Immediately after eating, metabolic activity is directed toward the processing and sequestration of energy-rich substrates that are absorbed by the intestines. This phase is dominated by insulin, which is secreted in response to three inputs to the beta cells. The cephalic, or psychological aspect of eating, stimulates insulin secretion through acetylcholine and vasoactive inhibitory peptide (VIP) released from vagal fibers that innervate islet cells. Food in the small intestine stimulates secretion of
When either growth hormone or glucocorticoids are present in excess for prolonged periods, diabetes mellitus often results. Approximately 30% of patients suffering from excess GH (acromegaly) and a similar percentage of persons suffering from Cushing's disease (excess gluco-corticoids) experience diabetes mellitus as a complication of their disease. Most of the others have some decrease in their ability to dispose of a glucose load (decreased glucose tolerance). In the early stages diabetes is reversible and disappears when the excess pituitary or adrenal secretion is corrected. Later, however, diabetes may become irreversible, and the islet cells may be destroyed. This so-called diabetogenic effect is an important consideration with chronic glucocorticoid therapy and argues against use of GH to build muscle mass in athletes.
TABLE 4 Hormonal Effects on Insulin Secretion and Sensitivity of Target Cells to Insulin
Glucagon " #b
Epinephrine, norepinephrine # #b
(I) Indirect effect; increases sensitivity to direct stimuli.
aDown-regulation of receptors.
bStimulates opposite effects in liver.
intestinal hormones, especially glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are potent secretagogues for insulin. Finally, the beta cells respond directly to increased glucose and amino acids in arterial blood (see Chapter 41). During the postprandial period the concentration of insulin in peripheral blood may rise from a resting value of about 10 mUnits/mL to perhaps as much as 50 mUnits/mL. Glucagon secretion may also increase at this time in response to amino acids in arterial blood. Dietary amino acids may also stimulate growth hormone secretion. Characteristically, the sympathetic nervous system is relatively quiet during the postprandial period, and there is little secretory activity of the adrenal medulla or cortex at this time. Under the dominant influence of insulin, dietary carbohydrates and lipids are transferred to storage depots in liver, adipose tissue, and muscle; and amino acids are converted to proteins in various tissues. Extrahepatic tissues use dietary glucose and fat to meet their needs instead of glucose derived from hepatic glycogen or fatty acids mobilized from adipose tissue. Hepatic glycogen increases by an amount equivalent to about half of the ingested carbohydrate. Fatty acid mobilization is inhibited by the high concentrations of insulin and glucose in blood. Of course, the composition of the diet profoundly affects postprandial responses. Obviously, a diet rich in carbohydrate elicits quantitatively different responses from one that is mainly composed of fat.
Several hours after eating, when metabolic fuels have largely been absorbed from the intestine, the body begins to draw on fuels that were stored during the postprandial period. During this period insulin secretion returns to relatively low basal rates and is governed principally by the concentration of glucose in blood, which has returned to about 5 mM (90 mg/dL). About 75% of the glucose secreted by the liver derives from glycogen, and the remainder comes from gluconeogenesis, driven principally by glucagon. Although the rate of glucagon secretion is relatively low at this time, the decline in insulin enables the actions of glucagon to prevail. Growth hormone and cortisol are also secreted at relatively low basal rates in the postabsorptive period. About 75% of the glucose consumed by extrahepatic tissues during this period is taken up by brain, blood cells, and other tissues whose consumption of fuels is independent of insulin. Muscle and adipose tissue, which are highly dependent on insulin account for the remaining 25%. FFA gradually increase as adipose tissue is progressively relieved of the restraint imposed by high levels of insulin during the postprandial period. Blood glucose remains constant during this period, but glucose metabolism in muscle decreases as the restrictive effects of the glucose-fatty acid cycle become operative. Liver gradually depletes its glycogen stores and begins to rely more heavily on gluconeogenesis from amino acids and glycerol to replace glucose consumed by extrahepatic tissues.
More than 24 hr after the last meal, the individual can be considered to be fasting. At this time, circulating insulin concentrations decrease further, and glucagon and GH increase. Cortisol secretion follows its basal diurnal rhythmic pattern (see Chapter 40) unaffected by fasting at this early stage; but basal concentrations of cortisol play their essential permissive role in allowing gluconeogenesis and lipolysis to proceed. Glucocorti-coids and GH also exert a restraining influence on glucose metabolism in muscle and adipose tissue. With the further decrease in insulin concentration, any remaining restraint on lipolysis is removed. The lipolytic cycle speeds up, fatty acid esterification decreases, and FFA mobilization is accelerated. This effect is supported and accelerated by GH and cortisol. Decreased insulin permits net breakdown of muscle protein; and the amino acids that consequently leave muscle, mainly as alanine, provide the substrate for gluconeogenesis. Fuel consumption after 24 hr of fasting is shown in Fig. 7.
With prolonged fasting of 3 days or more, increased GH and decreased insulin concentrations in blood result in even greater mobilization of FFA. Ketogenesis becomes significant, driven by the almost unopposed action of glucagon. By about the third day of starvation, ketone bodies in blood reach concentrations of 2-3 mM and begin to provide for an appreciable fraction of the brain's metabolic needs. Urinary nitrogen excretion decreases to the postabsorptive level or below as the rapidly turning over pool of proteins diminishes. During subsequent weeks of total starvation, nitrogen excretion
Insulin secretion Sensitivity of target by beta cells cells to insulin
Origin of Fuel
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