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1. The liver functions as an important blood glucose buffer system. That is, when the blood glucose rises to a high concentration after a meal and the rate of insulin secretion also increases, as much as two thirds of the glucose absorbed from the gut is almost immediately stored in the liver in the form of glycogen. Then, during the succeeding hours, when both the blood glucose concentration and the rate of insulin secretion fall, the liver releases the glucose back into the blood. In this way, the liver decreases the fluctuations in blood glucose concentration to about one third of what they would otherwise be. In fact, in patients with severe liver disease, it becomes almost impossible to maintain a narrow range of blood glucose concentration.

2. Both insulin and glucagon function as important feedback control systems for maintaining a normal blood glucose concentration. When the glucose concentration rises too high, insulin is secreted; the insulin in turn causes the blood glucose concentration to decrease toward normal. Conversely, a decrease in blood glucose stimulates glucagon secretion; the glucagon then functions in the opposite direction to increase the glucose toward normal. Under most normal conditions, the insulin feedback mechanism is much more important than the glucagon mechanism, but in instances of starvation or excessive utilization of glucose during exercise and other stressful situations, the glucagon mechanism also becomes valuable.

3. Also, in severe hypoglycemia, a direct effect of low blood glucose on the hypothalamus stimulates the sympathetic nervous system. In turn, the epinephrine secreted by the adrenal glands causes still further release of glucose from the liver. This, too, helps protect against severe hypoglycemia.

4. And finally, over a period of hours and days, both growth hormone and cortisol are secreted in response to prolonged hypoglycemia, and they both decrease the rate of glucose utilization by most cells of the body, converting instead to greater amounts of fat utilization. This, too, helps return the blood glucose concentration toward normal.

Importance of Blood Glucose Regulation. One might ask the question: Why is it so important to maintain a constant blood glucose concentration, particularly because most tissues can shift to utilization of fats and proteins for energy in the absence of glucose? The answer is that glucose is the only nutrient that normally can be used by the brain, retina, and germinal epithelium of the gonads in sufficient quantities to supply them optimally with their required energy. Therefore, it is important to maintain the blood glucose concentration at a sufficiently high level to provide this necessary nutrition.

Most of the glucose formed by gluconeogenesis during the interdigestive period is used for metabolism in the brain. Indeed, it is important that the pancreas not secrete any insulin during this time; otherwise, the scant supplies of glucose that are available would all go into the muscles and other peripheral tissues, leaving the brain without a nutritive source.

It is also important that the blood glucose concentration not rise too high for four reasons: (1) Glucose can exert a large amount of osmotic pressure in the extracellular fluid, and if the glucose concentration rises to excessive values, this can cause considerable cellular dehydration.(2) An excessively high level of blood glucose concentration causes loss of glucose in the urine. (3) Loss of glucose in the urine also causes osmotic diuresis by the kidneys, which can deplete the body of its fluids and electrolytes.(4) Long-term increases in blood glucose may cause damage to many tissues, especially to blood vessels. Vascular injury, associated with uncontrolled diabetes mellitus, leads to increased risk for heart attack, stroke, end-stage renal disease, and blindness.

Diabetes Mellitus

Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. There are two general types of diabetes mellitus:

1. Type I diabetes, also called insulin-dependent diabetes mellitus (IDDM), is caused by lack of insulin secretion.

2. Type II diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM), is caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance.

In both types of diabetes mellitus, metabolism of all the main foodstuffs is altered. The basic effect of insulin lack or insulin resistance on glucose metabolism is to prevent the efficient uptake and utilization of glucose by most cells of the body, except those of the brain. As a result, blood glucose concentration increases, cell utilization of glucose falls increasingly lower, and utilization of fats and proteins increases.

Type I Diabetes—Lack of Insulin Production by Beta Cells of the Pancreas

Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in many patients with type I diabetes, although heredity also plays a major role in determining the susceptibility of the beta cells to destruction by these insults. In some instances, there may be a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders.

The usual onset of type I diabetes occurs at about 14 years of age in the United States, and for this reason it is often called juvenile diabetes mellitus .Type I diabetes may develop very abruptly, over a period of a few days or weeks, with three principal sequelae: (1) increased blood glucose, (2) increased utilization of fats for energy and for formation of cholesterol by the liver, and (3) depletion of the body's proteins.

Blood Glucose Concentration Rises to Very High Levels in Diabetes Mellitus. The lack of insulin decreases the efficiency of peripheral glucose utilization and augments glucose production, raising plasma glucose to 300 to 1200 mg/100 ml. The increased plasma glucose then has multiple effects throughout the body.

Increased Blood Glucose Causes Loss of Glucose in the Urine

The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine. This normally occurs when the blood glucose concentration rises above 180 mg/100 ml, a level that is called the blood "threshold" for the appearance of glucose in the urine. When the blood glucose level rises to 300 to 500 mg/100 ml— common values in people with severe untreated dia-betes—100 or more grams of glucose can be lost into the urine each day.

Increased Blood Glucose Causes Dehydration The very high levels of blood glucose (sometimes as high as 8 to 10 times normal in severe untreated diabetes) can cause severe cell dehydration throughout the body. This occurs partly because glucose does not diffuse easily through the pores of the cell membrane, and the increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells.

In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis. That is, the osmotic effect of glucose in the renal tubules greatly decreases tubular reabsorption of fluid. The overall effect is massive loss of fluid in the urine, causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid, for reasons discussed in Chapter 26. Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.

Chronic High Glucose Concentration Causes Tissue Injury When blood glucose is poorly controlled over long periods in diabetes mellitus, blood vessels in multiple tissues throughout the body begin to function abnormally and undergo structural changes that result in inadequate blood supply to the tissues. This in turn leads to increased risk for heart attack, stroke, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of the limbs.

Chronic high glucose concentration also causes damage to many other tissues. For example, peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction are frequent complications of chronic, uncontrolled diabetes mellitus. These abnormalities can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in the extremities, and other symptoms of peripheral nerve damage.

The precise mechanisms that cause tissue injury in diabetes are not well understood but probably involve multiple effects of high glucose concentrations and other metabolic abnormalities on proteins of endothe-lial and vascular smooth muscle cells, as well as other tissues. In addition, hypertension, secondary to renal injury, and atherosclerosis, secondary to abnormal lipid metabolism, often develop in patients with diabetes and amplify the tissue damage caused by the elevated glucose.

Diabetes Mellitus Causes Increased Utilization of Fats and Metabolic Acidosis. The shift from carbohydrate to fat metabolism in diabetes increases the release of keto acids, such as acetoacetic acid and b-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidized by the tissue cells. As a result, the patient develops severe metabolic acidosis from the excess keto acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis. This leads rapidly to diabetic coma and death unless the condition is treated immediately with large amounts of insulin.

All the usual physiologic compensations that occur in metabolic acidosis take place in diabetic acidosis. They include rapid and deep breathing, which causes increased expiration of carbon dioxide; this buffers the acidosis but also depletes extracellular fluid bicarbonate stores. The kidneys compensate by decreasing bicarbonate excretion and generating new bicarbonate that is added back to the extracellular fluid.

Although extreme acidosis occurs only in the most severe instances of uncontrolled diabetes, when the pH of the blood falls below about 7.0, acidotic coma and death can occur within hours. The overall changes in the electrolytes of the blood as a result of severe diabetic acidosis are shown in Figure 78-11.

Excess fat utilization in the liver occurring over a long time causes large amounts of cholesterol in the circulating blood and increased deposition of cholesterol in

Figure 78-11

Changes in blood constituents in diabetic coma, showing normal values (lavender bars) and diabetic coma values (red bars).

the arterial walls. This leads to severe arteriosclerosis and other vascular lesions, as discussed earlier.

Diabetes Causes Depletion of the Body's Proteins. Failure to use glucose for energy leads to increased utilization and decreased storage of proteins as well as fat. Therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia). Without treatment, these metabolic abnormalities can cause severe wasting of the body tissues and death within a few weeks.

Type II Diabetes—Resistance to the Metabolic Effects of Insulin

Type II diabetes is far more common than type I, accounting for about 90 per cent of all cases of diabetes mellitus. In most cases, the onset of type II diabetes occurs after age 30, often between the ages of 50 and 60 years, and the disease develops gradually. Therefore, this syndrome is often referred to as adult-onset diabetes. In recent years, however, there has been a steady increase in the number of younger individuals, some less than 20 years old, with type II diabetes. This trend appears to be related mainly to the increasing prevalence of obesity, the most important risk factor for type II diabetes in children as well as in adults.

Obesity, Insulin Resistance, and "Metabolic Syndrome" Usually Precede Development of Type II Diabetes. Type II diabetes, in contrast to type I, is associated with increased plasma insulin concentration (hyperinsulinemia). This occurs as a compensatory response by the pancreatic beta cells for diminished sensitivity of target tissues to the metabolic effects of insulin, a condition referred to as insulin resistance. The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood glucose and stimulating a compensatory increase in insulin secretion.

Development of insulin resistance and impaired glucose metabolism is usually a gradual process, beginning with excess weight gain and obesity. The mechanisms that link obesity with insulin resistance, however, are still uncertain. Some studies suggest that there are fewer insulin receptors, especially in the skeletal muscle, liver, and adipose tissue, in obese than in lean subjects. However, most of the insulin resistance appears to be caused by abnormalities of the signaling pathways that link receptor activation with multiple cellular effects. Impaired insulin signaling appears to be closely related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver secondary to excess weight gain.

Insulin resistance is part of a cascade of disorders that is often called the "metabolic syndrome." Some of the features of the metabolic syndrome include: (1) obesity, especially accumulation of abdominal fat; (2) insulin resistance; (3) fasting hyperglycemia; (4) lipid abnormalities such as increased blood triglycerides and decreased blood high-density lipoprotein-cholesterol; and (5) hypertension. All of the features of the metabolic syndrome are closely related to excess weight gain, especially when it is associated with accumulation of adipose tissue in the abdominal cavity around the visceral organs.

The role of insulin resistance in contributing to some of the components of the metabolic syndrome is unclear, although it is clear that insulin resistance is the primary cause of increased blood glucose concentration. The major adverse consequence of the metabolic syndrome is cardiovascular disease, including atherosclerosis and injury to various organs throughout the body. Several of the metabolic abnormalities associated with the syndrome are risk factors for cardiovascular disease, and insulin resistance predisposes to the development of type II diabetes mellitus, also a major cause of cardiovascular disease.

Other Factors That Can Cause Insulin Resistance and Type II Diabetes. Although most patients with type II diabetes are overweight or have substantial accumulation of visceral fat, severe insulin resistance and type II diabetes can also occur as a result of other acquired or genetic conditions that impair insulin signaling in peripheral tissues (Table 78-2).

Polycystic ovary syndrome (PCOS), for example, is associated with marked increases in ovarian androgen production and insulin resistance and is one of the most common endocrine disorders in women, affecting approximately 6 per cent of all women during their reproductive life. Although the pathogenesis of PCOS remains uncertain, insulin resistance and hyperinsuline-mia are found in approximately 80 per cent of affected women. The long-term consequences include increased risk for diabetes mellitus, increased blood lipids, and cardiovascular disease.

Excess formation of glucocorticoids (Cushing's syndrome) or growth hormone (acromegaly) also decreases the sensitivity of various tissues to the metabolic effects of insulin and can lead to development of diabetes mel-litus. Genetic causes of obesity and insulin resistance, if severe enough, also can lead to type II diabetes as well as many other features of the metabolic syndrome, including cardiovascular disease.

Development of Type II Diabetes During Prolonged Insulin Resistance. With prolonged and severe insulin resistance, even the increased levels of insulin are not sufficient to maintain normal glucose regulation. As a result, moderate hyperglycemia occurs after ingestion of carbohydrates in the early stages of the disease.

Table 78-2 Some Causes of Insulin Resistance

• Obesity/overweight (especially excess visceral adiposity)

• Excess glucocorticoids (Cushing's syndrome or steroid therapy)

• Excess growth hormone (acromegaly)

• Pregnancy, gestational diabetes

• Polycystic ovary disease

• Lipodystrophy (acquired or genetic;associated with lipid accumulation in liver)

• Autoantibodies to the insulin receptor

• Mutations of insulin receptor

• Mutations of the peroxisome proliferators' activator receptor g (PPARg)

• Mutations that cause genetic obesity (e.g., melanocortin receptor mutations)

• Hemochromatosis (a hereditary disease that causes tissue iron accumulation)

In the later stages of type II diabetes, the pancreatic beta cells become "exhausted" and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after the person ingests a carbohydrate-rich meal.

Some obese people, although having marked insulin resistance and greater than normal increases in blood glucose after a meal, never develop clinically significant diabetes mellitus; apparently, the pancreas in these people produces enough insulin to prevent severe abnormalities of glucose metabolism. In others, however, the pancreas gradually becomes exhausted from secreting large amounts of insulin, and full-blown diabetes mellitus occurs. Some studies suggest that genetic factors play an important role in determining whether an individual's pancreas can sustain the high output of insulin over many years that is necessary to avoid the severe abnormalities of glucose metabolism in type II diabetes.

In many instances, type II diabetes can be effectively treated, at least in the early stages, with exercise, caloric restriction, and weight reduction, and no exogenous insulin administration is required. Drugs that increase insulin sensitivity, such as thiazolidinediones and met-formin, or drugs that cause additional release of insulin by the pancreas, such as sulfonylureas, may also be used. However, in the later stages of type II diabetes, insulin administration is usually required to control plasma glucose.

Physiology of Diagnosis of Diabetes Mellitus

Table 78-3 compares some of clinical features of type I and type II diabetes mellitus. The usual methods for diagnosing diabetes are based on various chemical tests of the urine and the blood.

Urinary Glucose. Simple office tests or more complicated quantitative laboratory tests may be used to determine the quantity of glucose lost in the urine. In general, a normal person loses undetectable amounts of glucose, whereas a person with diabetes loses glucose in small to

Table 78-3

Clinical Characteristics of Patients with Type I and Type II Diabetes Mellitus

Table 78-3

Feature

Type I

Type II

Age at onset

Usually <20 years

Usually >30 years

Body mass

Low (wasted) to normal

Obese

Plasma insulin

Low or absent

Normal to high initially

Plasma glucagon

High, can be

High, resistant to

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