Blood Sugar; Diabetes Mellitus; Non-Insulin Dependent Diabetes Mellitus; Type II Diabetes
Article: Diabetes mellitus
Diabetes mellitus is a medical disorder characterized by persistent variable hyperglycemia (high blood sugar levels), resulting either from inadequate biosynthesis, secretion or action of the hormone insulin, an inadequate response by the body's cells to insulin, or a combination of these factors.
The most common forms of diabetes are type 1, type 2 and gestational diabetes. Type 1 (10% of cases) is due to destruction of the islets of Langerhans, which produce insulin; it can only be treated with insulin injections. In type 2 (90% of cases) the main problem is decreased sensitivity of the body's cells to insulin, known as insulin resistance, although insulin production is often affected in the later stages; as well as diet and exercise, treatment usually is with tablets, or eventually with insulin injections. Gestational diabetes may develop during pregnancy and is similar to type 2 in its mechanism; it may affect fetal health and 40% of women with gestational diabetes develop type 2 diabetes later on in life.
Since the discovery of insulin (1921) diabetes has been a treatable but chronic condition, and the main risks to health are 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, erectile dysfunction (impotence), to gangrene with risk of amputation of toes, feet, and even legs.
The complications are less common and less severe in people who have well-controlled blood sugar levels.  In fact, the better the control, the lower the risk of complications. Hence patient education, understanding and participation is vital. Healthcare professionals who treat diabetes also address other health problems that may accelerate the deleterious effects of diabetes. These include smoking (abstain), elevated cholesterol levels (control with diet, exercise or medication), obesity (even modest weight loss can be beneficial), high blood pressure, and lack of regular exercise can cause further complications.
The term diabetes was coined by Aretaeus (81–133 CE) of Cappadocia. The Greek word diabaínein literally means "passing through," or "siphon," a reference to one of diabetes' major symptoms—excessive urine production. 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" (糖尿病); medieval European doctors tested for it by tasting the urine themselves, a scene which was occasionally depicted in Gothic reliefs.
While the term diabetes without a modifier usually refers to diabetes mellitus, there is another, rarer condition named diabetes insipidus (unquenchable diabetes) in which the urine is not sweet; it can be caused by either kidney or pituitary gland damage.
Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known since the Middle Ages, the elucidation of the pathogenesis of diabetes occurred mainly in the 20th century.
The discovery of the role of the pancreas in diabetes is generally ascribed to Joseph von Mering and Oskar Minkowski, 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 suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas—he proposed calling this substance insulin. The term is derived from the Latin insula, meaning island, in reference to the islets of Langerhans in the pancreas that produce insulin.
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 induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs. 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. Banting and Best 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.
Despite the availability of treatment, diabetes was still a major cause of deaths in its early ages. For instance, statistics reveal that the cause-specific mortality rate during 1927 amounted to about 47.7 per 100,000 population in Malta.
Other landmark discoveries 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)
- Dr Gerald Reaven's introduction of the metabolic syndrome in 1988
- identification of thiazolidinediones as effective antidiabetics in the 1990s
Causes and types
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 the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.
Most of the carbohydrate in food is converted within the first two hours to the monosaccharide glucose, the principal carbohydrate in blood. Insulin is produced by beta cells (β-cells) in the pancreas in response to rising levels of glucose in the blood (e.g. after a meal). Insulin enables most body 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 (the basic sugar used for fuel) to glycogen for storage in liver and muscle cells. Lower insulin levels result in the reverse conversion of glycogen to glucose when glucose levels fall, although only glucose produced this way by the liver re-enters the bloodstream.
Higher insulin levels increase many anabolic ("building up") processes such as cell growth and duplication, 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, such as acidosis.
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. Lifestyle does not affect the probability of getting type 1 diabetes.
Currently, type 1 diabetes can be treated only with insulin, with careful monitoring of blood glucose levels using blood testing monitors. Emphasis is also placed on lifestyle adjustments (diet and exercise). Apart from the common subcutaneous injections, it is also possible to deliver insulin via a pump, which allows infusion of insulin 24 hours a day at preset levels, and the ability to program a push dose (a bolus) of insulin as needed at meal times. This is at the expense of an indwelling subcutaneous catheter.
Type 1 treatment must be continued indefinitely. Treatment does not impair normal activities, if carried out with care and discipline. The average glucose level for the type 1 patient should be as close to normal (80–120 mg/dl, 4–6 mmol/l) as possible. Some physicians suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having trouble with lower values, such as frequent hypoglycemic attacks. Values above 200 mg/dl (10 mmol/l) are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl (15 mmol/l) usually require immediate treatment and may lead to ketoacidosis.
In type 2 diabetes insulin levels are initially normal or even elevated, but peripheral tissues lose responsiveness to insulin (known as "insulin resistance"), by the insulin receptor. There are numeous theories as to the exact cause for this resistance, but central obesity (fat concentrated around the waist) is known to predispose for insulin resistance, possibly due to its secretion of adipokines ( a group of hormones) that impair glucose tolerance. Obesity is found in approximately 85% of North American patients diagnosed with type 2 diabetes.
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 usually first treated by changes in physical activity (increase), diet (decrease carbohydrate intake), and through weight loss. These can restore insulin sensitivity, even when the weight loss is modest, for example, around 5 kg (10 to 15 lb). The next step, if necessary, is treatment with oral antidiabetic drugs. As insulin production is initially unimpaired, oral medication (often used in combination) can still be used that improves insulin production (sulfonylureas) and attenuate insulin resistance (metformin and thiazolidinediones) and glucose production by the liver (metformin). If these fail, insulin therapy will be necessary to maintain normal or near normal glucose levels. A disciplined regimen of blood glucose checks is recommended in most cases, particularly when taking medication.
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.
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 (autosomal or mitochondrial)
- Genetically-related insulin resistance, with or without lipodystrophy (abnormal body fat deposition)
- Diseases of the pancreas (e.g. chronic pancreatitis)
- Hormonal defects
- Chemicals or drugs
The tenth version of the International Statistical Classification of Diseases (ICD-10) contained a diagnostic entity named "malnutrition-related diabetes mellitus" (MRDM or MMDM, ICD-10 code E12). A subsequent WHO 1999 working group recommended that MRDM be deprecated, and proposed a new taxonomy for alternative forms of diabetes. Classifications of non-type 1, non-type 2, non-gestational diabetes remains controversial.
Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some mainly viral infections or less likely stress-related or environmental factors (such as 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 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. 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.
Signs and symptoms
The classical triad of diabetes symptoms is polyuria (frequent urination), polydipsia (increased thirst, and consequent increased fluid intake) and blurred vision. These symptoms may develop quite fast in type 1, particularly in children (weeks or months), but may be subtle or completely absent - as well as developing much slower - in type 2. In type 1 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 (above the "renal threshold") 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. Prolonged high blood glucose causes changes in the shape of the lens in the eye, leading to blurred vision.
Patients (usually with type 1 diabetes) may also present with diabetic ketoacidosis (DKA), an extreme state of dysregulation characterized by the smell of acetone on the patient's breath, Kussmaul breathing (a rapid, deep breathing), polyuria, nausea, vomiting and abdominal pain and any altered state of consciousness or arousal (hostility and mania or equally confusion and lethargy). In severe DKA, coma (unconsciousness) may follow, progressing to death if untreated.
A rarer but equally severe presentation is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration due to the polyuria. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle.
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 usually 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.
- 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).
- 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, fatty liver, hemochromatosis, 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).
- 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.
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:
- fasting plasma glucose level at or above 126 mg/dL or 7.0 mmol/l.
- plasma glucose at or above 200 mg/dL or 11.1 mmol/l two hours after a 75 g oral glucose load in a glucose tolerance test.
- random plasma glucose at or above 200 mg/dL or 11.1 mmol/l.
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 or 7.0 mmol/l 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 140mg/dL or 7.8 mmol/l 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.
- Diabetic ketoacidosis
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.
- Nonketotic hyperosmolar coma
While not always progressing to coma, this hyperosmolar nonketotic state (HNS) 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 300 mg/dl or 16 mmol/l), 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.
Hypoglycemia, or abnormally low blood glucose, is a complication of several diabetes treatments. It may develop if the glucose intake does not match the treatment. The patient may become agitated, sweaty, and have many symptoms of sympathetic activation of the autonomic nervous system resuling in 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. In patients with diabetes can be caused by several factors, such as too much or incorrectly timed insulin, too much exercise or incorrectly timed exercise (which decreases insulin requirements) or not enough food or insufficient amount of carbohydrates in food. In most cases, hypoglycemia is treated with sweet drinks or food. In severe cases, an injection of glucagon (a hormone with the opposite effects of insulin) or an intravenous infusion of glucose is used for treatment, but usually only if the diabetic is unconscious.
Chronic elevation of blood glucose level leads to damage of blood vessels. In diabetes, the resultant problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).
The damage to small blood vessels leads to a microangiopathy, which causes the following organ-related problems:
- Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
- Diabetic neuropathy, abnormal and decreased sensation, usually in a stocking distribution starting at the feet but potentially in other nerves. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy.
- Diabetic nephropathy, damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide.
Macrovascular disease leads to cardiovascular disease, mainly by accelerating atherosclerosis:
- Coronary artery disease, leading to myocardial infarction ("heart attack") or angina
- Stroke (mainly ischemic type)
- Peripheral vascular disease, which contributes to intermittent claudication (exertion-related foot pain) as well as diabetic foot.
Diabetic foot, often due to an overlap between neuropathy and arterial disease, may cause necrosis, infection and gangrene. It also the most common cause of amputation in the US and other Western countries, usually toes and feet.
However a recent literature review, whilst confirming "an increase prevalence of lower extremity arterial disease", found an "equivalent prevalence of carotid artery stenosis" and "demonstrated a decrease in AAA (Abdominal aortic aneurysm) prevalence among patients with diabetes" although with higher morbidity, mortality and operative risks.
Treatment and management
Diabetes is a chronic disease, and emphasis is on managing short-term as well as long-term diabetes-related problems. There is an important role for 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.
In countries with a general practitioner system, such as the United Kingdom, care may be extended mainly in the community, with hospital-based specialist input only in case of complications, difficult blood sugar control, or participation in research. In other circumstances, general practitioners and specialists may be sharing the care of a patient. Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, clinical nurse specialists or nurse practitioners may provide multidisciplinary expertise.
The fact that type 1 diabetes is due to the failure of one of the cell types of a single organ with a relatively simple function (i.e. the failure of the islets of Langerhans) has led to the study of several possible schemes to cure diabetes. In contrast, type 2 diabetes is more complex with fewer prospects of a curative measure, but further understanding of the underlying mechanism of insulin resistance may make a cure possible. Correcting insulin resistance may provide a cure for type 2 diabetes.
Only those type 1 diabetics who have received a kidney-pancreas transplant (when they have developed diabetic nephropathy) and become insulin-independent may be considered "cured" from their diabetes. Still, they generally remain on long-term immunosuppressive drug and there is a possibility the autoimmune phenomenon will develop in the transplanted organ.
Transplants of exogenous beta cells have been performed experimentally in both mice and humans, but this measure is not yet practical in regular clinical practice. Thus far, like any such transplant, it provokes an immune reaction and long-term immunosuppressive drug 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.
As little is known on the exact mechanism by which type 1 diabetes develops, there are no preventiative measures available for that form of diabetes. Some studies have attributed a protective effect of breastfeeding on the development of type 1 diabetes. In addition, breastfeeding might also be correlated with the prevention of type 2 of the disease in mothers.
Type 2 diabetes can be prevented in part by maintaining a stable body weight through diet and exercise. Some studies have shown delayed progression to diabetes in predisposed patients through the use of metformin or valsartan
The 1989 Declaration of St Vincent 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 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.
Epidemiology and 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.
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 (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. However, the criteria for diagnosing diabetes in the USA means that it is more readily diagnosed than in other countries. 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.