14.19: Insulin and Glucagon

Sources and Control of Secretion

Cells in the pancreas that secrete hormones are located in pinhead-sized clusters called islets of Langerhans, which are scattered throughout the pancreas (Figure 14.1). Some islet cells secrete insulin, and others secrete glucagon.

The secretion of both insulin and glucagon is regulated primarily by negative feedback mechanisms involving substrate control by blood glucose. High blood glucose levels stimulate insulin secretion and inhibit glucagon secretion, leading to a decline in blood glucose. Conversely, low blood glucose levels inhibit insulin secretion and stimulate glucagon secretion, leading to a rise in blood glucose. These mechanisms help maintain homeostasis of blood glucose.

Effects

Insulin

The principal target structures of insulin are muscle, liver, and fat cells. Insulin helps provide energy for these cells while simultaneously reducing blood glucose levels by stimulating entry of glucose into the cells; the breakdown of glucose for energy; storage of glucose as glycogen; and storage of glucose as fat. The first three processes occur primarily in muscle and liver cells, while liver and fat cells carry out most of the fourth. These three target cell types obtain and use blood glucose only if adequate insulin is supplied. Body cells other than muscle, liver, and fat cells can use glucose without the presence of insulin. Of all the glucose removed from the blood because of insulin, approximately 75 percent enters muscle cells. Insulin also stimulates both the passage of amino acids into cells and the synthesis of proteins from amino acids.

Glucagon

Unlike insulin, glucagon causes blood glucose levels rise by stimulating liver cells to produce and release glucose. The glucose is produced from glycogen in the liver, amino acids in the blood and liver, and fats in the liver and fat cells.

Combined Effects

The antagonistic effects of insulin and glucagon make up the body's main mechanism for providing proper and fairly stable blood glucose levels. Insulin is essentially the only control signal that causes a decrease in blood glucose. By contrast, though glucagon is the main control signal that causes an increase in blood glucose, sympathetic nerves and other hormones (e.g., growth hormone, epinephrine, glucocorticoids) can also cause such an increase.

Maintaining blood glucose homeostasis is important for two reasons. First, preventing low glucose levels assures that all body cells receive enough glucose to obtain energy and building materials. Second, avoiding high levels helps prevent many problems associated with the disease diabetes mellitus (see Diabetes Mellitus, below). The effects of insulin on amino acids and protein synthesis are also helpful to the body because they assist in the formation and replacement of parts of the body and secretions that contain protein.

Blood Glucose Homeostasis

The blood glucose level is often expressed as glucose per 100 ml (per deciliter) of blood plasma in a sample taken at least 2 hours after eating. The result, called the fasting plasma glucose (FPG) value, is normally 80 to 115 mg/dl. Glucose levels may fluctuate irregularly within this range because of changes in body activity, sympathetic nerve impulses, and hormone levels.

The ability of the body to reverse a dramatic rise in blood glucose and restore glucose homeostasis is called its glucose tolerance. For example, soon after a person has ingested large quantity of sugar, the blood glucose level may exceed 200 mg/dl. If that person has good glucose tolerance, blood glucose is brought down below 140 mg/dl within 2 hours of ingesting the sugars, and glucose levels stabilize at 80 to 115 mg/dl soon afterward.

Glucose tolerance can be tested by an oral glucose tolerance test (OGTT). In this procedure, blood glucose levels are measured during the 2-hour period after ingesting a large amount (75 grams) of glucose.

Age Changes

As age increases, the pancreas retains the ability to quickly increase blood insulin levels and glucagon levels and maintain them within the normal range for young adults. Furthermore, aging causes no significant changes in the ability of insulin and glucagon to regulate blood glucose levels. Because of the continued effectiveness of insulin and glucagon in regulating glucose levels, aging causes no important change in FPG values or glucose tolerance.

Abnormal Changes

Although aging has essentially no effect on the ability of the pancreas to regulate insulin levels, there is an average age-related increase in blood insulin levels. This is not an age change but is associated with reductions in physical activity and *VO₂ max and increases in body fat. Elevated insulin levels are closely associated with increased abdominal body fat near the waist, which is common (increased waist/hip ratio), in aging men.

The age-related increase in blood insulin seems to result from a decrease in target cell responsiveness to insulin, which is called insulin resistance. Because of insulin resistance, the target cells (muscle, liver, and fat cells) remove little blood glucose even when blood glucose and insulin levels are high. Since blood glucose remains high, the pancreas secretes additional insulin, further elevating insulin levels. Insulin levels are increased until they are high enough to stimulate the somewhat unresponsive target cells to remove some blood glucose and lower blood glucose levels.

In individuals with insulin resistance, once insulin levels become high, they stay high because more insulin is needed to counter the effects of glucagon. (Recall that the blood levels and the effectiveness of glucagon do not change with advancing age.) By themselves, small increases in insulin resistance and insulin levels do not cause problems, but they can be warning signs that more substantial changes in insulin may occur. Therefore, it is advisable to monitor these changes and take steps to prevent or reverse them.

Restoring Insulin Levels and Target Sensitivity

Elderly people with an age-related increase in insulin resistance can regain much insulin sensitivity and reduce high blood insulin levels through a program that combines vigorous exercise and weight loss. Although improvements in insulin sensitivity occur within a few days of starting such a program, regular exercise must be continued because exercise-induced gains in insulin sensitivity begin to decline within three days of ending the program. If the program is not reinstated, the original low levels of insulin sensitivity are reached within several days to 2 weeks.

Blood Glucose Levels

Individuals who have normal FPG values and take almost 2 hours during an OGTT to reduce blood glucose to less than 140 mg/dl are considered to have normal glucose regulation but decreased glucose tolerance. Individuals who have FPG values below 140 mg/dl and whose blood glucose levels at the end of an OGTT are 140 to 200 mg/dl have an abnormal condition called impaired glucose tolerance (IGT). Individuals with FPG values greater than 115 mg/dl have an abnormal condition called hyperglycemia. finally, individuals with FPG values below 80 mg/dl have an abnormal condition called hypoglycemia.

The proportion of people with decreased glucose tolerance rises rapidly after age 45. Since glucose tolerance depends on the action of insulin, the decrease in glucose tolerance usually occurs in those who also have insulin resistance and increased insulin levels. Like age-related changes in insulin, decreased glucose tolerance is probably not an age change.

Small decreases in glucose tolerance do not constitute a problem, though they may warn of impending difficulties with glucose regulation. Monitoring, preventing, and reversing decreases in glucose tolerance may be appropriate.

Decreased glucose tolerance in older people can be improved by the same techniques that improve high insulin levels and low insulin sensitivity (see above). Decreased glucose tolerance often worsens and becomes impaired glucose tolerance (IGT). Other than abnormally high OGTT values, individuals with IGT have no signs or symptoms of the disorder. This allows problems from IGT to develop insidiously.

Impaired glucose tolerance develops in up to 40 percent of those over age 60. Among these individuals, approximately 30 percent will improve with no medical intervention and their glucose tolerance will enter the normal range. Another 50 percent will continue to have only IGT and its risks. The remaining 20 percent will develop diabetes mellitus.

Impaired glucose tolerance can be caused by the same factors that cause insulin resistance and decreased glucose tolerance and by other factors that contribute to diabetes mellitus (see below). However, IGT can be prevented or reversed by methods used in connection with decreased glucose tolerance and diabetes mellitus. Such actions are highly advisable because of the complications that result from continued IGT and the subsequent development of diabetes mellitus. For example, elderly individuals who continue to have IGT are at high risk for developing atherosclerosis and its related disorders.