Diabetes mellitus

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Diabetes mellitus is a medical disorder characterized by persistent variable hyperglycemia (high blood sugar levels), resulting either from inadequate secretion of the hormone insulin or from an inadequate response by the body's cells to insulin. There are three kinds of diabetes mellitus, called type 1, type 2 and type 3, and some authors in the field of diabetes research identify a type 4 diabetes. The three types of diabetes mellitus include:

  • diabetes mellitus type 1 (previously called juvenile onset diabetes, insulin- dependent diabetes mellitus -- IDDM ). Type 1 diabetes is precipitated by a currently unknown event that leads initially to decreased, and then to absent production of insulin. Type 1 diabetes mellitus accounts for about 10% of all people with diabetes mellitus.
  • diabetes mellitus type 2 (previously called adult onset diabetes, obesity-related diabetes or non-insulin dependent diabetes mellitus -- NIDDM), involves insulin resistance by the body's cells to the action of normal insulin levels found in the bloodstream, and as the disease progresses, the production and secretion of insulin may also diminish. Type 2 diabetes mellitus is the most common form of diabetes, especially in highly developed countries, where it may account for as much as 90% of all people with diabetes. Its causes are obscure, but is connected with heredity, body weight and lifestyle.
  • gestational diabetes ('diabetes type 3' designation rarely used in medical practice) is a condition that occurs during pregnancy and is similar to type 2 diabetes in that it is related to a resistance of the body's cells to insulin. The elevated blood glucose levels may result in abnormal increased fetal (baby) weight polyhydramnios (increased surrounding amniotic fluid caused by increased fetal urination), fetal jaundice and low blood sugars after delivery and rarely intra-uterine death. Approximately 40% of women who had gestational diabetes will develop full type 2 diabetes within 5-10 years after delivery.<ref>MedlinePlus Gestational diabetes 2005-08-08 National Institutes of Health http://www.nlm.nih.gov/medlineplus/ency/article/000896.htm</ref>

Type 1 diabetes almost always requires insulin injections, and is generally fatal without proper treatment. Type 2 diabetes can sometimes be managed by weight reduction and exercise alone. Often oral medication and/or insulin are initially required. Most cases of type 2 diabetes are eventually treated with medication.

Type 1 diabetes is an autoimmune disorder, in which the body makes antibodies that attack the insulin-producing cells in the pancreas. The cause is complex and unclear, but may involve genetics, viruses, diet and environmental factors such as chemicals. Type 1 diabetes was once called juvenile diabetes because it is often diagnosed in childhood or early adulthood. People with type 1 diabetes must take insulin by injection, pump or other methods. Possible treatments, which are cures when successful, include transplant of a segment of pancreas or with islet beta cells.

While under- or over-treated diabetes can be extremely dangerous and until June, 1921 (when insulin was first discovered and made available), a clinical diagnosis of what is now called type 1 diabetes was an invariable more or less quick death sentence, for most treated patients today the main risks are from its characteristic long-term complications. These include cardiovascular disease (doubled risk), chronic renal failure (it is the main cause for dialysis in developed world adults), retinal damage which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world, nerve damage which can lead to impotence, to gangrene with risk of amputation of toes, feet, and even legs.

The complications are less common and less severe in people who control their blood sugars well. In fact,the better the control, the lower the risk of complications (down to that of non-diabetics). Hence patient understanding and participation is vital, as blood glucose levels change continuously throughout each day. Other health problems that accelerate the damaging effects of diabetes should also be addressed. These include smoking, elevated cholesterol levels (control with diet, exercise or medication), obesity (even small losses can be very helpful), high blood pressure, and lack of regular exercise.

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Etymology

The word diabetes was coined by Aretaeus (81–133 CE) of Cappadocia. The word is from the Greek diabaínein, and literally means "passing through", or "siphon", a reference to one of diabetes' major symptoms -- excessive urine discharge. The word became "diabetes" from the English adoption of the medieval Latin diabetes. In 1675 Thomas Willis added mellitus from the Greek word for honey (mel in the sense of "honey sweet") when he noted that a person with diabetes's urine and blood has a sweet taste. This had been noticed long before in ancient times by the Greeks, Chinese, Egyptians, and Indians. In 1776 it was confirmed the sweet taste was because of an excess of a kind of sugar in the urine and blood of people with diabetes.

The ancient Chinese tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease"; medieval European doctors tested for it by tasting the urine themselves, a scene which was occasionally depicted in Gothic reliefs.

Passing abnormal amounts of urine is a symptom common to several disorders (most commonly of the kidneys), and the single word diabetes has been given to many of them. The most common of them are diabetes insipidus and the subject of this article, diabetes mellitus.

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Causes and types

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The role of insulin

Mechanism of insulin release in normal pancreatic beta cells (i.e., glucose dependence). Insulin production does not depend on blood glucose levels; it is stored pending release which does depend on blood glucose levels

Since insulin is the principal hormone that regulates uptake of glucose into most cells from the blood (primarily muscle and fat cells, but not central nervous system cells), deficiency of insulin or its receptors plays a central role in all forms of diabetes mellitus.

Most of the carbohydrates in food are rapidly converted to glucose, the principal sugar in blood. Insulin is produced by beta cells (β-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 used for fuel) 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 liver glucose so produced goes back 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, and vice versa.

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.

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Gestational diabetes

Gestational diabetes mellitus occurs in about 2%–5% of all pregnancies. It is temporary, and fully treatable, but, if untreated, 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.

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Other types

There are several rare causes of diabetes mellitus 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.
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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 certain chemicals). There is a genetic element in individual susceptibility 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 people with type 1 diabetes 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 this type, so some experts believe that inheriting a tendency toward obesity may also contribute.

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Obesity

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. Obesity is found in approximately 85% of (North American) patients diagnosed with type 2 diabetes.

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Diagnosis

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Signs and symptoms

Type 2 diabetes almost always has a slow onset (often years), but, in type 1, particularly in children, onset may be quite fast (weeks or months). Early symptoms of type 1 diabetes are often polyuria (frequent urination) and polydipsia (increased thirst, and consequent increased fluid intake). There may also be weight loss (despite normal or increased eating), increased appetite, and irreducible fatigue. These symptoms may also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.

Thirst develops because of osmotic effects—sufficiently high glucose in the blood is excreted by the kidneys, but this requires water to carry it and causes increased fluid loss, which must be replaced. The lost blood volume will be replaced from water held inside body cells, causing dehydration.

Another common-presenting symptom is altered vision. Prolonged high blood glucose causes changes in the shape of the lens in the eye, leading to blurred vision and, perhaps, a visit to an optometrist. All unexplained quick changes in eyesight should force a fasting blood glucose test. These are now quick (10 seconds), using inexpensive materials (less than USD $1), and can be safely performed by almost anyone with minimal training.

Especially-dangerous symptoms include Kussmaul breathing (a rapid, deep breathing), and any altered state of consciousness or arousal (hostility and mania are both possible, as is confusion and lethargy). The most dangerous form of altered consciousness is the so-called "diabetic coma," which produces unconsciousness. Early symptoms of impending diabetic coma include polyuria, nausea, vomiting and abdominal pain, with lethargy and somnolence a later development, progressing to unconsciousness and death if untreated.

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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. Diabetes is often detected when a person suffers a problem 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.
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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 in a Glucose tolerance test.
  • 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 7.0 mmol/l (126 mg/dL) is considered diagnostic for diabetes mellitus.

Patients with fasting sugars between 6.1 and 7.0 mmol/l (110 and 125 mg/dL) are considered to have "impaired fasting glucose," and patients with plasma glucose at or above 7.8 mmol/l (140mg/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; 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 bound to hemoglobin (termed glycosylated hemoglobin or 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 within this goal have a significantly lower incidence of complications from diabetes, including retinopathy and diabetic nephropathy.

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Diabetic ketoacidosis and coma

See more detail in the articles 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 diabetes 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 mmol/l or 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 commonly occurs in type 2 diabetics; it is less common in type 1 diabetes.

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Hypoglycemia

Hypoglycemia in patients with diabetes can be caused by several factors, some of which are listed below:

  • Too much or incorrectly timed insulin.
  • Too much exercise or incorrectly timed exercise.
  • Not enough food or insufficient amount of carbohydrates in food.

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.

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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.

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.

In January 2006 research suggested that CBD, one of cannabis's active substances, may reduce cell death in the eyes of diabetic patients. <ref>AmJPathol-ElRemessy" El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, Liou GI Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes Am J Pathol 2006 pages=235-44 volume 168 issue 1 PMID 16400026</ref>

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Management of the disease

Diabetes is a chronic disease with treatment but no cure as of 2006. The long-term treatment of diabetes in general (both types I and II) include patient education, nutritional support, self glucose monitoring, as well as long-term glycemic control. A scrupulous control is needed to help reduce the risk of long term complications. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications must be implemented to control blood pressure and cholesterol by exercising more, smoking cessation, and consuming an appropriate diet.

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Home blood glucose monitoring

Control and outcomes of both types 1 and 2 diabetes may be improved by patients using home glucose meters to regularly measure their glucose levels. Glucose monitoring is both expensive (largely due to the cost of the consumable test strips) and requires significant commitment on the part of the patient. The effort and expense may be worthwhile for patients when they use the values to sensibly adjust food, exercise, and oral medications or insulin. These adjustments are generally made by the patients themselves following training by a clinician.

Self-testing is clearly important in type I diabetes where the use of insulin therapy risks episodes of hypoglycaemia and home-testing allows for adjustment of dosage on each administration. It has been suggested that some type 2 patients might do as well with home urine-testing alone.

Benefits of control and reduced hospital admission have been reported. However patients on oral medication who do not self-adjust their drug dosage will miss many of the benefits of self-testing, and so it is questionable in this group. This is particularly so for patients taking monotherapy with metformin who are not at risk of hypoglycaemia. Regular 6 monthly laboratory testing of HbAc1 (glycated haemoglobin) provides some assurance of longterm effective control and allows the adjustment of the patient's routine medication dosages in such cases. High frequency of self-testing in type 2 diabetes has not been shown to be associated with improved control.

The argument is made, though, that type 2 patients with poor long term control despite home blood glucose monitoring, either have not had this integrated into their overall management, or are long overdue for tighter control by a switch from oral medication to injected insulin.

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Curing diabetes

A disease consisting of the failure of a single organ with a relatively simple function (i.e., the failure of the Islets of Langerhans in type 1 diabetes), should be relatively straightforward to cure; merely replace the organ or its function. As of 2006, several possible schemes are under investigation. Type 2 diabetes is more complex and difficult, but further understanding of the underlying mechanism of insulin resistance may make more effective treatment possible, including perhaps a cure for some variants.

The most obvious approach to a Type 1 cure is to replace the failed organ (pancreatic beta cells) with more islet cells. A transplant of exogenous cells has been done experimentally in both mice and humans, but is not yet practical in regular clinical practice. Thus far, like any such transplant, it provokes an immune reaction and immuno-supressive drugs will be needed to protect the transplanted tissue. An alternative technique has been proposed to place the transplanted beta cells in a semi-permeable container, isolating them from the immune system. Stem cell research has also been suggested as a potential avenue for a cure since it may permit the regrowth of islet cells which are genetically part of the treated individual, thus eliminating the need for immuno-supressants. However, it has also been hypothesised that the same mechanism which led to islet destruction originally may simply destroy even stem-cell regenerated islets.

Microscopic or nanotechnological approaches are under investigation as well, with implanted stores of insulin metered out by a rapid response valve sensitive to blood glucose levels. At least two approaches have been proposed and demonstrated in vitro. These are, in some sense, closed-loop insulin pumps.

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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 Seattle, Washington area (by the health organization Group Health Cooperative) shows that over its large and varied patient population, specially retaining medical information on 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.

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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 patients will likely be found by 2030. The increase in incidence of diabetes in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a 'Western style' diet. there is likely a long term effect operating here as a May 06 JAMA article examining health status in those of 55-64 years in the US and UK. Diabetes rates in this US population are twice the UK rate, and from analysis of the data collected, is not primarily due to obesity, though it is higher in the US than the UK among this group as well.

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 there and elsewhere.

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 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; 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.

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See also

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External links and References

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