Diabetes mellitus
Classification and external resources
Universal blue circle symbol for diabetes.[1]
ICD-10	E10.–E14.
ICD-9	250
MedlinePlus	001214
eMedicine	med/546 emerg/134
MeSH	C18.452.394.750

Diabetes mellitus (pronounced /ˌdaɪ.əˈbiːtiːz/ or /ˌdaɪ.əˈbiːtɨs/; /mɨˈlaɪtəs/ or /ˈmɛlɨtəs/)—often referred to as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy. This causes glucose to accumulate in the blood, leading to various potential complications.^[2][3]

Many types of diabetes are recognized:^[3] The principal three are:

• Type 1: Results from the body's failure to produce insulin. It is estimated that 5–10% of Americans who are diagnosed with diabetes have type 1 diabetes. Presently most persons with type 1 diabetes take insulin injections.
• Type 2: Results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with absolute insulin deficiency. Most Americans who are diagnosed with diabetes have type 2 diabetes.
• Gestational diabetes: Pregnant women who have never had diabetes before but who have high blood sugar (glucose) levels during pregnancy are said to have gestational diabetes. Gestational diabetes affects about 4% of all pregnant women. It may precede development of type 2 (or rarely type 1) DM.

Other forms of diabetes mellitus are categorized separately from these. Examples include congenital diabetes 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.

All forms of diabetes have been treatable since insulin became medically available in 1921, but a cure is difficult. Pancreas transplants have been tried with limited success in type 1 DM; gastric bypass surgery has been successful in many with morbid obesity and type 2 DM; and gestational diabetes usually resolves after delivery. Diabetes without proper treatments can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, retinal damage. Adequate treatment of diabetes is thus important, as well as blood pressure control and lifestyle factors such as smoking cesation and maintaining a healthy body weight.

As of 2000 at least 171 million people worldwide suffer from diabetes, or 2.8% of the population.^[4]

Classification

Most cases of diabetes mellitus fall into the three broad categories of type 1 or type 2 and gestational diabetes. A few other types are described.

The term diabetes, without qualification, usually refers to diabetes mellitus, which roughly translates to excessive sweet urine (known as "glycosuria"). Several rare conditions are also named diabetes. The most common of these is diabetes insipidus in which large amounts of urine are produced (polyuria), which is not sweet (insipidus meaning "without taste" in Latin).

The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus (IDDM). Likewise, the term "type 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined "type 3 diabetes" as: gestational diabetes,^[5] insulin-resistant type 1 diabetes (or "double diabetes"), type 2 diabetes which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "type 1.5" diabetes.^[6])

Type 1 diabetes

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas leading insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, where beta cell loss is a T-cell mediated autoimmune attack.^[2] There is no known preventive measure against type 1 diabetes, which 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 it represents a majority of the diabetes cases in children.

Type 2 diabetes

Type 2 diabetes mellitus 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 due to a known defect are classified separately. Type 2 diabetes is the most common type.

In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity. At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver. As the disease progresses, the impairment of insulin secretion occurs, and therapeutic replacement of insulin often becomes necessary.^{[citation needed]}

Gestational diabetes

Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life.

Even 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 cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia 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. Induction may be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.

A 2008 study completed in the U.S. found that more American women are entering pregnancy with preexisting diabetes. In fact the rate of diabetes in expectant mothers has more than doubled in the past 6 years.^[7] This is particularly problematic as diabetes raises the risk of complications during pregnancy, as well as increasing the potential that the children of diabetic mothers will also become diabetic in the future.

Other types

Pre-diabetes 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 diabetes. Many people destined to develop type 2 diabetes spend many years in a state of pre-diabetes which has been termed "America's largest healthcare epidemic,"^[8]:10–11.

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.^[9]

Signs and symptoms

Overview of the most significant symptoms of diabetes.

The classical symptoms of DM are polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).^[10] Symptoms may develop quite rapidly (weeks or months) in type 1 diabetes, particularly in children. However, in type 2 diabetes symptoms usually develop much more slowly and may be subtle or completely absent. Type 1 diabetes may also cause a rapid yet significant weight loss (despite normal or even increased eating) and irreducible mental fatigue. All of these symptoms except weight loss can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled, although unexplained weight loss may be experienced at the onset of the disease. Final diagnosis is made by measuring the blood glucose concentration.

When the glucose concentration in the blood is raised beyond its renal threshold (about 10 mmol/L, although this may be altered in certain conditions, such as pregnancy), 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 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.

Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes; sustained sensible glucose control usually returns the lens to its original shape. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected.

Patients (usually with type 1 diabetes) may also initially 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 immediate hospitalization.

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.

A number of skin rashes can occur in diabetes that are collectively known as diabetic dermadromes.

Causes

Type 2 diabetes is determined primarily by lifestyle factors and genes.^[11]

Lifestyle

A number of lifestyle factors are known to be important to the development of type 2 diabtetes. In one study, those who had high levels of physical activity, a healthy diet, did not smoke, and consumed alcohol in moderation had an 82% lower rate of diabetes. When a normal weight was included the rate was 89% lower. In this study a health diet was defined as one high in fiber, with a high polyunsaturated to saturated fat ratio, and a lower mean glycemic index.^[12] Obesity has been found to contribute to approximately 55% type 2 diabetes,^[13] and decreasing consumption of saturated fats and trans fatty acids well replacing them with unsaturated fats may decrease the risk.^[11] The increased rate of childhood obesity in between the 1960s and 2000s is beleived to have lead to the increase in type 2 diabetes in children and adolescents.^[14]

Environmental toxins may contribute to recent increases in the rate of type 2 diabetes. A positive correlation has been found between the concentration in the urine of bisphenol A, a constituent of some plastics, and the incidence of type 2 diabetes.^[15]

Medical conditions

Subclinical Cushing's syndrome (cortisol excess) may be associated with DM type 2.^[16] The percentage of subclinical Cushing's syndrome in the diabetic population is about 9%.^[17] Diabetic patients with a pituitary microadenoma can improve insulin sensitivity by removal of these microadenomas.^[18]

Hypogonadism is often associated with cortisol excess, and testosterone deficiency is also associated with diabetes mellitus type 2,^[19][20] even if the exact mechanism by which testosterone improve insulin resistance is still not known.

Genetics

Both type 1 and type 2 diabetes are partly inherited. Type 1 diabetes may be triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger.

There is a stronger inheritance pattern for type 2 diabetes. Those with first-degree relatives with type 2 have a much higher risk of developing type 2, increasing with the number of those relatives. Concordance among monozygotic twins is close to 100%, and about 25% of those with the disease have a family history of diabetes. Genes significantly associated with developing type 2 diabetes, include TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX.^[21] KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1.^[2] Moreover, obesity (which is an independent risk factor for type 2 diabetes) is strongly inherited.^[22]

Monogenic forms, e.g., MODY, constitute 1–5 % of all cases.^[23]

Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.^[24]

Gene expression promoted by a diet of fat and glucose as well as high levels of inflammation related cytokines found in the obese results in cells that "produce fewer and smaller mitochondria than is normal," and are thus prone to insulin resistance.^[25]

Pathophysiology

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Mechanism of insulin release in normal pancreatic beta cells. Insulin production is more or less constant within the beta cells, irrespective of blood glucose levels. It is stored within vacuoles pending release, via exocytosis, which is primarily triggered by food, chiefly food containing absorbable glucose. The chief trigger is a rise in blood glucose levels after eating

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.

Most of the carbohydrates in food are converted within a few hours to the monosaccharide glucose, the principal carbohydrate found in blood and used by the body as fuel. The most significant exceptions are fructose, most disaccharides (except sucrose and in some people lactose), and all more complex polysaccharides, with the outstanding exception of starch. 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.

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 some 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.

Diagnosis

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Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:^[9]

• Fasting plasma glucose level at or above 7.0 mmol/L (126 mg/dL).
• Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test.
• Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol/L (200 mg/dL).

About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids) 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.

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any 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 and offers no prognostic advantage over the fasting test.^[27] 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 from 100 to 125 mg/dL (6.1 and 7.0 mmol/L) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL or 7.8 mmol/L, but not over 200, 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.^[28]

While not used for diagnosis, an elevated level of glucose irreversibly bound to hemoglobin (termed glycated 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) which is the average lifetime of red blood cells which contain hemoglobin in most patients. 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 6.5%.^[29][30]

Screening

Diabetes screening is recommended for many people at various stages of life, and for those with any of several risk factors. The screening test varies according to circumstances and local policy, and may be a random blood glucose test, a fasting blood glucose test, a blood glucose test two hours after 75 g of glucose, or an even more formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and often periodically thereafter. Earlier screening is typically recommended for those with risk factors such as obesity, family history of diabetes, high-risk ethnicity (Hispanic, Native American, Afro-Caribbean, Pacific Islander, or Maori).^[31][32]

Many medical conditions are associated with diabetes and warrant screening. A partial list includes: subclinical Cushing's syndrome,^[16] testosterone deficiency,^[19] high blood pressure, elevated cholesterol levels^{[citation needed]}, coronary artery disease^{[citation needed]}, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, fatty liver, hemochromatosis^{[citation needed]}, cystic fibrosis, several mitochondrial neuropathies and myopathies, myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal hyperinsulinism. The risk of diabetes is higher with chronic use of several medications, including long term corticosteroids, some chemotherapy agents (especially L-asparaginase), as well as some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics).

People with a confirmed diagnosis of diabetes are tested routinely for complications. This includes yearly urine testing for microalbuminuria and examination of the retina of the eye for retinopathy.

Prevention

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 be an infection, although none has proven definitive in all cases), and an uncontrolled autoimmune response that attacks the insulin producing beta cells.^[33] Some research has suggested that breastfeeding decreased the risk in later life;^[34][35] various other nutritional risk factors are being studied, but no firm evidence has been found.^[36] Giving children 2000 IU of Vitamin D during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.^[37]

Children with antibodies to beta cell proteins (ie at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin B-3 (niacin), had less than half the diabetes onset incidence in a 7-year time span as did the general population, and an even lower incidence relative to those with antibodies as above, but who received no vitamin B3.^[38]

Type 2 diabetes risk can be reduced in many cases by making changes in diet and increasing physical activity.^[39][40][41] The American Diabetes Association (ADA) recommends maintaining a healthy weight, getting at least 2½ hours of exercise per week (several brisk sustained walks appear sufficient), having a modest fat intake, and eating sufficient fiber (e.g., from whole grains). The ADA does not recommend alcohol consumption as a preventive, but it is interesting to note that moderate alcohol intake may reduce the risk (though heavy consumption absolutely and clearly increases damage to bodily systems significantly); a similarly confused connection between low dose alcohol consumption and heart disease is termed the French Paradox.

There is inadequate evidence that eating foods of low glycemic index is clinically helpful despite recommendations and suggested diets emphasizing this approach.^[42]

Diets that are very low in saturated fats reduce the risk of becoming insulin resistant and diabetic.^[43][44] Study group participants whose "physical activity level and dietary, smoking, and alcohol habits were all in the low-risk group had an 82% lower incidence of diabetes."^[45] In another study of dietary practice and incidence of diabetes, "foods rich in vegetable oils, including non-hydrogenated margarines, nuts, and seeds, should replace foods rich in saturated fats from meats and fat-rich dairy products. Consumption of partially hydrogenated fats should be minimized."^[46]

There are numerous studies which suggest connections between some aspects of Type II diabetes with ingestion of certain foods or with some drugs. Some studies have shown delayed progression to diabetes in predisposed patients through prophylactic use of metformin,^[40] rosiglitazone,^[47] or valsartan.^[48] In patients on hydroxychloroquine for rheumatoid arthritis, incidence of diabetes was reduced by 77% though causal mechanisms are unclear.^[49] Breastfeeding may also be associated with the prevention of type 2 of the disease in mothers.^[50] Clear evidence for these and any of many other connections between foods and supplements and diabetes is sparse to date; none, despite secondary claims for (or against), is sufficiently well established to justify as a standard clinical approach.

Management

Diabetes mellitus a chronic disease which is difficult to cure. Management concentrates on keeping blood sugar levels within normal limits. This can usually be via diet, exercise, and use of appropriate medications (oral medications and insulin).

Lifestyle modifications

There are roles for patient education, dietetic support, sensible exercise, with the goal of keeping both short-term and long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications should be undertaken to control blood pressure^[51] and cholesterol by exercising more, smoking less or ideally not at all, consuming an appropriate diet^{[citation needed]}, wearing diabetic socks^{[citation needed]}, wearing diabetic shoes^{[citation needed]}.

Medications

Oral medications

Insulin

Type 1 treatments usually include combinations of regular or NPH insulin, and/or synthetic insulin analogs.

Support

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, nursing specialists (e.g., DSNs (Diabetic Specialist Nurse)), nurse practitioners, or Certified Diabetes Educators, may jointly provide multidisciplinary expertise. In countries where patients must provide for their own health care (e.g. in the US, and in much of the undeveloped world).

Peer support links people living with diabetes. Within peer support, people with a common illness share knowledge and experience that others, including many health workers, do not have. Peer support is frequent, ongoing, accessible and flexible and can take many forms—phone calls, text messaging, group meetings, home visits, and even grocery shopping. It complements and enhances other health care services by creating the emotional, social and practical assistance necessary for managing disease and staying healthy.

Prognosis

Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-controlled blood sugar levels.^[52][53] Wider health problems accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise. 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.^[54] 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.

The way diabetes is managed changes 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.^[55] Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people.^[56] 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.^[57]

Epidemiology

Prevalence of diabetes worldwide in 2000 (per 1000 inhabitants). World average was 2.8%.

     no data      ≤ 7.5      7.5–15      15–22.5      22.5–30      30–37.5      37.5–45      45–52.5      52.5–60      60–67.5      67.5–75      75–82.5      ≥ 82.5

Disability-adjusted life year for diabetes mellitus per 100,000 inhabitants in 2002.^[58]

     no data      ≤ 100      100-200      200-300      300-400      400-500      500-600      600-700      700-800      800-900      900-1000      1000-1500      ≥ 1500

In 2000, according to the World Health Organization, at least 171 million people worldwide suffer from diabetes, or 2.8% of the population.^[4] Its incidence is increasing rapidly, and it is estimated that by the year 2030, this number will almost double.^[4] Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients will probably be found by 2030.^[4] The increase in incidence of diabetes in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented.^[4]

For at least 20 years, diabetes rates in North America have been increasing substantially. In 2008 there were about 24 million people with diabetes in the United States alone, from those 5.7 million people remain undiagnosed. Other 57 million people are estimated to have pre-diabetes.^[59]

The Centers for Disease Control has termed the change an epidemic.^[60] The National Diabetes Information Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year. About 5%–10% of diabetes cases in North America are type 1, with the rest being type 2. The fraction of type 1 in other parts of the world differs. Most of this difference is not currently understood. The American Diabetes Association cite the 2003 assessment of the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease Control and Prevention) that 1 in 3 Americans born after 2000 will develop diabetes in their lifetime.^[61][62]

According to the American Diabetes Association, approximately 18.3% (8.6 million) of Americans age 60 and older have diabetes.^[63] Diabetes mellitus prevalence increases with age, and the numbers of older persons with diabetes are expected to grow as the elderly population increases in number. The National Health and Nutrition Examination Survey (NHANES III) demonstrated that, in the population over 65 years old, 18% to 20% have diabetes, with 40% having either diabetes or its precursor form of impaired glucose tolerance.^[55]

Indigenous populations in first world countries have a higher prevalence and increasing incidence of diabetes than their corresponding non-indigenous populations. In Australia the age-standardised prevalence of self-reported diabetes in Indigenous Australians is almost 4 times that of non-indigenous Australians.^[64] Preventative community health programs such as Sugar Man (diabetes education) are showing some success in tackling this problem.

History

The term diabetes (Greek: διαβήτης, diabētēs) was coined by Aretaeus of Cappadocia. It was derived from the Greek verb διαβαίνειν, diabaínein, itself formed from the prefix dia-, "across, apart," and the verb bainein, "to walk, stand." The verb diabeinein meant "to stride, walk, or stand with legs asunder"; hence, its derivative diabētēs meant "one that straddles," or specifically "a compass, siphon." The sense "siphon" gave rise to the use of diabētēs as the name for a disease involving the discharge of excessive amounts of urine. Diabetes is first recorded in English, in the form diabete, in a medical text written around 1425. In 1675, Thomas Willis added the word mellitus, from the Latin meaning "honey", a reference to the sweet taste of the urine. This sweet taste had been noticed in urine by the ancient Greeks, Chinese, Egyptians, Indians, and Persians. In 1776, Matthew Dobson confirmed that the sweet taste was because of an excess of a kind of sugar in the urine and blood of people with diabetes.^[65]

Diabetes mellitus appears to have been a death sentence in the ancient era. Hippocrates makes no mention of it, which may indicate that he felt the disease was incurable. Aretaeus did attempt to treat it but could not give a good prognosis; he commented that "life (with diabetes) is short, disgusting and painful."^[66]

Sushruta (6th century BCE) identified diabetes and classified it as Medhumeha.^[67] He further identified it with obesity and sedentary lifestyle, advising exercises to help "cure" it.^[67] The ancient Indians tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (Madhumeha). The Korean, Chinese, and Japanese words for diabetes are based on the same ideographs (糖尿病) which mean "sugar urine disease".

In medieval Persia, Avicenna (980–1037) provided a detailed account on diabetes mellitus in The Canon of Medicine, "describing the abnormal appetite and the collapse of sexual functions," and he documented the sweet taste of diabetic urine. Like Aretaeus before him, Avicenna recognized a primary and secondary diabetes. He also described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed, which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern times. Avicenna also "described diabetes insipidus very precisely for the first time", though it was later Johann Peter Frank (1745–1821) who first differentiated between diabetes mellitus and diabetes insipidus.^[68]

Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in various regions since the Middle Ages, and in legend for much longer, pathogenesis of diabetes has only been understood experimentally since about 1900.^[69] The discovery of a role for the pancreas in diabetes is generally ascribed to Joseph von Mering and Oskar Minkowski, who in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes and died shortly afterwards.^[70] In 1910, Sir Edward Albert Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas—he proposed calling this substance insulin, from the Latin insula, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas.

The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not further clarified until 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski, and went further to demonstrate they could reverse induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs.^[71] Banting, Best, and colleagues (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases at the University of Toronto. This led to the availability of an effective treatment—insulin injections—and the first patient was treated in 1922. For this, Banting and laboratory director MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their Prize money with others in the team who were not recognized, in particular Best and Collip. Banting and Best made the patent available without charge and did not attempt to control commercial production. Insulin production and therapy rapidly spread around the world, largely as a result of this decision. Banting is honored by World Diabetes Day which is held on his birthday, November 14.

The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth, and published in January 1936.^[72]

Despite the availability of treatment, diabetes has remained a major cause of death. For instance, statistics reveal that the cause-specific mortality rate during 1927 amounted to about 47.7 per 100,000 population in Malta.^[73]

Other landmark discoveries include:^[69]

• Identification of the first of the sulfonylureas in 1942
• Reintroduction of the use of biguanides for Type 2 diabetes in the late 1950s. The initial phenformin was withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis and metformin was first marketed in France in 1979, but not until 1994 in the US.
• The determination of the amino acid sequence of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize)
• The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine)^[74]
• The three-dimensional structure of insulin (PDB 2INS)
• Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988
• Demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose levels approach 'normal' in a large longitudinal study,^[75] and also in type 2 diabetics in other large studies
• Identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s

In 1980, U.S. biotech company Genentech developed human insulin. The insulin is isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing human insulin), which produce large quantities of insulin. Scientists then purify the insulin and distribute it to pharmacies for use by diabetes patients.

Society and culture

The 1990 "St Vincent Declaration"^[76][77] was the result of international efforts to improve the care accorded to those with diabetes. Doing so is important both in terms of quality of life and life expectancy but also economically-expenses due to diabetes have been shown to be a major drain on health-and productivity-related resources for healthcare systems and governments.

Several countries established more and less successful national diabetes programmes to improve treatment of the disease.^[78]

A study shows that diabetic patients with neuropathic symptoms such as numbness or tingling in feet or hands are twice as likely to be unemployed as those without the symptoms.^[79]

Research

Diabetics are often advised to receive regular consultation from a physician (e.g., at least every three to six months) although research is underway to develop artificial intelligence systems which may reduce the frequency of such visits.^[80]

References

External links

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• Diabetesat the Open Directory Project
• American Diabetes Association
• IDF Diabetes Atlas
• International Diabetes Federation
• National Diabetes Education Program
• Peers for Progress
• World Diabetes Day