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Endocrine and Neural Control of the Absorptive and Postabsorptive States
- We now turn to the endocrine and neural factors that control and integrate these metabolic pathways.
- (1) What controls net anabolism of protein, glycogen, and triglyceride in the
- absorptive state, and net catabolism in the postabsorptive state?
- (2) What induces the cells to utilize primarily glucose for energy during the absorptive state but fat during the postabsorptive state?
- (3) What stimulates net glucose uptake by the liver during the absorptive state but gluconeogenesis and glucose release during the postabsorptive state?
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The most important controls of these transitions from feasting to fasting, and vice versa
- are two pancreatic hormone insulin and glucagon.
- Also having a function are the hormones epinephrine and cortisol from the adrenal glands, growth hormone from the anterior pituitary gland, and the sympathetic nerves to the liver and adipose tissue.
- Insulin and glucagon are polypeptide hormones secreted by the islets of Langerhans (or, simply, pancreatic islets), clusters of endocrine cells in the pancreas.
- There are several distinct types of islet cells, each of which secretes a different hormone.
- The beta cells (or B cells) are the source of insulin, and the alpha cells (or A cells) are the source of glucagon.
- There are other molecules secreted by still other islet cells, but the functions of these other molecules in humans are less well established.
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Insulin
- The beta cells (b cells) in pancreatic islets are the source of insulin.
- Insulin is the most important controller of organic metabolism.
- Its secretion—and, therefore, its plasma concentration—is increased during the absorptive state and decreased during the postabsorptive state.
- The metabolic effects of insulin are exerted mainly on muscle cells (both cardiac and skeletal), adipocytes, and hepatocytes.
- An increased plasma concentration of insulin is the major cause of the absorptive-state events, and a decreased plasma concentration of insulin is the major cause of the postabsorptive events.
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Insulin binding
- Like all polypeptide hormones, insulin induces its effects by binding to specific receptors on the plasma membranes of its target cells.
- This binding triggers signal transduction pathways that influence the plasma membrane transport proteins and intracellular enzymes of the target cell.
- For example, in skeletal muscle cells and adipocytes, an increased insulin concentration stimulates cytoplasmic vesicles that contain a particular type of glucose transporter (GLUT-4) in their membranes to fuse with the plasma membrane
- The increased number of plasma membrane glucose transporters resulting from this fusion results in a greater rate of glucose diffusion from the extracellular fluid into the cells by facilitated diffusion.
- Glucose enters most body cells by facilitated diffusion. Multiple subtypes of glucose transporters mediate this process, however, and the subtype GLUT-4, which is regulated by insulin, is found mainly in skeletal muscle cells and adipocytes.
- Of great significance is that the cells of the brain express a different subtype of GLUT, one that has very high affinity for glucose and whose activity is not insulin-dependent; it is always present in the plasma membranes of neurons in the brain.
- This ensures that even if the plasma insulin concentration is very low, as in prolonged fasting, cells of the brain can continue to take up glucose from the blood and maintain their function.
- The essential information to understand about the actions of insulin is the target cells’ ultimate responses (figure 16.6)
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The essential information to understand about the actions of insulin is the target cells’ ultimate responses (figure 16.6)
- A major principle illustrated by Figure 16.8 is that, in each of its target cells, insulin brings about its ultimate responses by multiple actions.
- Take, for example, its effects on skeletal muscle cells. In these cells, insulin favors glycogen formation and storage by
- (1) increasing glucose transport into the cell,
- (2) stimulating the key enzyme (glycogen synthase) that catalyzes (increases) the rate-limiting step in glycogen synthesis, [increases rate of glycogen synthesis] and
- (3) inhibiting the key enzyme (glycogen phosphorylase) that catalyzes glycogen catabolism.
- As a result, insulin favors glucose transformation to and storage as glycogen in skeletal muscle through three mechanisms.
- Similarly, for protein synthesis in skeletal muscle cells, insulin
- (1) increases the number of active plasma membrane transporters for amino acids, thereby increasing amino acid transport into the cells;
- (2) stimulates the ribosomal enzymes that mediate the synthesis of protein from these amino acids; and
- (3) inhibits the enzymes that mediate protein catabolism.
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Control of Insulin Secretion- plasma glucose and amino acid concentration
- The major controlling factor for insulin secretion is the plasma glucose concentration
- An increase in plasma glucose concentration, as occurs after a meal containing carbohydrate, acts on the beta cells of the islets of Langerhans to stimulate insulin secretion, whereas a decrease in plasma glucose removes the stimulus for insulin secretion.
- Following a meal: The insulin stimulates the entry of glucose into muscle and adipose tissue, as well as net uptake rather than net output of glucose by the liver.
- These effects subsequently decrease the blood concentration of glucose to its premeal level, thereby removing the stimulus for insulin secretion and causing it to return to its previous level. This is a classic example of a homeostatic process regulated by negative feedback.
- In addition to plasma glucose concentration, several other factors control insulin secretion (Figure 16.10).
- For example, increased amino acid concentrations stimulate insulin secretion.
- This is another negative feedback control; amino acid concentrations
- increase in the blood after ingestion of a protein-containing meal, and the increased plasma insulin stimulates the uptake of these amino acids by muscle and other cells, thereby lowering their concentrations.
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Control of Insulin Secretion- hormonal controls
- There are also important hormonal controls over insulin secretion.
- For example, a family of hormones known as incretins—secreted by enteroendocrine cells in the gastrointestinal tract in response to eating—amplifies the insulin response to glucose.
- The major incretins include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).
- The actions of incretins provide a feedforward component to glucose
- regulation during the ingestion of a meal.
- Consequently, insulin secretion increases more than it would if plasma glucose were the only controller, thereby minimizing the absorptive peak in plasma glucose concentration.
- This mechanism minimizes the likelihood of large increases in plasma glucose after a meal, which among other things could exceed the capacity of the kidneys to completely reabsorb all of the glucose that appears in the filtrate in the renal nephrons.
- An analog of GLP-1 is currently used for the treatment of type 2 diabetes mellitus, in which the pancreas often produces insufficient insulin and the body’s cells are less responsive to insulin.
- Finally, input of the autonomic neurons to the islets of Langerhans also influences insulin secretion.
- Activation of the parasympathetic neurons, which occurs during the ingestion of a meal, stimulates the secretion of insulin and constitutes a second type of feedforward regulation.
- In contrast, activation of the sympathetic neurons to the islets or an increase in the plasma concentration of epinephrine (the hormone secreted by the adrenal medulla) inhibits insulin secretion.
- The body’s response to low plasma glucose (hypoglycemia), stress, and exercise—all situations in which sympathetic activity is increased—in all of these situations an increase in plasma glucose concentration would be beneficial.
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glucose-counterregulatory controls.
- Other hormonal and neural factors, that oppose the action of insulin in one way or another and are known as glucose-counterregulatory controls.
- The most important of these are glucagon, epinephrine, sympathetic nerves, cortisol, and growth hormone.
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Glucagon
- As mentioned earlier, glucagon is the polypeptide hormone produced by the alpha cells of the pancreatic islets.
- The major physiological effects of glucagon occur within the liver and oppose those of insulin.
- Thus, glucagon
- (1) stimulates glycogenolysis,
- (2) stimulates gluconeogenesis, and
- (3) stimulates the synthesis of ketones.
- The are to increase the plasma concentrations of glucose and ketones, which are important for the postabsorptive state, and to prevent hypoglycemia.
- The effects, if any, of glucagon on adipocyte function in humans are still unresolved.
- The major stimulus for glucagon secretion is a decrease in the circulating concentration of glucose (which in turn causes a decrease in plasma insulin)
- By its effects on metabolism, serves to restore normal blood glucose concentration by glycogenolysis and gluconeogenesis.
- At the same time, glucagon supplies ketones for utilization by the brain.
- Conversely, an increased plasma glucose concentration inhibits the secretion of glucagon, thereby helping to return the plasma glucose concentration toward normal.
- As a result, during the postabsorptive state, there is an increase in the glucagon/insulin ratio in the plasma, and this accounts almost entirely for the transition from the absorptive to the postabsorptive state.
- The dual and opposite actions of glucagon and insulin on glucose homeostasis clearly illustrate the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition.
- The secretion of glucagon, like that of insulin, is controlled not only by the plasma concentration of glucose but also by amino acids and by neural and hormonal inputs to the islets.
- For example, significant increases in certain amino acids—as may occur after a meal rich in protein—stimulate an increase in plasma glucagon
- Recall that amino acids also stimulate insulin secretion.
- Glucagon secreted in such situations helps prevent hypoglycemia [decrease in glucose from normal] that may occur following the increase in insulin in a protein-rich meal.
- As another example, the sympathetic nerves to the islets stimulate glucagon secretion—just the opposite of their effect on insulin secretion.
- Glucagon, then, is part of the fight-or-flight responses. This is one way in which additional energy in the form of glucose is provided in times of stress or emergency.
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Epinephrine and Sympathetic Nerves to Liver and Adipose Tissue
- As just noted, epinephrine and the sympathetic nerves to the pancreatic islets inhibit insulin secretion and stimulate glucagon secretion.
- In addition, epinephrine also affects nutrient metabolism directly (Figure 16.12). Its major direct effects include stimulation of
- (1) glycogenolysis in both the liver and skeletal muscle,
- (2) gluconeogenesis in the liver, and
- (3) lipolysis in adipocytes.
- Activation of the sympathetic nerves to the liver and adipose tissue elicits the same responses from these organs as does circulating epinephrine.
- In adipocytes, epinephrine stimulates the activity of an enzyme called hormone-sensitive lipase (HSL).
- Once activated, HSL works along with other enzymes to catalyze the breakdown of triglycerides to free fatty acids and glycerol.
- Both are then released into the blood, where they serve directly as an energy source (fatty acids) or as a gluconeogenic precursor (glycerol).
- Not surprisingly, insulin inhibits the activity of HSL during the absorptive state, because it would not be beneficial to break down stored fat when the blood is receiving nutrients from ingested food.
- Thus, enhanced sympathetic nervous system activity exerts effects on organic metabolism—specifically, increased plasma concentrations of glucose, glycerol, and fatty acids—that are opposite those of insulin.
- As might be predicted from these effects, low blood glucose leads to increases in both epinephrine secretion and sympathetic nerve activity to the liver and adipose tissue.
- This is the same stimulus that leads to increased glucagon secretion, although the receptors and pathways are totally different.
- When the plasma glucose concentration decreases, glucose-sensitive cells in the central nervous system initiate the reflexes that lead to increased
- activity in the sympathetic pathways to the adrenal medulla, liver,
- and adipose tissue.
- The adaptive value of the response is the same as that for the glucagon response to hypoglycemia; blood glucose returns toward normal, and fatty acids are supplied for cell utilization.
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Cortisol
- Cortisol, the major glucocorticoid produced by the adrenal cortex, has an essential permissive function in the adjustments to fasting.
- We have described how fasting is associated with the stimulation of both gluconeogenesis and lipolysis; however, neither of these critical metabolic transformations occurs to the usual degree in a person deficient in cortisol.
- In other words, the plasma cortisol concentration does not need to increase much during fasting, but the presence of cortisol in the blood maintains the concentrations of the key liver and adipose-tissue enzymes required for gluconeogenesis and lipolysis—for example, HSL
- Therefore, in response to fasting, individuals with a cortisol deficiency can develop hypoglycemia significant enough to interfere with cellular function.
- Moreover, cortisol can have more than a permissive function when its plasma concentration does increase, as it does during stress.
- At high concentrations, cortisol elicits many metabolic events ordinarily associated with fasting. In fact, cortisol actually decreases the sensitivity of muscle and adipose cells to insulin, which helps to maintain plasma glucose concentration during fasting, thereby providing a regular source of energy for the brain.
- Clearly, here is another hormone that, in addition to glucagon and epinephrine, can exert actions opposite those of insulin.
- Indeed, individuals with pathologically high plasma concentrations of cortisol or who are treated with synthetic glucocorticoids for medical reasons can
- develop symptoms similar to those seen in individuals, such as those with type 2 diabetes mellitus, whose cells do not respond adequately to insulin.
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Growth Hormone
- The primary physiological effects of growth hormone are to stimulate both growth and protein synthesis.
- Compared to these effects, those it exerts on carbohydrate and lipid metabolism are less significant. Nonetheless, as is true for cortisol, either deficiency or excess of growth hormone does produce significant abnormalities in lipid and carbohydrate metabolism.
- Growth hormone’s effects on these nutrients, in contrast to those on protein metabolism, are similar to those of cortisol and opposite those of insulin.
- Growth hormone
- (1) increases the responsiveness of adipocytes to lipolytic stimuli,
- (2) stimulates gluconeogenesis by the liver, and
- (3) reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue.
- These three effects are often termed growth hormone’s “anti-insulin effects.”
- Because of these effects, some of the symptoms observed in individuals with acromegaly (excess growth hormone production) are similar to those observed in people with insulin resistance due to type 2 diabetes mellitus.
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Hypoglycemia
- Hypoglycemia is broadly defined as an abnormally low plasma glucose concentration
- The plasma glucose concentration can decrease to very low values, usually during the postabsorptive state, in persons with several types of disorders.
- Fasting hypoglycemia and the relatively uncommon disorders responsible for it can be understood in terms of the regulation of blood glucose concentration.
- They include (1) an excess of insulin due to an insulin-producing tumor, drugs that stimulate insulin secretion, or taking too much insulin (if the person is diabetic); and
- (2) a defect in one or more glucose-counterregulatory controls, for example, inadequate glycogenolysis and/or gluconeogenesis due to liver disease or cortisol deficiency.
- Fasting hypoglycemia causes many symptoms. Some— increased heart rate, trembling, nervousness, sweating, and anxiety—are accounted for by activation of the sympathetic nervous system caused reflexively by the hypoglycemia.
- Other symptoms, such as headache, confusion, dizziness, loss of coordination,
- and slurred speech, are direct consequences of too little glucose reaching neurons of the brain
- More serious neurological effects, including convulsions and coma, can occur if the plasma glucose decreases to very low concentrations.
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