (LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; VLDL, very low-density lipoproteins.)

In the Fed State, the Exogenous Metabolic Fuels Are Both Oxidized & Stored

 In response to a meal typically the caloric intake during the period the food is absorbed exceeds the energy requirements of the organism. The excess calories are stored either as glycogen or lipid. When substrates are oxidized oxygen is consumed and carbon dioxide is produced. When glucose (C₆H₁₂O₆ ) is oxidized (C₆H₁₂O₆ + 6O₂ → 6CO₂ + 6 H₂O) for each mole of glucose oxidized a mole of oxygen is consumed and mole of carbon dioxide is released. The molar ratio of CO₂ produced and O₂ consumed is called the respiratory quotient. For carbohydrates this ratio is one. For fatty acid and protein oxidation this ratio is less than one (Table 1). We can measure this ratio in expired air. This is called the respiratory exchange ratio. This ratio reflects the mixture of substrates being oxidized by all tissues. In a typical person this ratio averages ~0.85 in a 24-hour period for a person on a standard diet. For several hours after a carbohydrate-rich meal, while the products of digestion are being absorbed, there is an abundant supply of carbohydrate. Thus carbohydrate oxidation is the main substrate being oxidized so the respiratory exchange ratio increases toward 1. The process of storing excess calories as glycogen and lipid is an energy requiring process and is called the thermic effect of food, which can account for ~10% of daily energy expenditure. As a person transitions to a fast the rate of glucose oxidation decreases and the rate of fat oxidation increases (this is observed as a decrease in the respiratory exchange ratio toward 0.7 reflecting a shift to fat oxidation; see Table 1).

Table1. Energy Yields, Oxygen Consumption, & Carbon Dioxide Production in the Oxidation of Metabolic Fuels

The transport capacity for glucose into the liver is high and is independent of insulin, thus transport does not control the rate of glucose uptake in the liver. The liver, however, has an isoenzyme of hexokinase (glucokinase) with a high Km , so that as the concentration of glucose increases and enters the liver hepatocyte, so does the rate of synthesis of glucose-6 phosphate. Thus, when plasma glucose is elevated in the fed state the liver takes up glucose . If it is in excess of the liver’s requirement for energy-yielding metabolism, it is used mainly for synthesis of glycogen. In both liver and skeletal muscle, insulin, which increases in response to an increase in glucose acts to amplify glycogen synthesis by stimulating glycogen synthetase and inhibiting 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. Glucose is used to synthesize both the glycerol and fatty acid in triacylglycerol. It inhibits intracellular lipolysis and the release of nonesterified fatty acids by adipose tissue .

The products of lipid digestion enter the circulation as chylomicrons, the largest of the plasma lipoproteins, which are especially rich in triacylglycerol . 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. It is taken up by the liver and used for 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 triacyl glycerol is exported, together with that synthesized in the liver, in very low-density lipoprotein.

In healthy weight stable individuals the rates of tissue protein catabolism and anabolism are equal in a 24-hour period, thus whole-body protein stores are constant. While protein catabolism is relatively constant, the rate of protein synthesis does change through the 24-hour period. Protein synthesis falls during the fasting period and increases in the feeding period (a change of ~20-25%). It is only in cachexia associated with advanced cancer and other diseases that there is an increased rate of protein catabolism. The increased rate of protein synthesis in response to increased availability of amino acids and metabolic fuel is again a response to insulin. 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 2, Figure 2).

Table2. Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed & Fasting States

Fig2. 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; mobilizing glycogen stores.

The resulting glucose-6-phosphate is hydrolyzed by glucose 6-phosphatase, and glucose is released into the bloodstream for use primarily 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 and pyruvate potentially 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 or released as lactate. The alanine, lactate, and much of the keto acids resulting from this transamination are exported from muscle and are taken up by the liver to support gluconeogenesis. 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 . 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 , which are major metabolic fuels for skeletal and heart muscle and can meet up to 20% of the brain’s energy needs in states of long-term fasting. 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, an increasing amount of the amino acids released as a result of protein catabolism is utilized in the liver and kidneys for gluconeogenesis (Table 3).

Table3. Summary of the Major Metabolic Features of the Principal Organs

مواضيع ذات صلة

Biomedically, Glucose is the Most Important Monosaccharide

Saccharides are Aldehyde or Ketone Derivatives of Polyhydric Alcohols

Many Metabolic Fuels are Interconvertible

The Flux Through Metabolic Pathways Must be Regulated In A Concerted Manner

Metabolic Pathways at The Organ & Cellular Level

Pathways To Process The Major Products Of our Diet

Overview of Substrate Metabolism in Fasting & Feasting

The selective permeability of the inner mitochondrial membrane necessitates exchange transporters

Many Poisons Inhibit the Respiratory Chain

The Respiratory Chain Provides Most Of The Energy Captured During Catabolism

Electron Transport Via The Respiratory Chain Creates A Proton Gradient Which Drives The Synthesis of ATP

The Respiratory Chain Oxidizes Reducing Equivalents & Acts as A Proton Pump