Diabetes mellitus (IPA: [ˌdaɪəˈbiːtiːz] or [ˌdaɪəˈbiːtəs], [məˈlaɪtəs] or [ˈmɛlətəs]), often simply diabetes (Greek: Διαβήτης), is a syndrome characterized by disordered metabolism and inappropriately high blood sugar (hyperglycemia) resulting from either low levels of the hormone insulin or from abnormal resistance to insulin’s effects coupled with inadequate levels of insulin secretion to compensate. The characteristic symptoms are excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), and blurred vision; these symptoms are likely absent if the blood sugar is only mildly elevated.
The World Health Organization recognizes three main forms of diabetes mellitus: type 1, type 2, and gestational diabetes (occurring during pregnancy), which have similar signs, symptoms, and consequences, but different causes and population distributions. While, ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemia, the causes are different. Type 1 diabetes is usually due to autoimmune destruction of the pancreatic beta cells, which produce insulin. Type 2 diabetes is characterized by insulin resistance in target tissues, this causes a need for abnormally high amounts of insulin and diabetes develops when the beta cells cannot meet this demand. Gestational diabetes is similar to type 2 diabetes in that it involves insulin resistance; the hormones of pregnancy can cause insulin resistance in women genetically predisposed to developing this condition.
Gestational diabetes typically resolves with delivery of the child, however types 1 and 2 diabetes are chronic conditions. All types have been treatable since insulin became medically available in 1921. Type 1 diabetes, in which insulin is not secreted by the pancreas, is directly treatable only with injected or inhaled insulin, although dietary and other lifestyle adjustments are part of management. Type 2 may be managed with a combination of dietary treatment, tablets and injections and, frequently, insulin supplementation. While insulin was originally produced from natural sources such as porcine pancreas, most insulin used today is produced through genetic engineering, either as a direct copy of human insulin, or human insulin with modified molecules that provide different onset and duration of action. Insulin can also be delivered continuously by a specialized pump which subcutaneously provides insulin through a changeable catheter.
Diabetes can cause many complications. Acute complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications include cardiovascular disease (doubled risk), chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and microvascular damage, which may cause impotence and poor healing. Poor healing of wounds, particularly of the feet, can lead to gangrene, which may require amputation. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as not smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications. In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly, the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis.
Signs and Symptoms
The classical triad of diabetes symptoms is polyuria, polydipsia and polyphagia, which are, respectively, frequent urination; increased thirst and consequent increased fluid intake; and increased appetite. Symptoms may develop quite rapidly (weeks or months) in type 1 diabetes, particularly in children. However, in type 2 diabetes the symptoms develop much more slowly and may be subtle or completely absent. Type 1 diabetes may also cause weight loss (despite normal or increased eating) and irreducible fatigue. These symptoms can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.
When the glucose concentration in the blood is raised beyond the renal threshold, reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits the reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells, causing dehydration and increased thirst.
Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change whereas type 2 is generally more gradual, but should still be suspected.
Patients (usually with type 1 diabetes) may also present with diabetic ketoacidosis (DKA), an extreme state of metabolic dysregulation characterized by the smell of acetone on the patient’s breath; a rapid, deep breathing known as Kussmaul breathing; polyuria; nausea; vomiting and abdominal pain; and any of many altered states of consciousness or arousal (such as hostility and mania or, equally, confusion and lethargy). In severe DKA, coma may follow, progressing to death. Diabetic ketoacidosis is a medical emergency and requires hospital admission.
A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration due to loss of body water. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.
Drugs such as steroids, Dilantin, and others may elevate the blood sugar through a variety of mechanisms. Certain other drugs, such as alloxan, streptozocin, and thiazide diuretics, are toxic to the beta cells of the pancreas and can cause diabetes. Certain syndromes (for example, Prader-Willi, Down’s, Progeria, and Turner’s) may result in a hyperglycemic state; if this state is prolonged, the result can be permanent diabetes.
Diabetes resulting in an insulin-dependent state is classified as Type 1 diabetes. While Type 1 diabetes affects only between 5 to 10 percent of the diabetic population, its effects on the body can be worse than other forms of diabetes. In the past, Type 1 has been known as juvenile or juvenile-onset diabetes (because it is usually diagnosed in those under thirty), brittle diabetes, unstable diabetes, and ketosis-prone diabetes. People in this classification more frequently exhibit the classic symptoms, usually with ketones present in blood and urine. A blood-sugar level of 800 mg/dl (44 mmol) or more, especially if ketones are not present, indicates a diagnosis of hyperglycemic hyperosmolar nonketotic syndrome (a state in which the body is extremely dry [dehydrated], the chemicals in the body are concentrated, and the blood sugar is high).
As stated before, diabetes is a syndrome or group of diseases (rather than one disease), leading to the prolonged hyperglycemic state. Type 1 is most associated with the killing of the beta cells, most likely by the body’s own immune system. Either the immune system cannot kill an infecting agent, which then kills the beta cells, or the immune system itself goes “wild,” attacking the body’s own tissue and destroying the beta cells. The cells of the islets of Langerhans are inflamed, resulting from an infectious-disease process (for example, mumps) or, more commonly, from an autoimmune (allergic to self) response.
The autoimmune process results in the circulation of antibodies that may either cause or be caused by beta-cell death. If it is found that the antibodies cause beta-cell destruction (the body fighting what it now considers foreign to itself), the body’s response to the Type 1 diabetes is much less severe (i.e., easier to control) with treatment. Until then, the outcome is a lack of available insulin. While the onset is said to be sudden, changes resulting in decreased insulin availability may have occurred over a longer period of time. In short, insulin-dependent diabetes mellitus is an inherited defect of the body’s immune system, resulting in destruction of the insulin-producing beta cells of the pancreas.
Heredity is a major cause of diabetes. If both parents who have Type 2 diabetes, there is a chance that nearly all of their children will have diabetes. If both parents have Type 1 diabetes, fewer than 20 percent of their children will develop Type 1 diabetes. In identical twins, if one twin develops Type 2 diabetes, the chance is nearly 100 percent that the other twin will also develop it. In Type 1 diabetes, however, only 40 to 50 percent of the second twins will develop the disease, indicating that while inheritance is important, environmental factors (for example, too much food, too much stress, viral infection, and so forth) are also involved in the development of Type 1 diabetes.
The diagnosis of type 1 diabetes, and many cases of type 2, is usually prompted by recent-onset symptoms of excessive urination (polyuria) and excessive thirst (polydipsia), often accompanied by weight loss. These symptoms typically worsen over days to weeks; about a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening; detection of hyperglycemia during other medical investigations; and secondary symptoms such as vision changes or unexplainable fatigue. Diabetes is often detected when a person suffers a problem that is frequently caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia.
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:
· fasting plasma glucose level at or above 126 mg/dL (7.0 mmol/l).
· plasma glucose at or above 200 mg/dL (11.1 mmol/l) two hours after a 75 g oral glucose load as in a glucose tolerance test.
· random plasma glucose at or above 200 mg/dL (11.1 mmol/l).
A positive result, in the absence of clinical symptoms of diabetes, should be confirmed by another of the above-listed methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/l) is considered diagnostic for diabetes mellitus.
Patients with fasting glucose levels between 110 and 125 mg/dL (6.1 and 7.0 mmol/l) are considered to have impaired fasting glycemia. Patients with plasma glucose at or above 140 mg/dL or 7.8 mmol/l two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus as well as cardiovascular disease.
While not used for diagnosis, an elevated level of glucose irreversibly bound to hemoglobin (termed glycosylated hemoglobin or HbA1c) of 6.0% or higher (the 2003 revised U.S. standard) is considered abnormal by most labs; HbA1c is primarily used as a treatment-tracking test reflecting average blood glucose levels over the preceding 90 days (approximately). However, some physicians may order this test at the time of diagnosis to track changes over time. The current recommended goal for HbA1c in patients with diabetes is <7.0%, which is considered good glycemic control, although some guidelines are stricter (<6.5%). People with diabetes who have HbA1c levels within this range have a significantly lower incidence of complications from diabetes, including retinopathy and diabetic nephropathy.
Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.
Much of the carbohydrate in food is converted within a few hours to the monosaccharide glucose, the principal carbohydrate found in blood and used by the body as fuel. Some carbohydrates are not so converted. Notable examples include fruit sugar (fructose), usable as cellular fuel but it is not converted to glucose, and which therefore does not participate in the insulin/glucose metabolic regulatory mechanism. Additionally, the carbohydrate cellulose (though it is actually many glucose molecules in long chains) is not converted to glucose, as humans and many animals have no digestive pathway capable of breaking up cellulose.
Insulin is released into the blood by beta cells (β-cells), found in the Islets of Langerhans in the pancreas, in response to rising levels of blood glucose after eating. Insulin is used by about two-thirds of the body’s cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the beta cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon which acts in an opposite manner to insulin. Glucose thus recovered by the liver re-enters the bloodstream; muscle cells lack the necessary export mechanism.
Higher insulin levels increase many anabolic (“building up”) processes such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat burning metabolic phase).
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.
Type 1 diabetes risk is known to depend upon a genetic predisposition based on HLA types (particularly types DR3 and DR4), an unknown environmental trigger (suspected to an infection in most cases), and an uncontrolled autoimmune response that attacks the insulin producing beta cells. Some research has suggested that breastfeeding decreased the risk; various other nutritional risk factors are being studied, but no firm evidence has been found.
Type 2 diabetes risk can be reduced in many cases by making changes in diet and increasing physical activity. The American Diabetes Association (ADA) recommends maintaining a healthy weight, getting at least 2½ hours of exercise per week (a brisk sustained walk appears sufficient), having a modest fat intake, and eating a good amount of fiber and whole grains. The ADA does not recommend alcohol consumption as a preventative, but it is interesting to note that moderate alcohol intake may reduce the risk (though heavy consumption clearly increases damage to body systems significantly). There is inadequate evidence that eating foods of low glycemic index is clinically helpful.
Some studies have shown delayed progression to diabetes in predisposed patients through prophylactic use of metformin, rosiglitazone, or valsartan. In patients on hydroxychloroquine for rheumatoid arthritis, incidence of diabetes was reduced by 77%. Breastfeeding might also be correlated with the prevention of type 2 of the disease in mothers.
Diabetes mellitus is currently a chronic disease, without a cure, and medical emphasis must necessarily be on managing/avoiding possible short-term as well as long-term diabetes-related problems. There is an exceptionally important role for patient education, dietetic support, sensible exercise, self glucose monitoring, with the goal of keeping both short-term blood glucose levels, and long term levels as well, within acceptable bounds. Careful control is needed to reduce the risk of long term complications. This can be achieved with combinations of diet, exercise and weight loss (type 2), various oral diabetic drugs (type 2 only), and insulin use (type 1 and increasingly for type 2 not responding to oral medication). In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications should be undertaken to control blood pressure and cholesterol by exercising more, smoking cessation, consuming an appropriate diet, wearing diabetic socks, and if necessary, taking any of several drugs to reduce pressure.
In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or research projects. In other circumstances, general practitioners and specialists share care of a patient in a team approach. Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, clinical nurse specialists (eg, Certified Diabetes Educators and DSNs (Diabetic Specialist Nurse)), or nurse practitioners may jointly provide multidisciplinary expertise. In countries where patients must provide their own health care, the impact of out-of-pocket costs of diabetic care can be high. In addition to the medications and supplies needed, patients are often advised to receive regular consultation from a physician (eg, at least every three to six months).
Diabetes doubles the risk of vascular problems, including cardiovascular disease.
According to one study, women with high blood pressure (hypertension) were three times more likely to develop type 2 diabetes as compared with women with optimal BP after adjusting for various factors such as age, ethnicity, smoking, alcohol intake, body mass index (BMI), exercise, family history of diabetes, etc. The study was conducted by researchers from the Brigham and Women’s Hospital, Harvard Medical School and the Harvard School of Public Health, USA, who followed over 38,000 female health professionals for ten years.
Except in the case of type 1 diabetes, which always requires insulin replacement, the way type 2 diabetes is managed may change with age. Insulin production decreases because of age-related impairment of pancreatic beta cells. Additionally, insulin resistance increases because of the loss of lean tissue and the accumulation of fat, particularly intra-abdominal fat, and the decreased tissue sensitivity to insulin. Glucose tolerance progressively declines with age, leading to a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Treatment goals for older patients with diabetes vary with the individual, and take into account health status, as well as life expectancy, level of dependence, and willingness to adhere to a treatment regimen. Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.
People with diabetes may experience many serious, long-term complications. Some of these complications begin within months of the onset of diabetes, although most tend to develop after a few years. Most of the complications are progressive. The more tightly a person with diabetes is able to control the levels of sugar in the blood, the less likely it is that these complications will develop or become worse.
High sugar levels cause narrowing of both the small and large blood vessels. Complex sugar-based substances build up in the walls of small blood vessels, causing them to thicken and leak. As they thicken, they supply less blood, especially to the skin and nerves. Poor control of blood sugar levels also tends to cause the levels of fatty substances in the blood to rise, resulting in atherosclerosis and decreased blood flow in the larger blood vessels. Atherosclerosis is between 2 and 6 times more common in people with diabetes than in people who do not have the disease and tends to occur at younger ages.
Over time, elevated levels of sugar in the blood and poor circulation can harm the heart, brain, legs, eyes, kidneys, nerves, and skin, resulting in angina, heart failure, strokes, leg cramps on walking (claudication), poor vision, renal failure, damage to nerves (neuropathy), and skin breakdown. Heart attacks and strokes are more common among people with diabetes.
Poor circulation to the skin can lead to ulcers and infections, and all wounds heal slowly. People with diabetes are particularly likely to have ulcers and infections of the feet and legs. Too often, these wounds heal slowly or not at all, and amputation of the foot or part of the leg may be needed.
People with diabetes often develop bacterial and fungal infections, typically of the skin. When the levels of sugar in the blood are high, white blood cells cannot effectively fight infections. Any infection that develops tends to be more severe.
Damage to the blood vessels of the eye can cause loss of vision (diabetic retinopathy). Laser surgery can seal the leaking blood vessels of the eye and prevent permanent damage to the retina. Therefore, people with diabetes should have yearly eye examinations to check for damage.
The kidneys can malfunction, resulting in kidney failure that may require dialysis or kidney transplantation. Doctors usually check the urine of people with diabetes for abnormally high levels of protein (albumin), which is an early sign of kidney damage. At the earliest sign of kidney complications, the person is often given angiotensin-converting enzyme (ACE) inhibitors, drugs that slow the progression of kidney disease.
Damage to nerves can manifest in several ways. If a single nerve malfunctions, an arm or leg may suddenly become weak. If the nerves to the hands, legs, and feet become damaged (diabetic polyneuropathy), sensation may become abnormal, and tingling or burning pain and weakness in the arms and legs may develop. Damage to the nerves of the skin makes repeated injuries more likely because the person cannot sense changes in pressure or temperature.