To maintain a continuous supply of nutrients in the bloodstream in the face of intermittent dietary intake, a complex set of regulatory mechanisms have evolved. These allow the storage of nutrients during feeding, and their release from storage pools during the interdigestive period so as to maintain nutrient levels in the bloodstream within remarkably narrow limits. Short-term regulation between the fed state and the interdigestive state is mediated principally by (1) the concentration of several key substrates and (2) a set of regulatory hormones, which include insulin, glucagon, catecholamines and corticosteroids (Table 1).

The fate of glucose in the fed and the fasting states is detailed in Figure 1. Glucose is rapidly absorbed following ingestion as starch, disaccharides or monosaccharides. The glucose is transported via the portal system to the liver, which extracts a considerable fraction of portal venous glucose. The remainder enters the systemic circulation and causes pancreatic secretion of insulin. The high portal vein insulin and glucose concentrations lead to hepatic glucose uptake with conversion to glycogen and fatty acids. The peripheral rise in insulin, which occurs in association with the rise in plasma glucose concentration, causes a large peripheral uptake of glucose, first by muscle cells, and second by adipocytes. Glucose is the essential substrate for brain, renal medulla and red cell metabolism; other organs mainly use fatty acids for energy. The rise in plasma insulin also leads to amino acid uptake by muscle and has an antiproteolytic effect. These effects on muscle protein have led to the designation of insulin as an "anabolic hormone." In the postabsorptive or interdigestive state, plasma glucose is low, with low plasma insulin levels. The low plasma insulin influences the metabolism of all three macronutrients (i.e., carbohydrates, fat and protein). Glycogenolysis occurs in the liver to maintain plasma glucose levels. The low plasma insulin also allows lipolysis to take place, such that fatty acids can be utilized as the major energy substrate. Finally, the low plasma insulin leads to proteolysis, particularly of muscle protein, which leads to release of alanine and glutamine, which can be used for gluconeogenesis in the liver. This gluconeogenesis occurs in concert with glycogenolysis to assure an ongoing supply of glucose for the body.

Other hormones, such as glucagon, catecholamines and growth hormone, play less important roles in macronutrient metabolism, but in general have been termed the "stress hormones," since they are released during times of stress and have anti-insulin effects. In particular, if for any reason there is a low blood sugar, all these hormones are released and will promote an elevation in plasma glucose.

The flux of lipid nutrients in the fed and the interdigestive states is contrasted in Figure 2. In the fed state, fat enters the circulation from the intestine as chylomicrons, which are large droplets of triglyceride emulsified by a surface monolayer of phospholipid and apolipoproteins. Additional apolipoproteins are transferred onto the chylomicrons from HDL. The artificial fat emulsions used for parenteral nutrition are very similar to chylomicrons in that they contain a core of triglyceride with a surface monolayer of phospholipid. They initially contain no apolipoproteins, but acquire these from HDL very rapidly once they have entered the circulation. One of the apolipoproteins, apolipoprotein C-II, is particularly important in that it is an essential cofactor for the action of lipoprotein lipase. This enzyme is attached to the capillary endothelium in tissues, such as the heart and adipose tissue, that are active in utilizing fatty acids. Chylomicrons bind to the enzyme and the core triglyceride is rapidly hydrolyzed. The released fatty acids are then taken up and utilized in the peripheral tissues. As the chylomicron particle shrinks in size, the excess surface material is transferred back to HDL, and ultimately the remnant particles are cleared via a specific receptor in the liver. The process of lipolysis is extremely efficient, and the half-life of chylomicron triglyceride in the circulation is normally less than 15 minutes. The lower panel of Figure 2 depicts the postabsorptive or interdigestive state. Chylomicrons are absent, but triglyceride fuels are available in the circulation in the form of VLDL, which are secreted by the liver. The substrates for triglyceride assembly include free fatty acids released from adipose tissue through the action of a hormone-sensitive lipase, and fatty acids synthesized in the liver from acetyl-CoA. The newly secreted VLDL acquire apolipoproteins and cholesterol ester from HDL. Lipolysis of VLDL in peripheral tissues is mediated by lipoprotein lipase. As the particle decreases in size, free cholesterol transfers to HDL, where it is esterified through the action of lecithin-cholesterol acyltransferase (LCAT), and the resultant cholesterol ester is then transferred back to the lipolyzed particle, where it forms part of the core. When lipolysis is completed, what is left behind is termed an LDL particle. This is smaller and more dense than VLDL, has lost all apolipoproteins except apolipoprotein B, and has a core of cholesterol ester rather than triglyceride. LDL is cleared relatively slowly, with a half-life of several days. The uptake of LDL is mediated by a specific membrane receptor, termed the LDL receptor, whose activity in turn is regulated by intracellular cholesterol levels. The most active tissues (on a weight basis) for LDL clearance are steroidogenic tissues, such as the adrenals, gonads and the liver; because of its size, the liver accounts for over half of total LDL catabolism. As peripheral tissues cannot degrade cholesterol, excess cholesterol is returned to the liver via HDL, where it is used for bile acid synthesis or excreted in the bile.

In addition to the short-term regulation mediated by substrates and hormones outlined above, additional adaptive responses occur in response to particular dietary circumstances. For example, a diet rich in carbohydrate at the expense of fat will lead to the induction of enzymes involved in glycolysis, the pentose phosphate pathway and fatty acid synthesis (e.g., glucokinase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, acetyl-CoA carboxylase). A diet containing predominantly fat at the expense of carbohydrate will lead to induction of fatty acid oxidation, with increased acyl-CoA-carnitine acyltransferase, and induction of enzymes involved in gluconeogenesis, including glucose-6-phosphatase, fructose diphosphatase and transaminases. A diet rich in protein but low in carbohydrate will also lead to induction of gluconeogenic enzymes and transaminases, as well as other enzymes involved in amino acid interconversion and degradation, and induction of urea cycle enzymes to deal with the enhanced production of ammonia.

Starvation leads to a number of adaptive responses. There is a depletion of liver glycogen within 24 to 48 hours, with stimulation of gluconeogenic enzymes to allow the production of glucose from amino acids released through protein breakdown in skeletal muscle. Lipolysis in adipose tissue leads to increased fatty acid levels and activation of enzymes responsible for ß-oxidation of fatty acid in the liver (acyl-CoA-carnitine acyltransferase). In addition to acetyl-CoA, fatty acid oxidation generates ketone bodies. One important adaptive response to starvation is the induction of 3-hydroxybutyrate dehydrogenase in the brain, which allows this organ to utilize ketone bodies as a fuel. Decreased dependence on glucose reduces the need for excess gluconeogenesis and spares muscle protein. In a relatively lean 70 kg man with 12% body fat, survival without food can be expected to be about 60 days or longer.