Regulation of Insulin and Glucagon Secretion

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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-

Insulin Release Glucagon

■ 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

Glucose Panreas Process

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

Glucagon Secretion RegulationGlucagon Secretion Concentration

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.

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