What is diabetes mellitus?

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An endocrine disorder characterized by hyperglycemia due to autoimmune destruction of insulin-secreting pancreatic beta cells or from variable degrees of insulin resistance and deficiency. Chronic hyperglycemia of diabetes can lead to multiorgan damage, resulting in renal, neurologic, cardiovascular, and other serious complications.
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Causes and Symptoms

Diabetes mellitus is by far the most common of all endocrine disorders (hormonal disorders). The disorder's name is derived from the Greek word diabetes, meaning "siphon" or "running through," a reference to the potentially large urine volume that can accompany the condition. The Latin word mellitus, meaning “honey,” was added to the name when physicians began to make the diagnosis of diabetes mellitus based on the sweet taste of the patient’s urine. The disease has been depicted as a state of starvation in the midst of plenty. Although there is plenty of sugar in the blood, without proper insulin action the sugar does not reach the cells that need it for energy. Glucose, the simplest form of sugar, is the primary source of energy for many vital functions. Deprived of glucose, cells starve and tissues begin to degenerate. The unused glucose builds up in the bloodstream, which leads to a series of secondary complications.

The most common symptoms of diabetes mellitus are related to hyperglycemia, glycosuria, and ketoacidosis. The acute symptoms of diabetes mellitus are all attributable to inadequate insulin action. The immediate consequence of an insulin insufficiency is a marked decrease in the ability of muscle, liver, and adipose (fat) tissue to remove glucose from the blood. In the presence of inadequate insulin action, a second problem manifests itself. People with diabetes continue to make the hormone glucagon. Glucagon, which raises the level of blood sugar, can be considered insulin’s biological opposite. Like insulin, glucagon is released from the pancreatic islets. The release of glucagon is normally inhibited by insulin; therefore, in the absence of insulin, glucagon action elevates concentrations of glucose. For this reason, diabetes may be considered a two-hormone disease.

With a reduction in the conversion of glucose into its storage forms of glycogen in liver and muscle tissue and lipids in adipose cells, concentrations of glucose in the blood steadily increase (hyperglycemia). When the amount of glucose in the blood exceeds the capacity of the kidney to reabsorb this nutrient, glucose begins to spill into the urine (glucosuria). Glucose in the urine then drags additional body water along with it so that the volume of urine dramatically increases. In the absence of adequate fluid intake, the loss of body water and accompanying electrolytes (sodium) leads to dehydration and, ultimately, death caused by the failure of the peripheral circulatory system.

Insulin deficiency also results in a decrease in the synthesis of triglycerides (storage forms of fatty acids) and stimulates the breakdown of fats in adipose tissue. Although glucose cannot enter the cells and be used as an energy source, the body can use its supply of lipids from the fat cells as an alternate source of energy. Fatty acids increase in the blood, causing hyperlipidemia. With large amounts of circulating free fatty acids available for processing by the liver, the production and release of ketone bodies (breakdown products of fatty acids) into the circulation are accelerated, causing both ketonemia and an increase in the acidity of the blood. Since the ketone levels soon also exceed the capacity of the kidney to reabsorb them, ketone bodies soon appear in the urine (ketonuria).

Insulin deficiency and glucagon excess also cause pronounced effects on protein metabolism and result in an overall increase in the breakdown of proteins and a reduction in the uptake of amino acid precursors into muscle protein. This leads to the wasting and weakening of skeletal muscles and, in children who have diabetes, results in a reduction in overall growth. The increased level of amino acids in the blood provides an additional source of material for glucose production (gluconeogenesis) by the liver. All these acute metabolic changes in carbohydrates, lipids, and protein metabolism can be prevented or reversed by the administration of insulin.

There are three distinct types of diabetes mellitus. Type 1, or insulin-dependent diabetes mellitus (IDDM), is an absolute deficiency of insulin that accounts for approximately 5 to 10 percent of all cases of diabetes. Until the discovery of insulin, people stricken with type 1 diabetes faced certain death within about a year of diagnosis. In type 2, or non-insulin-dependent diabetes mellitus (NIDDM), the most common form of the disorder, insulin secretion may be normal or even increased, but the target cells for insulin are less responsive than normal (insulin resistance); therefore, insulin is not as effective in lowering blood glucose concentrations. Although either type can be manifested at any age, type 1 diabetes has a greater prevalence in children, whereas the incidence of type 2 diabetes increases markedly after the age of forty. Environmental and genetic factors are important in the expression of both of these types of diabetes mellitus. The third type is gestational diabetes, which is characterized by high blood glucose during pregnancy in a person who did not previously have diabetes.

Type 1 diabetes is an autoimmune process that involves the selective destruction of the insulin-producing beta cells in the islets of Langerhans (insulitis). The triggering event that initiates this process in genetically susceptible persons is linked to environmental factors that result from an infection, a virus, or, more likely, the presence of toxins in the diet. The body’s own T lymphocytes progressively attack the beta cells but leave the other hormone-producing cell types intact. T lymphocytes are white blood cells that normally attack virus-invaded cells and cancer cells. For up to ten years, there remains a sufficient number of insulin-producing cells to respond effectively to a glucose load, but when approximately 80 percent of the beta cells are destroyed, there is insufficient insulin release in response to a meal and the deadly spiral of the consequences of diabetes mellitus is triggered. Insulin injection can halt this lethal process and prevent it from recurring but cannot mimic the normal pattern of insulin release from the pancreas. It is interesting that not everyone who has insulitis actually progresses to experience overt symptoms of the disease. Idiopathic type 1 diabetes has no evidence of autoimmunity, but it has a strong degree of heritability, particularly in individuals of African or Asian descent.

Type 2 diabetes is normally associated with obesity and lack of exercise. In recent decades, with the reported increased rates of obesity and inactivity in children, there has also been an increase of type 2 diabetes at younger and younger ages. Genetic factors also play a key role in the development of the disorder. Research has shown that individuals who have a sibling or parent with type 2 diabetes are about three times as likely to develop diabetes themselves.

Because there is a reduction in the sensitivity of the target cells to insulin, people with type 2 diabetes must secrete more insulin to maintain blood glucose at normal levels. Because insulin is a storage, or anabolic, hormone, this increased secretion further contributes to obesity. In response to the elevated insulin concentrations, the number of insulin receptors on the target cell gradually decreases, which triggers an even greater secretion of insulin. In this way, the excess glucose is stored despite the decreased availability of insulin binding sites on the cell. Over time, the demands for insulin eventually exceed even the reserve capacity of the “genetically weakened” beta cells, and symptoms of insulin deficiency develop as the plasma glucose concentrations remain high for increasingly longer periods of time. This phenomenon is known as beta-cell burnout. Because the symptoms of type 2 diabetes are usually less severe than those of type 1 diabetes, many persons have the disease but remain unaware of it. By the time the diagnosis of diabetes is made in these individuals, they often also exhibit symptoms of long-term complications that include atherosclerosis and nerve damage. Hence, type 2 diabetes has been called the silent killer.

Gestational diabetes develops during pregnancy in a person who did not have diabetes before becoming pregnant. It occurs in 3 to 8 percent of all pregnancies. Women with gestational diabetes have an increased risk of developing diabetes after pregnancy. Children of women with gestational diabetes have a higher risk of obesity, glucose intolerance, and diabetes in adolescence.

Prediabetes is a condition in which individuals have blood glucose levels that are high, but not high enough for them to be diagnosed with type 2 diabetes. Persons with prediabetes are at higher risk to develop diabetes in the future.

Treatment and Therapy

Insulin is the only treatment available for type 1 diabetes, and in many cases it is used to treat individuals with type 2 diabetes. Insulin is available in many formulations, which differ in respect to the time of onset of action, activity, and duration of action. Insulin preparations are classified as fast acting, intermediate acting, and long acting; the effects of fast-acting insulin last for thirty minutes to twenty-four hours, while those of long-acting preparations last from four to thirty-six hours. Some of the factors that affect the rate of insulin absorption include the site of injection, the patient’s age and health status, and the patient’s level of physical activity. For a person with diabetes, however, insulin is a reprieve, not a cure. Lifestyle interventions such as dietary management, physical activity, and diabetes self-management education are also highly recommended in the treatment of diabetes.

Because of the complications that arise from chronic exposure to glucose, it is recommended that glucose concentrations in the blood be maintained as close to physiologically normal levels as possible. For this reason, it is preferable to administer multiple doses of insulin during the day. By monitoring plasma glucose concentrations, the patient can adjust the dosage of insulin administered and thus mimic normal concentrations of glucose relatively closely. Basal concentrations of plasma insulin can also be maintained throughout the day by means of electromechanical insulin delivery systems. Whether internal or external, such insulin pumps can be programmed to deliver a constant infusion of insulin at a rate designed to meet minimum requirements. The infusion can then be supplemented by a bolus injection prior to a meal. Increasingly sophisticated systems automatically monitor blood glucose concentrations and adjust the delivery rate of insulin accordingly. These alternative delivery systems are intended to prevent the development of long-term tissue complications. In 2014 the US Food and Drug Administration (FDA) approved a form of inhalable insulin, potentially representing another easier method of delivery. Adjuvant glucose-lowering medications such as metformin and pramlintide may also improve glycemic control.

There are a number of chronic complications that account for the shorter life expectancy of persons with diabetes. These include atherosclerotic changes throughout the entire vascular system. The thickening of basement membranes that surround the capillaries can affect their ability to exchange nutrients. Cardiovascular lesions are the most common cause of premature death in persons with diabetes. Kidney disease, which is commonly found in persons with longtime diabetes, can ultimately lead to kidney failure. For these persons, expensive medical care, including dialysis and the possibility of a kidney transplant, overshadows their lives. Diabetes is the leading cause of new blindness in the United States. Delayed gastric emptying (gastroparesis) occurs when the stomach takes too long to empty its contents; it results from damage to the vagus nerve from long-term exposure to high glucose levels. In addition, diabetes leads to a gradual decline in the ability of nerves to conduct sensory information to the brain. For example, the feet of some people with diabetes feel more like stumps of wood than living tissue. Consequently, weight is not distributed properly; in concert with the reduction in blood flow, this problem can lead to pressure ulcers. If not properly cared for, areas of the foot can develop gangrene, which may then lead to amputation of the foot. Finally, in male patients, there are problems with reproductive function that generally result in impotence.

The mechanism responsible for the development of these long-term complications of diabetes is genetic in origin and dependent on the amount of time the tissues are exposed to the elevated plasma glucose concentrations. What, then, is the link between glucose concentrations and diabetic complications?

As an animal ages, most of its cells become less efficient in replacing damaged material, while its tissues lose their elasticity and gradually stiffen. For example, the lungs and heart muscle expand less successfully, blood vessels become increasingly rigid, and ligaments begin to tighten. These apparently diverse age-related changes are accelerated in diabetes, and the causative agent is glucose. Glucose becomes chemically attached to proteins and deoxyribonucleic acid (DNA) in the body without the aid of enzymes to speed the reaction along. What is important is the duration of exposure to the elevated glucose concentrations. Once glucose is bound to tissue proteins, a series of chemical reactions is triggered that, over the passage of months and years, can result in the formation and eventual accumulation of cross-links between adjacent proteins. The higher glucose concentrations in persons with diabetes accelerate this process, and the effects become evident in specific tissues throughout the body.

Understanding the chemical basis of protein cross-linking in diabetes has permitted the development and study of compounds that can intervene in this process. Certain compounds, when added to the diet, can limit the glucose-induced cross-linking of proteins by preventing their formation. One of the best-studied compounds, aminoguanidine, can help prevent the cross-linking of collagen; this fact is shown in a decrease in the accumulation of trapped lipoproteins on artery walls. Aminoguanidine also prevents thickening of the capillary basement membrane in the kidney. Aminoguanidine acts by blocking glucose’s ability to react with neighboring proteins. Vitamins C and B6 are also effective in reducing cross-linking. Aminoguanidine and vitamins C and B6 are thought to have antiaging properties and may also improve the complications resulting from the high blood-glucose levels seen in diabetes mellitus.

Alternatively, transplantation of the entire pancreas is an effective means of achieving an insulin-independent state in persons with type 1 diabetes mellitus. Both the technical problems of pancreas transplantation and the possible rejection of the foreign tissue, however, have limited this procedure as a treatment for diabetes. Diabetes is usually manageable; therefore, a pancreas transplant is not necessarily lifesaving. Success in treating diabetes has also been achieved by transplanting only the insulin-producing islet cells from the pancreas or grafts from fetal pancreas tissue. It may one day be possible to use genetic engineering to permit cells of the liver to self-regulate glucose concentrations by synthesizing and releasing their own insulin into the blood.

Some of the less severe forms of type 2 diabetes mellitus can be controlled by the use of oral hypoglycemic agents that bring about a reduction in blood glucose. These drugs can be taken orally to drive the beta cells to release even more insulin than usual. These drugs also increase the ability of insulin to act on the target cells, which ultimately reduces the insulin requirement. The use of these agents remains controversial, because they overwork the already strained beta cells. If a person with diabetes is reliant on these drugs for extended periods of time, the insulin cells could “burn out” and completely lose their ability to synthesize insulin. In this situation, the previously non-insulin-dependent person would have to be placed on insulin therapy for life. Other hypoglycemic agents lower blood glucose by decreasing hepatic glucose output, reducing insulin resistance, and delaying the absorption of glucose from the gastrointestinal tract.

If obesity is a factor in the expression of type 2 diabetes, as it is in most cases, the best therapy is a combination of a reduction of calorie intake and an increase in activity to achieve weight loss. More than any other disease, type 2 diabetes is related to lifestyle. It is often the case that people prefer having an injection or taking a pill to improving their quality of life by changing their diet and level of activity. Attention to diet and exercise results in a dramatic decrease in the need for drug therapy in most people with diabetes. In some cases, the loss of only a small percentage of body weight results in an increased sensitivity to insulin. Exercise is particularly helpful in the management of both types of diabetes, because working muscle does not require insulin to metabolize glucose. Thus, exercising muscles take up and use some of the excess glucose in the blood, which reduces the overall need for insulin. Permanent weight reduction and exercise also help to prevent long-term complications and permit a healthier and more active lifestyle.

Perspective and Prospects

Diabetes mellitus is a disease of ancient origin. The first written reference to diabetes, which was discovered in the tomb of Thebes in Egypt (1500 BCE), described an illness associated with the passage of vast quantities of sweet urine and an excessive thirst.

The study of diabetes owes much to the Franco-Prussian War. In 1870, during the siege of Paris, it was noted by French physicians that the widespread famine in the besieged city had a curative influence on patients with diabetes. Their glycosuria decreased or disappeared. These observations supported the view of clinicians at the time who had previously prescribed periods of fasting and increased muscular work for the treatment of the overweight individual with diabetes.

It was Oscar Minkowski of Germany who, in 1889, accidentally traced the origin of diabetes to the pancreas. Following the complete removal of the pancreas from a dog, Minkowski’s technician noted the animal’s subsequent copious urine production. Acting on the basis of a hunch, Minkowski tested the urine and determined that its sugar content was greater than 10 percent.

In 1921, Frederick Banting and Charles Best, at the University of Toronto in Canada, successfully isolated the hormone insulin by extracting the antidiabetic substance insulin using a cold alcohol-hydrochloric acid mixture to inactivate the harsh digestive enzymes of the pancreas. Using this substance, they first controlled the disease in a depancreatized dog and then, a few months later, successfully treated the first human patient with diabetes. The clinical application of a discovery normally takes a long time, but in this case a mere twenty weeks had passed between the first injection of insulin into the diabetic dog and the first trial with a human with diabetes. Three years later, in 1923, Banting and Best were awarded the Nobel Prize in physiology or medicine for their remarkable achievement.

Although insulin, when combined with an appropriate diet and exercise, alleviates the symptoms of diabetes to such an extent that a person with diabetes can lead an essentially normal life, insulin therapy is not a cure. The complications that arise in patients with diabetes are typical of those found in the general population, except that they happen much earlier. With regard to these glucose-induced complications, it was first postulated in 1908 that sugars could react with proteins. In 1912, Louis Camille Maillard further characterized this reaction at the Sorbonne and realized that the consequences of this reaction were relevant to diabetes. Maillard suggested that sugars were destroying the body’s amino acids, which then led to increased excretion in patients with diabetes. It was not until the mid-1970s, however, that Anthony Cerami in New York introduced the concept of the nonenzymatic attachment of glucose to protein and recognized its potential role in diabetic complications. A decade later, this development led to the discovery of aminoguanidine, the first compound to limit the cross-linking of tissue proteins and thus delay the development of certain diabetic complications.

In 1974, Josiah Brown published the first report showing that diabetes could be reversed by transplanting fetal pancreatic tissue. By the mid-1980s, procedures had been devised for the isolation of massive numbers of human islets that could then be transplanted into patients with diabetes. For persons with diabetes, both procedures represent more than a treatment; they may offer a cure for the disease.

By the turn of the twenty-first century, there was a noticeable rise in the prevalence of type 2 diabetes in both developing and developed countries. According to the International Diabetes Federation (IDF), an estimated 387 million people worldwide had diabetes in 2014 and a projected 592 million people worldwide will have diabetes by 2035, if current trends continue. 4.9 million deaths in 2014 were caused by diabetes, a rate of one death every seven seconds. Although the incidence of type 2 diabetes typically increases with age, the first decades of the twenty-first century have seen a dramatic rise in the number of cases in younger people. Diabetes also creates economic problems, with a significant amount of medical spending directed at the disease—$612 billion in 2014 alone.

Obesity is clearly linked to the increase of type 2 diabetes. The growing sedentary lifestyle and increase in energy-dense food intake are significant risk factors. The World Health Organization (WHO) reported that worldwide obesity nearly doubled between 1980 and 2013. According to the IDF, 77 percent of those with diabetes lived in countries with low or middle income rates as of 2014, and as many of 179 million cases of diabetes went undiagnosed. Due in large part to these factors, the WHO has predicted that diabetes will become the seventh leading cause of death worldwide by 2030. Data released by the Centers for Disease Control and Prevention (CDC) in December 2015 suggested that overall health in the United States may be experiencing an upswing. According to the data, there was a sustained, if gradual, decrease in newly diagnosed cases of diabetes mellitus between 2008 and 2014. In 2008, 1.7 million new patients were found to have the disease, while in 2014, 1.4 million people were diagnosed.

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