1. Introduction Any detailed understanding of the integrated actions of glucagon and insulin to effect blood glucose homeostasis cannot be achieved by limiting the assessment of their actions to those on carbohydrate metabolism alone. Due to the ready metabolic interchanges that occur between carbohydrate, protein, and fat constituents, it is essential to have a clear understanding of the intermediary metabolism of all of these substances. In addition, some appreciation of the principles of dietary nutrition is required because many key enzymes of intermediary metabolism of higher animals are adaptively regulated to reflect the current dietary intake of carbohydrate, protein, and lipid. The general design is such that the ingested components are diverted to storage sites during periods of feeding and are later reutilized by the metabolic processes of glycogenolysis, gluconeogenesis, and ketogenesis during intervals of food deprivation.
2. Substrate Stores
The three categories of food substances that con tribute significantly to caloric intake are carbohydrates, proteins, and fat (as triglycerides). Table 1 summarizes the caloric contribution of these prime nutrients when they are metabolized completely to CO2 and H2O.
Table1. Caloric Yield of Food Substances
Table 2 lists for a normal (70 kg) man the magnitudes of body pools of carbohydrate, fat, and protein and their theoretical caloric yields (in kilocalories) if they were completely metabolized to CO2 and water.
Table2. Body Pools of Carbohydrate, Fat, and Protein in a Normal (70 kg) Man a
Virtually the complete body pool of protein is in a continuous state of flux. In the steady state there is a balance between biosynthesis and degradation. The amino acid efflux from human muscle is 0.5–1.0 g/kg/day. The released amino acids are further catabolized principally by the liver. Physiological amounts of insulin are known to markedly reduce amino acid efflux from muscle. Although a normal 70-kg man has a total of 10 kg of protein, only ~60% of this is theoretically metabolically mobilizable; the remaining 40% represents structural proteins, e.g., collagen. In reality, no more than 2 kg of body protein can be metabolically mobilized before there is marked muscular hypertrophy (large cell volume) and myopathy (weakness). In cases of extreme starvation, death ensues not from hypoglycemia but from loss of respiratory muscle function, which usually leads to terminal pneumonia.
Fat is the body’s principal form of stored energy; 76% of the calories derived from the substrate stores tabulated in Table 2 comes from metabolic oxidation of triglycerides and free fatty acids. Fat or adipose tissue represents the most efficient body storage form of energy. This results not only from the higher caloric yield per gram mass of adipose tissue (see Table 1) but also from the fact that the biological “packing” of triglycerides is more condensed than that of protein or glycogen due to the absence of water molecules in the triglyceride structures. It is the fat depots that allow humans to tolerate prolonged intervals of dietary calorie deprivation. The energy stored in the body fat depots is sufficient to permit the average individual to survive 2–3 months of total food deprivation. Lipolysis or hydrolysis of adipose tissue triglycerides leads to the release of glycerol and free fatty acids into the blood stream. The free fatty acids are then further catabolized by both muscle and liver tissue.
Approximately 80% of the storage form of carbo hydrate, namely, glycogen, is found in muscle; the glycogen concentration is 9–16 g/kg of wet muscle or a total of 350 grams (see Table 2). The muscle glycogen levels are depleted rapidly during vigorous exercise, but are reduced only slowly during prolonged fasting, because muscle, in contrast to the liver, does not contain the enzyme glucose 6-phosphatase, and because normally there is no hydrolysis of the phosphate esters of the various glycolytic pathway intermediates. As a consequence, it is not possible for significant amounts of glycogen (glucose) to leave the muscle. Thus, muscle glycogen can only serve as a metabolic fuel in the cell in which it is localized.
The liver glycogen pool (~85 g) plays a key role in facilitating the metabolic adjustment by the body to varying energy requirements. The concentration of hepatic glycogen is 50 g/kg of wet tissue; it represents ~20% of the total body glycogen pool. Liver glycogen may be depleted gradually during periods of fasting. Within 10–12 hr of fasting, the hepatic glycogen is mobilized at a rate of 50 mg/min/kg of liver. In contrast, during 40 min of severe exercise, the liver glycogen pool may be depleted by 18–20 g; that is, glycogen is mobilized at a rate of 330 mg/min/kg wet weight. Replenishment of the hepatic levels of glucose occurs only relatively slowly; a period of 12–36 hr is required, depending on the diet and extent of physical activity.
The body pool of extracellular glucose is quite modest by comparison with the muscle and liver stores; only ~20 g of free glucose is present in the extracellular water and the intracellular pool of the liver. The principal function of the blood pool of glucose is to provide a continuous supply of glucose to all of the glucose- dependent tissues. In the basal state, the brain is the chief glucose-consuming tissue. During a 24-hr interval the brain requires 125 g of glucose.
The exclusive source of replenishment of the blood glucose pool is the liver. Under usual circumstances, 70% of the hepatic output of glucose is derived from liver glycogenolysis and 30% from gluconeogenesis. During intervals of prolonged exercise (40 min), ~50% of the oxidative metabolism of skeletal muscle is derived from glucose uptake from blood.
Ketones or “ketone bodies” accumulate in the blood under normal circumstances, where they function to ensure the survival of the organism, and under pathological conditions, where they can cause coma and death. The ketone bodies are produced almost exclusively by the liver from fatty acids and other carbon fragments derived from amino acids. Acetone is removed from the body via the lungs. The metabolic role of the ketones varies depending upon the nutritional state. Their principal function is to serve under conditions of fasting as a substitute substrate for energy metabolism by muscle, heart, and particularly the brain. Although muscle and heart have the capacity for cellular uptake and oxidation of free fatty acids (derived from lipolysis of adipose tissue), the brain does not have this capacity. Thus, under conditions of fasting when the liver glycogen and eventually blood glucose pools become depleted, the physiological significance of the ketone bodies assumes a far greater importance. Under conditions of adequate feeding, the blood levels of the ketones are quite low.
The liver is the source of glucose for all tissues of the body. The human liver is the principal site of storage of glucose in its polymeric form known as glycogen. A single molecule of glycogen, when broken down completely by the process of glycogenolysis, can provide 120,000 molecules of glucose. The free glucose is then released into the blood compartment for transport to the brain, muscle, and red and white blood cells. Figure1 summarizes the balance of glucose pro duction and utilization in humans that ensues over a 24-hr interval after dietary intake and in the absence of excessive exercise. The values for glucose consumption represent the amounts in grams consumed per day by the brain (125 g), red and white blood cells (each 50 g), and muscle (50 g) while in the resting state. Thus in an average day, approximately 275 grams of glycogen are broken down by the liver and released as glucose. When starvation extends beyond 12 hr, the hepatic glycogen stores begin to be depleted. This then activates the process of gluconeogenesis in the muscle that results in the release of amino acid fragments from the breakdown of muscle proteins. The amino acid fragments then are transferred via the blood compartment to the liver for conversion by the process of gluconeogenesis into glucose and storage as glycogen.
Fig1. Glucose production by the liver and its transport as blood glucose to the brain, muscle, and red and white blood cells. This schematic diagram describes the production of glucose from amino acid fragments and its storage as glycogen by the liver. Then in times of need, as judged by a low blood glucose concentration, the liver’s stored glycogen is mobilized and released as glucose to be transferred via the blood circulatory system to the brain, muscle, and red and white cells. The liver is the source of glucose for all tissues of the body. The glucose is provided by breaking down the stored hepatic glycogen by the process of glycogenolysis and releasing the glucose into the blood compartment. Gluconeogenesis is the formation of glucose, especially by the liver, from noncarbohydrate sources, such as amino acids supplied by muscle and the glycerol supplied by adipose tissue. Abbreviations: RBC, red blood cell; WBC, white blood cell; AA, amino acid. Modified with permission from the author, P. Felig, and the publisher (1979). “Starvation” In Endocrinology (L. J. DeGroot et al., eds.), Vol. 3, pp. 1927–1940. Grune & Stratton, New York.
Maintenance of a constant blood glucose level is governed by the liver and the regulatory actions of the pancreatic hormones. In the absence of hepatic glucose production, the blood level of glucose would fall by 50% in 40–60 min.
3. Dietary Nutritional Requirements
The daily caloric requirements can be met by adequate dietary intake of protein, fat, and carbohydrate. One current recommendation is that 15%, 30%, and 55% of the daily energy intake should be derived from protein, fat, and carbohydrate, respectively. Each food substance has its own characteristic energy yield (see Table1), which reflects the relative extent of reduction of the carbon atoms of that food component.
In addition to kilocalories or kilojoules, the diet must supply, on a regular basis, adequate amounts of the various essential dietary constituents; these include water and fat-soluble vitamins, the essential unsaturated fatty acids, the essential amino acids, and both bulk and trace minerals.
