Regulation of Insulin and Glucagon Secretion

Insulin and glucagon secretion is largely regulated by the plasma concentrations of glucose and, to a lesser degree, of amino acids. The alpha and beta cells, therefore, act as both the sensors and effectors in this control system. Since the plasma concentration of glucose and amino acids rises during the absorption of a meal and falls during fasting, the secretion of insulin and glucagon likewise fluctuates between the absorptive and postabsorptive states. These changes in insulin and gluca-gon secretion, in turn, cause changes in plasma glucose and amino acid concentrations and thus help to maintain homeosta-sis via negative feedback loops (fig. 19.6).

As described in chapter 6, insulin stimulates the insertion of GLUT4 channels into the plasma membrane (due to the fusion of intracellular vesicles with the plasma membrane—see fig. 6.15) of its target cells, primarily in the skeletal and cardiac muscles, adipose tissue, and liver. This permits the entry of glucose into its target cells by facilitated diffusion. As a result, in-

■ Figure 19.6 The regulation of insulin and glucagon secretion. The secretion from the P (beta) cells and a (alpha) cells of the pancreatic islets is regulated largely by the blood glucose concentration. (a) A high blood glucose concentration stimulates insulin and inhibits glucagon secretion. (b) A low blood glucose concentration stimulates glucagon and inhibits insulin secretion.

sulin promotes the production of the energy-storage molecules of glycogen and fat. Both actions decrease the plasma glucose concentration. Insulin also inhibits the breakdown of fat, induces the production of fat-forming enzymes, and inhibits the breakdown of muscle proteins. Thus, insulin promotes an-abolism as it regulates the blood glucose concentration.

The mechanisms that regulate insulin and glucagon secretion and the actions of these hormones normally prevent the plasma glucose concentration from rising above 170 mg per 100 ml after a meal or from falling below about 50 mg per 100 ml between meals. This regulation is important because abnormally high blood glucose can damage certain tissues (as may occur in diabetes mellitus), and abnormally low blood glucose can damage the brain. The latter effect results from the fact that glucose enters the brain by facilitated diffusion; when the rate of this diffusion is too low, as a result of low plasma glucose concentrations, the supply of metabolic energy for the brain may become inadequate. This can result in weakness, dizziness, personality changes, and ultimately in coma and death.

Insulin

Opens voltage-Ca2+ gated Ca2+ \ channels

, Stimulus

* Blood glucose

-GLUT2

Glucose

Krebs cycle

Glycolysis

[ Oxidative phosphorylation

I Ratio of ATP to ADP Depolarization -

Vesicle containing insulin

Fusion and exocytosis of vesicles

Glycolysis

Closes K+ channels

Response

- Insulin secreted

■ Figure 19.7 Regulation of insulin secretion. When glucose enters the ß cells of the pancreatic islets, it stimulates the secretion of insulin. This figure illustrates the steps involved in this process.

Effects of Glucose and Amino Acids

The fasting plasma glucose concentration is in the range of 65 to 105 mg/dl. During the absorption of a meal, the plasma glucose concentration usually rises to a level between 140 and 150 mg/dl. This rise in plasma glucose (1) stimulates the beta cells to secrete insulin (fig 19.7), and (2) inhibits the secretion of glucagon from the alpha cells. Insulin then acts to stimulate the cellular uptake of plasma glucose. A rise in insulin secretion therefore lowers the plasma glucose concentration. Since glucagon has the antagonistic effect of raising the plasma glucose concentration by stimulating glycogenolysis in the liver, the inhibition of glucagon secretion complements the effect of increased insulin during the absorption of a carbohydrate meal. A rise in insulin and a fall in glucagon secretion thus help to lower the high plasma glucose concentration that occurs during periods of absorption.

During fasting, the plasma glucose concentration falls. At this time, therefore, (1) insulin secretion decreases and (2) glu-cagon secretion increases. These changes in hormone secretion prevent the cellular uptake of blood glucose into organs such as the muscles, liver, and adipose tissue and promote the release of glucose from the liver (through the stimulation of glycogen breakdown by glucagon). A negative feedback loop is therefore completed (fig. 19.6), helping to retard the fall in plasma glucose concentration that occurs during fasting.

The oral glucose tolerance test (fig. 19.8) is a measure of the ability of the beta cells to secrete insulin and of the ability of insulin to lower blood glucose. In this procedure, a person drinks a glucose solution and blood samples are taken periodically for plasma glucose measurements. In a normal person, the rise in blood glucose produced by drinking this solution is reversed to normal levels within 2 hours following glucose ingestion. In contrast, the plasma glucose concentration remains at 200 mg/dl or higher 2 hours after the oral glucose challenge in a person with diabetes mellitus.

Clinical Investigation Clues

Remember that Phyllis had a fasting blood glucose concentration of 150 mg/dl and a 2-hour measurement of 220 mg/dl in the oral glucose tolerance test.

■ What does her fasting blood glucose concentration indicate?

■ What additional information does her oral glucose tolerance test provide?

Regulation of Metabolism 613

Time (hours)

■ Figure 19.8 The oral glucose tolerance test. Changes in blood glucose and plasma insulin concentrations after the ingestion of 100 grams of glucose in an oral glucose tolerance test. The insulin is measured in activity units (U).

Insulin secretion is also stimulated by particular amino acids derived from dietary proteins. Meals that are high in protein, therefore, stimulate the secretion of insulin; if the meal is high in protein and low in carbohydrates, glucagon secretion will be stimulated as well. The increased glucagon secretion acts to raise the blood glucose, while the increased insulin promotes the entry of amino acids into tissue cells.

Effects of Autonomic Nerves

The islets of Langerhans receive both parasympathetic and sympathetic innervation. The activation of the parasympathetic system during meals stimulates insulin secretion at the same time that gastrointestinal function is stimulated. The activation of the sympathetic system, by contrast, stimulates glucagon secretion and inhibits insulin secretion. The effects of glucagon, together with those of epinephrine, produce a "stress hyperglycemia" when the sympathoadrenal system is activated.

Effects of Intestinal Hormones

Surprisingly, insulin secretion increases more rapidly following glucose ingestion than it does following an intravenous injection of glucose. This is due to the fact that the intestine, in response to glucose ingestion, secretes hormones that stimulate insulin secretion before the glucose has been absorbed. Insulin secretion thus begins to rise "in anticipation" of a rise in blood glucose. One of the intestinal hormones that mediates this effect is GIP—gastric inhibitory peptide, or, more appropriately in this context, glucose-dependent insulinotropic peptide (chapter 18). Other polypeptide hormones secreted by the intestine that have similar effects are cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), as described in chapter 18.

Insulin and Glucagon:Absorptive State

The lowering of plasma glucose by insulin is, in a sense, a side effect of the primary action of this hormone. Insulin is the major hormone that promotes anabolism in the body. During absorption of the products of digestion and the subsequent rise in the plasma concentrations of circulating energy substrates, insulin promotes the cellular uptake of plasma glucose and its incorporation into energy-reserve molecules of glycogen in the liver and muscles, and of triglycerides in adipose cells (chapter 11; see fig. 11.31). Quantitatively, skeletal muscles are responsible for most of the insulin-stimulated glucose uptake. Insulin also promotes the cellular uptake of amino acids and their incorporation into proteins. The stores of large energy-reserve molecules are thus increased while the plasma concentrations of glucose and amino acids are decreased.

A nonobese 70-kg (155-lb) man has approximately 10 kg (about 82,500 kcal) of stored fat. Since 250 g of fat can supply the energy requirements for 1 day, this reserve fuel is sufficient for about 40 days. Glycogen is less efficient as an energy reserve, and less is stored in the body; there are about 100 g (400 kcal) of glycogen stored in the liver and 375 to 400 g (1,500 kcal) in skeletal muscles. Insulin promotes the cellular uptake of glucose into the liver and muscles and the conversion of glucose into glucose 6-phosphate. In the liver and muscles, this can be changed into glucose 1-phosphate, which is used as the precursor of glycogen. Once the stores of glycogen have been filled, the continued ingestion of excess calories results in the production of fat rather than of glycogen.

Insulin and Glucagon: Postabsorptive State

The plasma glucose concentration is maintained surprisingly constant during the fasting, or postabsorptive, state because of the secretion of glucose from the liver. This glucose is derived from the processes of glycogenolysis and gluconeogenesis, which are promoted by a high secretion of glucagon coupled with a low secretion of insulin.

Glucagon stimulates and insulin suppresses the hydrolysis of liver glycogen, or glycogenolysis. Thus during times of fasting, when glucagon secretion is high and insulin secretion is low, liver glycogen is used as a source of additional blood glucose. This results in the liberation of free glucose from glucose 6-phosphate by the action of an enzyme called glucose 6-phosphatase (chapter 5; see fig. 5.4). Only the liver has this enzyme, and therefore only the liver can use its stored glycogen as a source of additional blood glucose. Since muscles lack glucose 6-phosphatase, the glucose 6-phosphate produced from muscle glycogen can be used for glycolysis only by the muscle cells themselves.

Since there are only about 100 grams of stored glycogen in the liver, adequate blood glucose levels could not be maintained

614 Chapter Nineteen

Fasting (i insulin, T glucagon)

Epinephrin Glucagon

■ Figure 19.9 Catabolism during fasting. Increased glucagon secretion and decreased insulin secretion during fasting favors catabolism. These hormonal changes promote the release of glucose, fatty acids, ketone bodies, and amino acids into the blood. Notice that the liver secretes glucose that is derived both from the breakdown of liver glycogen and from the conversion of amino acids in gluconeogenesis.

for very long during fasting using this source alone. The low levels of insulin secretion during fasting, together with elevated glu-cagon secretion, however, promote gluconeogenesis, the formation of glucose from noncarbohydrate molecules. Low insulin allows the release of amino acids from skeletal muscles, while glucagon and cortisol (an adrenal hormone) stimulate the production of enzymes in the liver that convert amino acids to pyruvic acid and pyruvic acid into glucose. During prolonged fasting and exercise, gluconeogenesis in the liver using amino acids from muscles may be the only source of blood glucose.

The secretion of glucose from the liver during fasting compensates for the low blood glucose concentrations and helps to provide the brain with the glucose that it needs. But because insulin secretion is low during fasting, skeletal muscles cannot utilize blood glucose as an energy source. Instead, skeletal muscles—as well as the heart, liver, and kidneys—use free fatty acids as their major source of fuel. This helps to "spare" glucose for the brain.

The free fatty acids are made available by the action of glucagon. In the presence of low insulin levels, glucagon activates an enzyme in adipose cells called hormone-sensitive lipase. This enzyme catalyzes the hydrolysis of stored triglycerides and the release of free fatty acids and glycerol into the blood. Glucagon also activates enzymes in the liver that convert some of these fatty acids into ketone bodies, which are secreted into the blood (fig. 19.9). Several organs in the body can use ketone bodies, as well as fatty acids, as a source of acetyl CoA in aerobic respiration.

Through the stimulation of lipolysis (the breakdown of fat) and ketogenesis (the formation of ketone bodies), the high glucagon and low insulin levels that occur during fasting provide circulating energy substrates for use by the muscles, liver, and other organs. Through liver glycogenolysis and gluconeo-genesis, these hormonal changes help to provide adequate levels of blood glucose to sustain the metabolism of the brain. The antagonistic action of insulin and glucagon (fig. 19.10) thus promotes appropriate metabolic responses during periods of fasting and periods of absorption.

Test Yourself Before You Continue

1. Describe how the secretions of insulin and glucagon change during periods of absorption and periods of fasting. How are these changes in hormone secretion produced?

2. Explain how the synthesis of fat in adipose cells is regulated by insulin. Also, explain how fat metabolism is regulated by insulin and glucagon during periods of absorption and fasting.

3. Define the following terms: glycogenolysis, gluconeogenesis, and ketogenesis. How do insulin and glucagon affect each of these processes during periods of absorption and fasting?

4. Describe two pathways used by the liver to produce glucose for secretion into the blood. Why can't skeletal muscles secrete glucose into the blood?

Regulation of Metabolism

Absorptive Post Absorptive State

■ Figure 19.10 The effect of feeding and fasting on metabolism.

Metabolic balance is tilted toward anabolism by feeding (absorption of a meal) and toward catabolism by fasting. This occurs because of an inverse relationship between insulin and glucagon secretion. Insulin secretion rises and glucagon secretion falls during food absorption, whereas the opposite occurs during fasting.

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