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 efficiencyof peripheral glucose utilization and augmentsglucose production, raising plasma glucose to 300 to 1200 mg/100 ml.The increased plasma glucose then hasmultiple 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 above180 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 diabetes—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 10times 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 theurine, causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid. 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 arefrequent 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 endothelial 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 ketoacids, 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. Excess fat utilization in the liver occurring over a longtime causes large amounts of cholesterol in the circulating blood and increased deposition of cholesterol.

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 60years, 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 20years 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.

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 hyperinsulinemia

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 mellitus.

Genetic causes of obesity and insulin resistance, if severe enough, also can lead to type II diabetes and 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.

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 thiazolidine diones and metformin, or drugs that cause additional release of insulin by pancreas, like 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

Usual methods for diagnosing diabetes are based on various chemical tests of urine and 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

large amounts, in proportion to the severity of disease and the intake of carbohydrates.

Fasting Blood Glucose and Insulin Levels. The fasting blood glucose level in the early morning is normally 80 to 90 mg/100 ml, and 110 mg/100 ml is considered to be the upper limit of normal. A fasting blood glucose level above this value often indicates diabetes mellitus or a least marked insulin resistance.

In type I diabetes, plasma insulin levels are very low or undetectable during fasting and even after a meal. In type II diabetes, plasma insulin concentration may be several fold higher than normal and usually increases to a greater extent after ingestion of a standard glucose load during a glucose tolerance test.

Glucose Tolerance Test. As demonstrated by the bottom curve, called a “glucose tolerance curve,” when a normal, fasting person ingests 1 gram of glucose per kilogram of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours.

In a person with diabetes, the fasting blood glucose concentration is almost always above 110 mg/100 ml and often above 140 mg/100 ml. Also, the glucose tolerance test is almost always abnormal. On ingestion of glucose, these people exhibit a much greater than normal rise in blood glucose level and the glucose level falls back to the control value only after 4 to 6 hours; furthermore, it fails to fall below the control level. The slow fall of this curve and its failure to fall below the control level demonstrate that either (1) the normal increase in insulin secretion after glucose ingestion does not occur or (2) there is decreased sensitivity to insulin.

A diagnosis of diabetes mellitus can usually be established on the basis of such a curve, and type I and type II diabetes can be distinguished from each other by measurements of plasma insulin, with plasma insulin being low or undetectable in type I diabetes and increased in type II diabetes.

Acetone Breath. Small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone. This is volatile and vaporized into the expired air. Consequently, one can frequently make a diagnosis of type I diabetes mellitus simply by smelling acetone on the breath of a patient. Also, keto acids can be detected by chemical means in the urine, and their quantitation aids in determining the severity of the diabetes.

In the early stages of type II diabetes, however, keto acids are usually not produced in excess amounts. However, when insulin resistance becomes very severe and there is greatly increased utilization of fats for energy, keto acids are then produced in persons with type II diabetes.

Treatment of Diabetes

The theory of treatment of type I diabetes mellitus is to administer enough insulin so that the patient will have carbohydrate, fat, and protein metabolism that is as normal as possible. Insulin is available in several forms. “Regular” insulin has a duration of action that lasts from 3 to 8 hours, whereas other forms of insulin (precipitated with zinc or with various protein derivatives) are absorbed slowly from the injection site and therefore have effects that last as long as 10 to 48 hours. Ordinarily, a patient with severe type I diabetes is given a single dose of one of the longer-acting insulins each day to increase overall carbohydrate metabolism throughout the day. Then additional quantities of regular insulin are given during the day at those times when the blood glucose level tends to rise too high, such as at mealtimes. Thus, each patient is provided with an individualized pattern of treatment.

In persons with type II diabetes, dieting and exercise are usually recommended in an attempt to induce weight loss and to reverse the insulin resistance. If this fails, drugs may be administered to increase insulin sensitivity or to stimulate increased production of insulin by the pancreas. In many persons, however, exogenous insulin must be used to regulate blood glucose.

In the past, the insulin used for treatment was derived from animal pancreata. However, human insulin produced by the recombinant DNA process has become more widely used because some patients develop immunity and sensitization against animal insulin, thus limiting its effectiveness.

Relation of Treatment to Arteriosclerosis. Diabetic patients, mainly because of their high levels of circulating cholesterol and other lipids, develop atherosclerosis, arteriosclerosis, severe coronary heart disease, and multiple microcirculatory lesions far more easily than do normal people. Indeed, those who have poorly controlled diabetes throughout childhood are likely to die of heart disease in early adulthood.

In the early days of treating diabetes, the tendency was to severely reduce the carbohydrates in the diet so that the insulin requirements would be minimized. This procedure kept the blood glucose from increasing too high and attenuated loss of glucose in the urine, but it did not prevent many of the abnormalities of fat metabolism. Consequently, the current tendency is to allow the patient an almost normal carbohydrate diet and to give large enough insulin to metabolize the carbohydrates. This decreases the rate of fat metabolism and depresses

the high level of blood cholesterol.

Because the complications of diabetes—such as atherosclerosis, greatly increased susceptibility to infection, diabetic retinopathy, cataracts, hypertension, and chronic renal disease—are closely associated with the level of blood lipids as well as the level of blood glucose, most physicians also use lipid-lowering drugs to help prevent these disturbances.

Insulinoma—Hyperinsulinism

Although much rarer than diabetes, excessive insulin production occasionally occurs from an adenoma of an islet of Langerhans. About 10 to 15 per cent of these adenomas are malignant, and occasionally metastases from the islets of Langerhans spread throughout the body, causing tremendous production of insulin by both the primary and the metastatic cancers. Indeed, more than 1000 grams of glucose have had to be administered every 24 hours to prevent hypoglycemia in some of these patients.

Insulin Shock and Hypoglycemia. As already emphasized, the central nervous system normally derives essentially all its energy from glucose metabolism, and insulin is not necessary for this use of glucose. However, if high levels of insulin cause blood glucose to fall to low values, the metabolism of the central nervous system becomes depressed. Consequently, in patients with insulin-secreting tumors or in patients with diabetes who administer too much insulin to themselves, the syndrome called insulin shock may occur as follows.

As the blood glucose level falls into the range of 50 to 70 mg/100 ml, the central nervous system usually becomes quite excitable, because this degree of hypoglycemia sensitizes neuronal activity. Sometimes various forms of hallucinations result, but more often

the patient simply experiences extreme nervousness, trembles all over, and breaks out in a sweat. As the blood glucose level falls to 20 to 50 mg/100 ml, clonic seizures and loss of consciousness are likely to occur.As the glucose level falls still lower, the seizures cease and only a state of coma remains. Indeed, at times it is difficult by simple clinical observation to distinguish between diabetic coma as a result of insulin-lack acidosis and coma due to hypoglycemia caused by excess insulin. The acetone breath and the rapid, deep breathing of diabetic coma are not present in hypoglycemic coma.

Proper treatment for a patient who has hypoglycemic shock or coma is immediate intravenous administration of large quantities of glucose. This usually brings the patient out of shock within a minute or more. Also, the administration of glucagon (or, less effectively, epinephrine) can cause glycogenolysis in the liver and thereby increase the blood glucose level extremely rapidly. If treatment is not effected immediately, permanent damage to the neuronal cells of the central nervous system often occurs.