Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes. Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. There are three main types of diabetes mellitus:
- Type 1 DM results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown.
- Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The most common cause is excessive body weight and not enough exercise.
- Gestational diabetes is the third main form and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.
Signs and symptomsThe classic symptoms of untreated diabetes are weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger). Symptoms may develop rapidly (weeks or months) in type 1 DM, while they usually develop much more slowly and may be subtle or absent in type 2 DM. Several other signs and symptoms can mark the onset of diabetes although they are not specific to the disease. In addition to the known ones above, they include blurry vision, headache, fatigue, slow healing of cuts, and itchy skin. Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.
Diabetic emergenciesLow blood sugar is common in persons with type 1 and type 2 DM. Most cases are mild and are not considered medical emergencies. Effects can range from feelings of unease, sweating, trembling, and increased appetite in mild cases to more serious issues such as confusion, changes in behavior such as aggressiveness, seizures, unconsciousness, and (rarely) permanent brain damage or death in severe cases. Moderate hypoglycemia may easily be mistaken for drunkenness; rapid breathing and sweating, cold, pale skin are characteristic of hypoglycemia but not definitive. Mild to moderate cases are self-treated by eating or drinking something high in sugar. Severe cases can lead to unconsciousness and must be treated with intravenous glucose or injections with glucagon. People (usually with type 1 DM) may also experience episodes of diabetic ketoacidosis, a metabolic disturbance characterized by nausea, vomiting and abdominal pain, the smell of acetone on the breath, deep breathing known as Kussmaul breathing, and in severe cases a decreased level of consciousness. A rare but equally severe possibility is hyperosmolar hyperglycemic state, which is more common in type 2 DM and is mainly the result of dehydration.
ComplicationsAll forms of diabetes increase the risk of long-term complications. These typically develop after many years (10–20) but may be the first symptom in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease. Other "macrovascular" diseases are stroke, and peripheral artery disease. The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and blindness. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplantation. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy causes painful muscle atrophy and weakness. There is a link between cognitive deficit and diabetes. Compared to those without diabetes, those with the disease have a 1.2 to 1.5-fold greater rate of decline in cognitive function. Being diabetic, especially when on insulin, increases the risk of falls in older people.
CausesDiabetes mellitus is classified into four broad categories: type 1, type 2, gestational diabetes, and "other specific types". The "other specific types" are a collection of a few dozen individual causes. Diabetes is a more variable disease than once thought and people may have combinations of forms. The term "diabetes", without qualification, usually refers to diabetes mellitus.
Type 1Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the pancreatic islets, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a T cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin. It causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these diabetes cases were in children. "Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, frequently with ketosis, and sometimes with serious low blood sugar levels. Other complications include an impaired counterregulatory response to low blood sugar, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes. Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes. In genetically susceptible people, the onset of diabetes can be triggered by one or more environmental factors, such as a viral infection or diet. Several viruses have been implicated, but to date there is no stringent evidence to support this hypothesis in humans. Among dietary factors, data suggest that gliadin (a protein present in gluten) may play a role in the development of type 1 diabetes, but the mechanism is not fully understood.
Type 2Type 2 DM is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are classified separately. Type 2 DM is the most common type of diabetes mellitus. In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, high blood sugar can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce the liver's glucose production. Type 2 DM is primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important to the development of type 2 DM, including obesity (defined by a body mass index of greater than 30), lack of physical activity, poor diet, stress, and urbanization. Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders. Even those who are not obese often have a high waist–hip ratio. Dietary factors also influence the risk of developing type 2 DM. Consumption of sugar-sweetened drinks in excess is associated with an increased risk. The type of fats in the diet is also important, with saturated fat and trans fats increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk. Eating lots of white rice also may increase the risk of diabetes. A lack of physical activity is believed to cause 7% of cases.
Gestational diabetesGestational diabetes mellitus (GDM) resembles type 2 DM in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2–10% of all pregnancies and may improve or disappear after delivery. However, after pregnancy approximately 5–10% of women with gestational diabetes are found to have diabetes mellitus, most commonly type 2. Gestational diabetes is fully treatable, but requires careful medical supervision throughout the pregnancy. Management may include dietary changes, blood glucose monitoring, and in some cases, insulin may be required. Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital heart and central nervous system abnormalities, and skeletal muscle malformations. Increased levels of insulin in a fetus's blood may inhibit fetal surfactant production and cause respiratory distress syndrome. A high blood bilirubin level may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A Caesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
Maturity onset diabetes of the youngMaturity onset diabetes of the young (MODY) is an autosomal dominant inherited form of diabetes, due to one of several single-gene mutations causing defects in insulin production. It is significantly less common than the three main types. The name of this disease refers to early hypotheses as to its nature. Being due to a defective gene, this disease varies in age at presentation and in severity according to the specific gene defect; thus there are at least 13 subtypes of MODY. People with MODY often can control it without using insulin.
Other typesPrediabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 DM. Many people destined to develop type 2 DM spend many years in a state of prediabetes. Latent autoimmune diabetes of adults (LADA) is a condition in which type 1 DM develops in adults. Adults with LADA are frequently initially misdiagnosed as having type 2 DM, based on age rather than cause. Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations ( autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999. Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes. "Type 3 diabetes" has been suggested as a term for Alzheimer's disease as the underlying processes may involve insulin resistance by the brain. The following is a comprehensive list of other causes of diabetes:Unless otherwise specified, reference is: Table 20-5 in
- Genetic defects of β-cell function
- * Maturity onset diabetes of the young
- *Mitochondrial DNA mutations
- Genetic defects in insulin processing or insulin action
- *Defects in proinsulin conversion
- *Insulin gene mutations
- *Insulin receptor mutations
- Exocrine pancreatic defects
- * Chronic pancreatitis
- * Pancreatectomy
- * Pancreatic neoplasia
- * Cystic fibrosis
- * Hemochromatosis
- * Fibrocalculous pancreatopathy
- *Growth hormone excess ( acromegaly)
- * Cushing syndrome
- * Hyperthyroidism
- * Pheochromocytoma
- * Glucagonoma
- * Cytomegalovirus infection
- * Coxsackievirus B
- * Glucocorticoids
- * Thyroid hormone
- * β-adrenergic agonists
- * Statins
Pathophysiology(blue) in humans during the course of a day with three meals. One of the effects of a sugar-rich vs a starch-rich meal is highlighted.]] Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, adipose tissue and muscle, except smooth muscle, in which insulin acts via the IGF-1. Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus. The body obtains glucose from three main places: the intestinal absorption of food; the breakdown of glycogen, the storage form of glucose found in the liver; and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body. Insulin plays a critical role in balancing glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen. 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, typically 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. Lower glucose levels result in decreased insulin release from the beta cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin. If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin ( insulin insensitivity or insulin resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis. When the glucose concentration in the blood remains high over time, the kidneys will reach a threshold of reabsorption, and glucose will be excreted in the urine ( glycosuria). This increases the osmotic pressure of the urine and inhibits 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 and other body compartments, causing dehydration and increased thirst ( polydipsia).
DiagnosisDiabetes mellitus is characterized by recurrent or persistent high blood sugar, and is diagnosed by demonstrating any one of the following:
- Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)
- Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a 75 g oral glucose load as in a glucose tolerance test
- Symptoms of high blood sugar and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
- Glycated hemoglobin (HbA1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %).