Diabetes

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Etymology

The word diabetes was coined by Aretaeus (81–133 CE) of Cappadocia. The word is taken from Greek diabaínein, and literally means "passing through", or "siphon", a reference to one of the diabetes major symptoms of excessive urine discharge. The word became "diabetes" from the English adoption of the medieval Latin diabetes. In 1675 Thomas Willis added mellitus to the name (Greek mel, "honey", sense "honey sweet") when he noted that a diabetic's urine and blood has a sweet taste (first noticed by ancient Indians). In 1776 it was confirmed the sweet taste was because of an excess of sugar in the urine and blood.
The ancient Chinese tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (糖尿病); medieval European doctors tested for it by tasting the urine themselves, a scene occasionally depicted in Gothic reliefs.
Passing abnormal amounts of urine is a symptom shared by several diseases (most commonly of the kidneys), and the single word diabetes is applied to many of them. The most common of them are diabetes insipidus and the subject of this article, diabetes mellitus.

History

Although diabetes has been recognized since antiquity, and treatments were known since the Middle Ages, the elucidation of the pathogenesis of diabetes occurred mainly in the 20th century6.
The discovery of the role of the pancreas in diabetes is generally credited to Joseph von Mering and Oskar Minkowski, two European researchers who in 1889 found that when they completely removed the pancreas of dogs, the dogs developed all the signs and symptoms of diabetes and died shortly afterward. In 1910, Sir Edward Albert Sharpey-Schafer of Edinburgh in Scotland suggested that diabetics were deficient in a single chemical that was normally produced by the pancreas — he proposed calling this substance insulin.
Until 23rd June, 1921, when insulin was first discovered and made clinically available, a clinical diagnosis of what is now called type 1 diabetes was an invariable death sentence, more or less quickly.
The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not fully clarified until 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski, but went a step further and demonstrated that they could reverse the induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs7. They and their colleagues went on to isolate the hormone insulin from bovine pancreases at the University of Toronto in Canada.
This led to the availability of an effective treatment — insulin injections — and the first clinical patient was treated in 1922. For this, Banting et al received the Nobel Prize in Physiology or Medicine in 1923. The two researchers made the patent available and did not attempt to control commercial production. Insulin production and therapy rapidly spread around the world, largely as a result of their decision.
The distinction between what is now known as type 1 diabetes and type 2 diabetes was made by Sir Harold Percival (Harry) Himsworth in 1935; he published his findings in January 1936 in The Lancet8.Other landmark discoveries⁶ include:

identification of sulfonylureas in 1942
the radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine)
Reaven's introduction of the metabolic syndrome in 1988
identification of thiazolidinediones as effective antidiabetics in the 1990s
Causes and types

The role of insulin

Since insulin is the principal hormone that regulates uptake of glucose into most cells (primarily muscle and fat cells, but not central nervous sytem cells) from the blood, deficiency of insulin or its action plays a central role in all forms of diabetes.
Most of the carbohydrates in food are rapidly converted to glucose, the principal sugar in blood. Insulin is produced by beta cells in the pancreas in response to rising levels of glucose in the blood, as occurs after a meal. Insulin makes it possible for most body tissues to remove 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 (the basic sugar unit) to glycogen for storage in liver and muscle cells. Lowered insulin levels result in the reverse conversion of glycogen to glucose when glucose levels fall — though only glucose so produced in the liver goes into the blood. Higher insulin levels increase many anabolic ("building up") processes such as cell growth, cellular protein synthesis, and fat storage. Insulin is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction.
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, glucose is not handled properly by body cells (about 2/3 require it) or stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements.
Types

Type 1

Type 1 diabetes (formerly known as insulin-dependent diabetes, childhood diabetes, or juvenile-onset diabetes) is most commonly diagnosed in children and adolescents, but can occur in adults, as well. It is characterized by β-cell destruction, which usually leads to an absolute deficiency of insulin. Most cases of type 1 diabetes are immune-mediated characterized by autoimmune destruction of the body's β-cells in the Islets of Langerhans of the pancreas, destroying them or damaging them sufficiently to reduce insulin production. However, some forms of type 1 diabetes are characterized by loss of the body's β-cells without evidence of autoimmunity.
Currently, type 1 diabetes is treated with insulin injections, lifestyle adjustments, and careful monitoring of blood glucose levels using blood test kits. Insulin delivery is also possible via an insulin pump, which allows the infusion of insulin 24 hours a day at preset levels, and the ability to program push doses (bolus) of insulin as needed at meal times, though at the expense of an indwelling subcutaneous catheter. Treatment must be continued indefinitely. Treatment does not impair normal activities if carried out systematically with discipline. The average glucose level for the type I diabetic patient should be as close to normal (80-120 mg/dl) as possible. Many type 1 patients target the 110 mg/dl–140 mg/dl range if possible. Some physicians suggest up to 150 mg/dl for those having trouble with lower values. Values above 200 mg/dl are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl require immediate treatment and may lead to ketoacidosis.

Type 2

In type 2 diabetes insulin levels are initially normal or elevated, later falling, but peripheral tissues are no longer/ less responsive to insulin "insulin resistance," (i.e., body cells do not respond appropriately when insulin is present). Hence drugs like "Metformin" are given to decrease the response threshold to insulin.
Type 2 diabetes is a more complex problem than type 1 but is often easier to treat, since insulin is still produced, especially in the initial years. Type 2 diabetes may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (no ketoacidosis) and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including renal failure and coronary artery disease.
Type 2 diabetes is initially treated by changes in physical activity, diet and through weight loss. This can restore insulin sensitivity, even when the weight lost is modest, e.g., around 5 kg (10 to 15 lb). The next step, if necessary, is treatment with oral antidiabetic drugs: the sulphonylureas, metformin, or thiazolidinediones. If these fail, insulin therapy may be necessary to maintain normal glucose levels. For patients with diabetes, a disciplined regimen of blood glucose checks is required.
For both types of diabetes, there is good evidence that maintaining normal blood glucose levels reduces the incidence of organ damage due to diabetes (eyesight, kidneys, circulation, etc.). This may require blood glucose testing several times per day, and careful supervision of food intake and exercise.

Gestational diabetes

Gestational diabetes mellitus appears in about 2%–5% of all pregnancies. It is temporary and fully treatable, but, if untreated, it may cause problems with the pregnancy, including macrosomia (high birth weight) of the child. It requires careful medical supervision during the pregnancy. In addition, about 20%–50% of these women go on to develop type 2 diabetes.

Other types

There are several causes of diabetes that do not fit into type 1, type 2, or gestational diabetes:

• Genetic defects in beta cells
• Genetically-related insulin resistance
• Diseases of the pancreas
• Hormonal defects
• Chemicals or drugs.

"Malnutrition-related diabetes mellitus" (MRDM or MMDM) was introduced by the WHO as the third major category of diabetes in the 1980s. However, in 1999, a WHO working group recommended that MRDM be deprecated, and proposed a new taxonomy for alternative forms of diabetes. Classification of non-type 1, non-type 2, non-gestational diabetes remains controversial.

Genetics

Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some infection types, stress, or environmental factors (e.g., exposure to a causative agent). There is a genetic element in the susceptibility of individuals to some of these triggers which has been traced to particular HLA genotypes (i.e., genetic "self" identifiers used by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger. A small proportion of type 1 diabetics carry a mutated gene that causes maturity onset diabetes of the young (MODY).
There is an even stronger inheritance pattern for type 2 diabetes: those with type 2 ancestors or relatives have very much higher chances of developing type 2. Concordance among monozygotic twins is close to 100%, and 25% of those with the disease have a family history of diabetes. It is also often connected to obesity, which is found in approximately 85% of (North American) patients diagnosed with that form of the disease, so some experts believe that inheriting a tendency toward obesity seems also to contribute. However, without regard to any genetic predisposition, many experts believe that lifestyle factors (lack of exercise, poor diet, etc.) are the greatest contributors to the development of type 2 diabetes, and that stringent weight control in persons with a genetic predisposition will go far in preventing the disease and its consequences. Age is also thought to be a contributing factor, as most type 2 patients in the past were older. The exact reasons for these any of these connections are unknown.
Diagnosis

Signs and symptoms

Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some infection types, stress, or environmental factors (e.g., exposure to a causative agent). There is a genetic element in the susceptibility of individuals to some of these triggers which has been traced to particular HLA genotypes (i.e., genetic "self" identifiers used by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger. A small proportion of type 1 diabetics carry a mutated gene that causes maturity onset diabetes of the young (MODY).
There is an even stronger inheritance pattern for type 2 diabetes: those with type 2 ancestors or relatives have very much higher chances of developing type 2. Concordance among monozygotic twins is close to 100%, and 25% of those with the disease have a family history of diabetes. It is also often connected to obesity, which is found in approximately 85% of (North American) patients diagnosed with that form of the disease, so some experts believe that inheriting a tendency toward obesity seems also to contribute. However, without regard to any genetic predisposition, many experts believe that lifestyle factors (lack of exercise, poor diet, etc.) are the greatest contributors to the development of type 2 diabetes, and that stringent weight control in persons with a genetic predisposition will go far in preventing the disease and its consequences. Age is also thought to be a contributing factor, as most type 2 patients in the past were older. The exact reasons for these any of these connections are unknown.

Diagnostic approach

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 25% of people with new type 1 diabetes have developed a degree of diabetic ketoacidosis by the time the diabetes is recognized.

The diagnosis of other types of diabetes is made in many other ways. The most common are (1) health screening, (2) detection of hyperglycemia when a doctor is investigating a complication of longstanding, unrecognized diabetes, and (3) new signs and symptoms attributable to the diabetes.

1. Diabetes screening is recommended for many types of people at various stages of life or with several different risk factors. The screening test varies according to circumstances and local policy and may be a random glucose, a fasting glucose and insulin, a glucose two hours after 75 g of glucose, or a formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and sometimes occasionally thereafter. Earlier screening is recommended for those with risk factors such as obesity, family history of diabetes, high-risk ethnicity (Hispanic [Latin American], American Indian, African American, Pacific Island, and South Asian ancestry).
2. Many medical conditions are associated with a higher risk of various types of diabetes and warrant screening. A partial list includes: high blood pressure, elevated cholesterol levels, coronary artery disease, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, hepatic steatosis (fatty liver), cystic fibrosis, several mitochondrial neuropathies and myopathies, myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal hyperinsulinism, and many others. Risk of diabetes is higher with chronic use of several medications, including high-dose glucocorticoids, some chemotherapy agents (especially L-asparaginase), and some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics).
3. Many medical conditions are associated with a higher risk of various types of diabetes and warrant screening. A partial list includes: high blood pressure, elevated cholesterol levels, coronary artery disease, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, hepatic steatosis (fatty liver), cystic fibrosis, several mitochondrial neuropathies and myopathies, myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal hyperinsulinism, and many others. Risk of diabetes is higher with chronic use of several medications, including high-dose glucocorticoids, some chemotherapy agents (especially L-asparaginase), and some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics).

Criteria for diagnosis

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 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
• random plasma glucose at or above 11.1 mmol/L (200 mg/dL).

A positive result should be confirmed by any of the above-listed methods on a different day, unless there is no doubt as to the presence of significantly-elevated glucose levels. Most physicians prefer measuring a fasting glucose level because of the ease of measurement and time commitment of formal glucose tolerance testing, which can take two hours to complete. By definition, two fasting glucose measurements above 126 mg/dL is considered diagnostic for diabetes mellitus.

Patients with fasting blood sugars between 100 and 125 mg/dL are considered to have "impaired fasting glucose," and patients with plasma glucose at or above 140-199 mg/dL two hours after a 75 g oral glucose load are considered to have "impaired glucose tolerance". "Prediabetes" is either impaired fasting gluose or impaired glucose tolerance; it is a major risk factor for progression to full-blown diabetes mellitus as well as cardiovascular disease.

While not used for diagnosis, an elevated glucose bound to hemoglobin, HbA1c, of 6.0% or higher (2003 revised U.S. standard) is considered abnormal by most labs; HbA1c is primarily 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%, as defined as "good glycemic control," although some guidelines are stricter(<6.5%). People with diabetes that have HbA1c levels below goal have a significantly lower incidence of complications from diabetes, including retinopathy and diabetic nephropathy.

Glucose Monitoring

Control and outcomes are diabetes is improved by patients using glucose meters to regularly measure their glucose levels regardless of type of diabetes.

In all cases, glucose monitoring is expensive (largely due to the cost of the consumable test strips), and the expense is justifiable only if the patient actually discusses the results with his/her physician or other diabetes health professional who may recommend that he/she use the values to adjust food, exercise, and oral medications or insulin.

Diabetic ketoacidosis and coma

See more detail in the articles diabetic ketoacidosis and diabetic coma

Diabetic ketoacidosis (DKA) is an acute, dangerous complication and is always a medical emergency. On presentation at hospital, the patient in DKA is typically dehydrated and breathing both fast and deeply. Abdominal pain is common and may be severe. The level of consciousness is normal until late in the process, when lethargy (dulled or reduced level of alertness or consciousness) may progress to coma. The ketoacidosis can become severe enough to cause hypotension and shock. Prompt proper treatment usually results in full recovery, though death can result from inadequate treatment, delayed treatment or from a variety of complications. It is much more common in type 1 diabetics than type 2, but can still occur in patients with type 2 diabetes.
Hyperosmotic diabetic coma is another acute problem associated with diabetes mellitus. It has many symptoms in common with DKA, but a different cause, and requires different treatment. In anyone with very high blood glucose levels (usually considered to be above 16.6 mmol/l [300 mg/dl]), water will be osmotically driven out of cells into the blood. The kidneys will also be "dumping" glucose into the urine, resulting in concomitant loss of water, causing an increase in blood osmolality. If the fluid is not replaced (by mouth or intravenously), the osmotic effect of high glucose levels combined with the loss of water will eventually result in such a high serum osmolality (dehydration). The body's cells may become progressively dehydrated as water is drawn out from them and excreted. Electrolyte imbalances are also common. This combination of changes, especially if prolonged, will result in symptoms of lethargy (dulled or reduced level of alertness or consciousness) and may progress to coma. As with DKA urgent medical treatment is necessary, especially volume replacement. This is the diabetic coma which more commmonly occurs in type 2 diabetics; it is less common in type 1 diabetes.

Hypoglycemia

Hypoglycemia in patients with diabetes almost always arises as a result of poor control of the disease, either from too much or poorly timed insulin or oral hypoglycemics or too much exercise, not enough food, or poor timing of either. If blood glucose levels are low enough, the patient may become agitated, sweaty, and have many symptoms of sympathetic activation of the autonomic nervous system—they may experience feelings similar to dread and immobilized panic. Consciousness can be altered, or even lost, in extreme cases, leading to coma and/or seizures or even brain damage and death. Those experienced with their diabetes can often recognize the symptoms early on—all with diabetes should carry something sugary to eat or drink as these symptoms can be rapidly reduced if treated early enough. In the case of children, this can be a type of candy disliked by the patient, to prevent concerns about non-emergency use.

Other ways of treating hypoglycemia include an intra muscular injection of glucagon, which causes the liver to convert its internal stores of glycogen to be released as glucose into the blood. This cannot be repeated until after the next meal, as once the liver glycogen stores have been mobilized they will no longer be available until replenished. Oral or intravenous dextrose can also be given. In most cases recovery is rapid and trouble free. Longstanding hypoglycemia may require hospital admission to allow supervised recovery and adjustment of diabetic medications.

Long-term complications

Among the major risks of the disorder are chronic problems affecting multiple organ systems which will eventually arise in patients with poor glycemic control. Many of these arise from damage to the blood vessels. These illnesses can be divided into those arising from large blood vessel disease, macroangiopathy, and those arising from small blood vessel disease, microangiopathy. Interestingly, small vessel disease is minimized by tight blood glucose control, but large vessel disease is unaffected by tight blood glucose control.

• Small vessel disease complications:
  Proliferative retinopathy and macular edema, which can lead to severe vision loss or blindness
  Peripheral neuropathy, which, particularly when combined with damaged blood vessels, can lead to foot ulcers and possibly progressing to necrosis, infection and gangrene, sometimes requiring limb amputation, see below
  Diabetic nephropathy (due to microangiopathy) which can lead to renal failure
  Large vessel disease complications:

Ischemic heart disease caused by both large and small vessel disease
Stroke
Peripheral vascular disease, which contributes to foot ulcers and the risk of amputation
Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the U.S., usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the U.S. A number of studies have found that those with diabetes are more at risk for dry eye syndrome. Advanced glycosylation end products (AGEs) are believed to play a role in the pathogenesis of angiopathy resulting from diabetes mellitus.

In Januay 2006 research suggested that CBD, one of cannabis's active substances, may reduce cell death in the eyes of diabetic patients.

Management of the disease

Main article: Diabetes management

Diabetes is a chronic disease with treatment but no cure as of 2006. Management of this disease may include lifestyle modifications such as achieving and maintaining proper weight, diet, exercise and foot care. Additionally, it may involve the use of oral medications or insulin therapy. In the case of type 1, insulin therapy is generally required.
In addition, self-monitoring via self-administered glucose testing using a glucose monitor is an essential element of any diabetes management program. The success in management can be monitored by measuring the proportion of the HbA1c variant of hemoglobin, or less commonly the Fructosamine test.

Curing diabetes

A disease consisting of the failure of a single organ (type 1 diabetes, the Islets of Langerhans) with a relatively simple function, points at the cure. Type 2 diabetes is more complex and difficult, but increasing physical activity and correcting body mass may be very helpful.

Biological

The most obvious approach is to replace the failed organ with more islet cells. A transplant of exogenous cells will provoke an immune reaction; this is not yet practical. Research continues and hopefully will be available to be offered to those with diabetes in the future.

Mechanical

A microscopic or nanotechnological approach, with implanted stores of insulin metered out by a rapidly sensitive glucose measure - closed-loop insulin pump, would be very useful, but is currently beyond available technology.

Public health, policy and health economics

The Declaration of St Vincent was the result of international efforts to improve the care accorded to those with diabetes. Doing so is important if only economically. Diabetes is enormously expensive for healthcare systems and governments. In North America it is the largest single non-traumatic cause in adults of amputation, blindness, and dialysis, all extremely expensive events.

Work in the Puget Sound area of North America (by the health organization Group Health) shows that, over its large and varied patient population, specially retaining medical information on diabetic patients, keeping it up to date, and basing their continuing care on that data reduced total healthcare costs for those patients by US$1000 per year per patient for the rest of life. Recognition of this reality drove the Hawkes Bay initiative which established such a system, and resulted in various activities throughout the world including the Black Sea Telediab project, which produced elements of a distributed diabetic record and management system as an open source computer program.

Some researchers believe breast-feeding may protect children from developing diabetes. Research published in JAMA in November 2005 also suggests that breast-feeding might also be correlated with the prevention of the disease in mothers. The study found that the women's risk of developing diabetes was reduced the longer they nursed.

Statistics

In 2006, according to the World Health Organization, at least 171 million people worldwide suffer from diabetes. Its incidence is increasing rapidly, and it is estimated that by the year 2030, this number will double. 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 of the diabetic patients will be seen by 2030. The increase in incidence of diabetes in the developing countries follows the trend of urbanization and lifestyle changes.

Diabetes is in the top 10, and perhaps the top 5, of the most significant diseases in the developed world, and is gaining in significance (see big killers).

For at least 20 years, diabetes rates in North America have been increasing substantially. In 2005 there are about 20.8 million people with diabetes in the United States alone. According to the American Diabetes Association, there are about 6.2 million people undiagnosed and about 41 million people that would be considered prediabetic. The Centers for Disease Control has termed the change an epidemic. The National Diabetes Information Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year. About 5%–10% of these cases of diabetes are type 1 diabetics. The fraction of type 1 diabetics in other parts of the world differs; this is likely due to both differences in the rate of type 1 and differences in the rate of other types, most prominently type 2. Most of this difference is not currently understood.