The endogenous glucose production rate, and thus the utilization rate, depends on the duration of starvation. Glucose production has been determined in a number of laboratories using isotopically labeled glucose (Amiel et al., 1991; Arslanian and Kalhan, 1992; Bier et al., 1977; Denne and Kalhan, 1986; Kalhan et al., 1986; King et al., 1982; Patel and Kalhan, 1992). In overnight fasted adults (i.e., postabsorptive state), glucose production is approximately 2 to 2.5 mg/kg/min, or approximately 2.8 to 3.6 g/kg/d. In a 70-kg man, this represents approximately 210 to 270 g/d. In the postabsorptive state, approximately 50 percent of glucose production comes from glycogenolysis in liver and 50 percent from gluconeogenesis in the liver (Chandramouli et al., 1997; Landau et al., 1996).
The minimal amount of carbohydrate required, either from endogenous or exogenous sources, is determined by the brain's requirement for glucose. The brain is the only true carbohydrate-dependent organ in that it oxidizes glucose completely to carbon dioxide and water. Normally, the brain uses glucose almost exclusively for its energy needs. The endogenous glucose production rate in a postabsorptive state correlates very well with the estimated size of the brain from birth to adult life. However, not all of the glucose produced is utilized by the brain (Bier et al., 1977; Felig, 1973). The requirement for glucose has been reported to be approximately 110 to 140 g/d in adults (Cahill et al., 1968). Nevertheless, even the brain can adapt to a carbohydrate-free, energy-sufficient diet, or to starvation, by utilizing ketoacids for part of its fuel requirements. When glucose production or availability decreases below that required for the complete energy requirements for the brain, there is a rise in ketoacid production in the liver in order to provide the brain with an alternative fuel. This has been referred to as "ketosis." Generally, this occurs in a starving person only after glycogen stores in the liver are reduced to a low concentration and the contribution of hepatic glycogenolysis is greatly reduced or absent (Cahill et al., 1968). It is associated with approximately a 20 to 50 percent decrease in circulating glucose and insulin concentration (Carlson et al., 1994; Owen et al., 1998; Streja et al., 1977). These are signals for adipose cells to increase lipolysis and release nonesterified fatty acids and glycerol into the circulation. The signal also is reinforced by an increase in circulating epinephrine, norepinephrine, glucagon, and growth hormone concentration (Carlson et al., 1994). The nonesterified fatty acids are removed by the liver and converted into ketoacids, which then diffuse out of the liver into the circulation. The increase in nonesterified fatty acids results in a concentration-dependent exponential increase in ketoacids (Hanson et al., 1965); glucagon facilitates this process (Mackrell and Sokal, 1969).
In an overnight fasted person, the circulating ketoacid concentration is very low, but with prolonged starvation the concentration increases dramatically and may exceed the molar concentration of glucose (Cahill, 1970; Streja et al., 1977). In individuals fully adapted to starvation, ketoacid oxidation can account for approximately 80 percent of the brain's energy requirements (Cahill et al., 1973). Thus, only 22 to 28 g/d of glucose are required to fuel the brain. This is similar to the total glucose oxidation rate integrated over 24 hours determined by isotope-dilution studies in these starving individuals (Carlson et al., 1994; Owen et al., 1998).
Overall, the key to the metabolic adaptation to extended starvation is the rise in circulating nonesterified fatty acid concentrations and the large increase in ketoacid production. The glycerol released from the hydrolysis of triacylglycerols stored in fat cells becomes a significant source of substrate for gluconeogenesis, but the conversion of amino acids derived from protein catabolism into glucose is also an important source. Interestingly, in people who consumed a protein-free diet, total nitrogen excretion was reported to be in the range of 2.5 to 3.5 g/d (35 to 50 mg/kg), or the equivalent of 16 to 22 g of catabolized protein in a 70-kg man (Raguso et al., 1999). Thus, it is similar to that in starving individuals (3.7 g/d) (Owen et al., 1998). Overall, this represents the minimal amount of protein oxidized through gluconeogenic pathways (Du Bois, 1928). This amount of protein is considerably less than the Recommended Dietary Allowance (RDA) of 0.8 g/kg/d for adults with a normal body mass index (Chapter 10). For a 70-kg lean male, this equals 56 g/d of protein, which is greater than the estimated obligate daily loss in body protein from the shedding of cells, secretions, and other miscellaneous functions (approximately 6 to 8 g/d for a 70-kg man; see Chapter 10) and has been assumed to be due to inefficient utilization of amino acids for synthesis of replacement proteins and other amino acid-derived products (Gannon and Nuttall, 1999). In part, it also may represent the technical difficulty in determining a minimal daily protein requirement (see Chapter 10).
If 56 g/d of dietary protein is required for protein homeostasis, but the actual daily loss of protein is only approximately 7 g, then presumably the remaining difference (49 g) is metabolized and may be utilized for new glucose production. It has been determined that for ingested animal protein, approximately 0.56 g of glucose can be derived from every 1 g of protein ingested (Janney, 1915). Thus, from the 49 g of protein not directly utilized to replace loss of endogenous protein or not used for other synthetic processes, approximately 27 g (0.56 X 49) of glucose may be produced. In people on a protein-free diet or who are starving, the 16 to 22 g of catabolized protein could provide 10 to 14 g of glucose.
If the starving individual's energy requirement is 1,800 kcal/d and 95 percent is supplied by fat oxidation either directly or indirectly through
DIETARY CARBOHYDRATES: SUGARS AND STARCHES 279
oxidation of ketoacids (Cahill et al., 1973), then fat oxidation represents 1,710 kcal/d, or 190 g based upon approximately 9 kcal/g fat. The glycerol content of a typical triacylglycerol is 10 percent by weight, or in this case 19 g of glycerol, which is equivalent to approximately 19 g of glucose. This, plus the amount of glucose potentially derived from protein, gives a total of approximately 30 to 34 g ([10 to 14] + 19). Thus, a combination of protein and fat utilization is required to supply the small amount of glucose still required by the brain in a person fully adapted to starvation. Presumably this also would be the obligatory glucose requirement in people adapted to a carbohydrate-free diet. Thus, the normal metabolic adaptation to a lack of dietary protein, as occurs in a starving person in whom the protein metabolized is in excess of that lost daily, is to provide the glucose required by the brain. Nevertheless, utilization of this amount of glucose by the brain is vitally important. Without it, function deteriorates dramatically, at least in the brain of rats (Sokoloff, 1973).
The required amount of glucose could be derived easily from ingested protein alone if the individual was ingesting a carbohydrate-free, but energy-adequate diet containing protein sufficient for nitrogen balance. However, ingested amounts of protein greater than 30 to 34 g/d would likely stimulate insulin secretion unless ingested in small amounts throughout a 24-hour period. For example, ingestion of 25 to 50 g of protein at a single time stimulates insulin secretion (Krezowski et al., 1986; Westphal et al., 1990), despite a lack of carbohydrate intake. This rise in insulin would result in a diminution in the release of fatty acids from adipose cells and as a consequence, reduce ketoacid formation and fatty acid oxidation. The ultimate effect would be to increase the requirement for glucose of the brain and other organs. Thus, the minimal amount of glucose irreversibly oxidized to carbon dioxide and water requires utilization of a finely balanced ratio of dietary fat and protein.
Azar and Bloom (1963) reported that 100 to 150 g/d of protein was necessary for maintenance of nitrogen balance. This amount of protein could typically provide amino acid substrate sufficient for the production of 56 to 84 g of glucose daily. However, daily infusion of 90 g of an amino acid mixture over 6 days to both postoperative and nonsurgical starving adults has been reported to reduce urinary nitrogen loss without a significant change in glucose or insulin concentration, but with a dramatic increase in ketoacids (Hoover et al., 1975). Thus, the issue becomes complex in nonstarving people.
Glucose utilization by the brain has been determined either by measuring arteriovenous gradients of glucose, oxygen, lactate, and ketones across the brain and the respiratory quotient (Kety, 1957; Sokoloff, 1973), or with estimates of brain blood flow determined by different methods (e.g., NO2 diffusion). A major problem with studies based on arteriovenous
differences is the limited accuracy of the blood flow methods used (Settergren et al., 1976, 1980). Using 18F-2-fluoro-2-deoxyglucose and positron emission tomography, the rate of glucose accumulation in the brain also has been determined (Chugani, 1993; Chugani and Phelps, 1986; Chugani et al., 1987; Hatazawa et al., 1987). This is an indirect method for measuring glucose utilization, and also has limitations (Hatazawa et al., 1987). Brain O2 consumption in association with the brain respiratory quotient also has been used as an indirect estimate of glucose utilization (Kalhan and Kilif, 1999).
Only data determined by direct measurement of glucose arteriovenous difference across the brain in association with determination of brain blood flow can be considered for setting an Estimated Average Requirement (EAR), although the other, indirect methods yield similar results. The glucose consumption by the brain can be used along with information from Dobbing and Sands (1973) and Dekaban and Sadowsky (1978), which correlated weight of the brain with body weight to calculate glucose utilization.
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