Immediate Dumping Of Available Preformed Insulin

►Depolarization

Figure 78-8

Increase in plasma insulin concentration after a sudden increase in blood glucose to two to three times the normal range. Note an initial rapid surge in insulin concentration and then a delayed but higher and continuing increase in concentration beginning 15 to 20 minutes later.

Figure 78-7

Basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas. GLUT, glucose transporter.

metabolism, it has become apparent that blood amino acids and other factors also play important roles in controlling insulin secretion (see Table 78-1).

Table 78-1

Factors and Conditions That Increase or Decrease Insulin Secretion

Increase Insulin Secretion

• Increased blood glucose

• Increased blood free fatty acids

• Increased blood amino acids

• Gastrointestinal hormones (gastrin, cholecystokinin, secretin, gastric inhibitory peptide)

• Glucagon, growth hormone, cortisol

• Parasympathetic stimulation; acetylcholine

• ^-Adrenergic stimulation

• Insulin resistance;obesity

• Sulfonylurea drugs (glyburide, tolbutamide)

Decrease Insulin Secretion

• Decreased blood glucose

• Somatostatin

• a-Adrenergic activity

• Leptin effect that triggers insulin secretion, making these drugs very useful in stimulating insulin secretion in patients with type II diabetes, as we will discuss later. Table 78-1 summarizes some of the factors that can increase or decrease insulin secretion.

Increased Blood Glucose Stimulates Insulin Secretion. At the normal fasting level of blood glucose of 80 to 90 mg/100 ml, the rate of insulin secretion is minimal— on the order of 25 ng/min/kg of body weight, a level that has only slight physiologic activity. If the blood glucose concentration is suddenly increased to a level two to three times normal and kept at this high level thereafter, insulin secretion increases markedly in two stages, as shown by the changes in plasma insulin concentration seen in Figure 78-8.

1. Plasma insulin concentration increases almost 10-fold within 3 to 5 minutes after the acute elevation of the blood glucose; this results from immediate dumping of preformed insulin from the beta cells of the islets of Langerhans. However, the initial high rate of secretion is not maintained; instead, the insulin concentration decreases about halfway back toward normal in another 5 to 10 minutes.

2. Beginning at about 15 minutes, insulin secretion rises a second time and reaches a new plateau in 2 to 3 hours, this time usually at a rate of secretion even greater than that in the initial phase. This secretion results both from additional release of preformed insulin and from activation of the enzyme system that synthesizes and releases new insulin from the cells.

Control of Insulin Secretion

Formerly, it was believed that insulin secretion was controlled almost entirely by the blood glucose concentration. However, as more has been learned about the metabolic functions of insulin for protein and fat

Feedback Relation Between Blood Glucose Concentration and Insulin Secretion Rate. As the concentration of blood glucose rises above 100 mg/100 ml of blood, the rate of insulin secretion rises rapidly, reaching a peak some 10 to 25 times the basal level at blood glucose concentrations between 400 and 600 mg/100 ml, as shown

Plasma glucose concentration (mg/100 ml)

Figure 78-9

Approximate insulin secretion at different plasma glucose levels.

in Figure 78-9. Thus, the increase in insulin secretion under a glucose stimulus is dramatic both in its rapidity and in the tremendous level of secretion achieved. Furthermore, the turn-off of insulin secretion is almost equally as rapid, occurring within 3 to 5 minutes after reduction in blood glucose concentration back to the fasting level.

This response of insulin secretion to an elevated blood glucose concentration provides an extremely important feedback mechanism for regulating blood glucose concentration. That is, any rise in blood glucose increases insulin secretion, and the insulin in turn increases transport of glucose into liver, muscle, and other cells, thereby reducing the blood glucose concentration back toward the normal value.

Other Factors That Stimulate Insulin Secretion

Amino Acids. In addition to the stimulation of insulin secretion by excess blood glucose, some of the amino acids have a similar effect. The most potent of these are arginine and lysine. This effect differs from glucose stimulation of insulin secretion in the following way: Amino acids administered in the absence of a rise in blood glucose cause only a small increase in insulin secretion. However, when administered at the same time that the blood glucose concentration is elevated, the glucose-induced secretion of insulin may be as much as doubled in the presence of the excess amino acids. Thus, the amino acids strongly potentiate the glucose stimulus for insulin secretion.

The stimulation of insulin secretion by amino acids is important, because the insulin in turn promotes transport of amino acids into the tissue cells as well as intracellular formation of protein. That is, insulin is important for proper utilization of excess amino acids in the same way that it is important for the utilization of carbohydrates.

Gastrointestinal Hormones. A mixture of several important gastrointestinal hormones—gastrin, secretin, cholecystokinin, and gastric inhibitory peptide (which seems to be the most potent)—causes a moderate increase in insulin secretion. These hormones are released in the gastrointestinal tract after a person eats a meal. They then cause an "anticipatory" increase in blood insulin in preparation for the glucose and amino acids to be absorbed from the meal. These gastrointestinal hormones generally act the same way as amino acids to increase the sensitivity of insulin response to increased blood glucose, almost doubling the rate of insulin secretion as the blood glucose level rises.

Other Hormones and the Autonomic Nervous System. Other hormones that either directly increase insulin secretion or potentiate the glucose stimulus for insulin secretion include glucagon, growth hormone, cortisol, and, to a lesser extent, progesterone and estrogen. The importance of the stimulatory effects of these hormones is that prolonged secretion of any one of them in large quantities can occasionally lead to exhaustion of the beta cells of the islets of Langerhans and thereby increase the risk for developing diabetes mellitus. Indeed, diabetes often occurs in people who are maintained on high pharmacological doses of some of these hormones. Diabetes is particularly common in giants or acromegalic people with growth hormone-secreting tumors, or in people whose adrenal glands secrete excess glucocorticoids.

Under some conditions, stimulation of the parasym-pathetic nerves to the pancreas can increase insulin secretion. However, it is doubtful that this effect is of physiologic significance for regulating insulin secretion.

Role of Insulin (and Other Hormones) in "Switching" Between Carbohydrate and Lipid Metabolism

From the preceding discussions, it should be clear that insulin promotes the utilization of carbohydrates for energy, whereas it depresses the utilization of fats. Conversely, lack of insulin causes fat utilization mainly to the exclusion of glucose utilization, except by brain tissue. Furthermore, the signal that controls this switching mechanism is principally the blood glucose concentration. When the glucose concentration is low, insulin secretion is suppressed and fat is used almost exclusively for energy everywhere except in the brain. When the glucose concentration is high, insulin secretion is stimulated and carbohydrate is used instead of fat, and the excess blood glucose is stored in the form of liver glycogen, liver fat, and muscle glycogen. Therefore, one of the most important functional roles of insulin in the body is to control which of these two foods from moment to moment will be used by the cells for energy.

At least four other known hormones also play important roles in this switching mechanism: growth hormone from the anterior pituitary gland, cortisol from the adrenal cortex, epinephrine from the adrenal medulla, and glucagon from the alpha cells of the islets of Langerhans in the pancreas. Glucagon is discussed in the next section of this chapter. Both growth hormone and cortisol are secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while promoting fat utilization. However, the effects of both of these hormones develop slowly, usually requiring many hours for maximal expression.

Epinephrine is especially important in increasing plasma glucose concentration during periods of stress when the sympathetic nervous system is excited. However, epinephrine acts differently from the other hormones in that it increases the plasma fatty acid concentration at the same time. The reasons for these effects are as follows: (1) epinephrine has the potent effect of causing glycogenolysis in the liver, thus releasing within minutes large quantities of glucose into the blood; (2) it also has a direct lipolytic effect on the adipose cells because it activates adipose tissue hormone-sensitive lipase, thus greatly enhancing the blood concentration of fatty acids as well. Quantitatively, the enhancement of fatty acids is far greater than the enhancement of blood glucose. Therefore, epinephrine especially enhances the utilization of fat in such stressful states as exercise, circulatory shock, and anxiety.

Glucagon and Its Functions

Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when the blood glucose concentration falls, has several functions that are diametrically opposed to those of insulin. Most important of these functions is to increase the blood glucose concentration, an effect that is exactly the opposite that of insulin.

Like insulin, glucagon is a large polypeptide. It has a molecular weight of 3485 and is composed of a chain of 29 amino acids. On injection of purified glucagon into an animal, a profound hyperglycemic effect occurs. Only 1 mg/kg of glucagon can elevate the blood glucose concentration about 20 mg/100 ml of blood (a 25 per cent increase) in about 20 minutes. For this reason, glucagon is also called the hyperglycemic hormone.

Effects on Glucose Metabolism

The major effects of glucagon on glucose metabolism are (1) breakdown of liver glycogen (glycogenolysis) and (2) increased gluconeogenesis in the liver. Both of these effects greatly enhance the availability of glucose to the other organs of the body.

Glucagon Causes Glycogenolysis and Increased Blood Glucose Concentration. The most dramatic effect of glucagon is its ability to cause glycogenolysis in the liver, which in turn increases the blood glucose concentration within minutes.

It does this by the following complex cascade of events:

1. Glucagon activates adenylyl cyclase in the hepatic cell membrane,

2. Which causes the formation of cyclic adenosine monophosphate,

3. Which activates protein kinase regulator protein,

4. Which activates protein kinase,

5. Which activates phosphorylase b kinase,

6. Which converts phosphorylase b into phosphorylase a,

7. Which promotes the degradation of glycogen into glucose-1-phosphate,

8. Which then is dephosphorylated; and the glucose is released from the liver cells.

This sequence of events is exceedingly important for several reasons. First, it is one of the most thoroughly studied of all the second messenger functions of cyclic adenosine monophosphate. Second, it demonstrates a cascade system in which each succeeding product is produced in greater quantity than the preceding product. Therefore, it represents a potent amplifying mechanism; this type of amplifying mechanism is widely used throughout the body for controlling many, if not most, cellular metabolic systems, often causing as much as a millionfold amplification in response. This explains how only a few micrograms of glucagon can cause the blood glucose level to double or increase even more within a few minutes.

Infusion of glucagon for about 4 hours can cause such intensive liver glycogenolysis that all the liver stores of glycogen become depleted.

Glucagon Increases Gluconeogenesis. Even after all the glycogen in the liver has been exhausted under the influence of glucagon, continued infusion of this hormone still causes continued hyperglycemia. This results from the effect of glucagon to increase the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose by gluconeogenesis. This is achieved by activating multiple enzymes that are required for amino acid transport and gluconeogenesis, especially activation of the enzyme system for converting pyruvate to phospho-enolpyruvate, a rate-limiting step in gluconeogenesis.

Other Effects of Glucagon

Most other effects of glucagon occur only when its concentration rises well above the maximum normally found in the blood. Perhaps the most important effect is that glucagon activates adipose cell lipase, making increased quantities of fatty acids available to the energy systems of the body. Glucagon also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids from the blood; this also helps make additional amounts of fatty acids available for the other tissues of the body.

Glucagon in very high concentrations also (1) enhances the strength of the heart; (2) increases blood flow in some tissues, especially the kidneys; (3) enhances bile secretion; and (4) inhibits gastric acid secretion. All these effects are probably of minimal importance in the normal function of the body.

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