Encyclopedia
Diabetes mellitus is a disease characterized by persistent hyperglycemia . It is a metabolic disease that requires medical diagnosis, treatment and lifestyle changes. The
World Health Organization recognizes three main forms of diabetes:
type 1,
type 2 and
gestational diabetes , although these three "types" of diabetes are more accurately considered patterns of
pancreatic failure rather than single diseases. Type 1 is due to autoimmune destruction of the insulin-producing cells, while type 2 and gestational diabetes are due to insulin resistance by tissues.
Since the first therapeutic use of insulin diabetes has been a treatable but chronic condition, and the main risks to health are its characteristic long-term complications. These include cardiovascular disease , chronic renal failure ,
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 , to
gangrene with risk of
amputation of toes, feet, and even legs.
Terminology
The term 'diabetes' was coined by Aretaeus 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 Latin word for honey when he noted that the blood and urine of a diabetic 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
Indians 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.
While the term
diabetes without a modifier usually refers to diabetes mellitus, there is another, rarer condition named diabetes insipidus in which the urine is not sweet; it can be caused by either
kidney or pituitary gland damage.
History
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.
Banting, Best, and 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; both shared their Prize money with others in the team who were not recognized. 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.
Despite the availability of treatment, diabetes 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.
The distinction between what is now known as type 1 diabetes and type 2 diabetes was made by Sir Harold Percival Himsworth in 1935 and the findings were published in January 1936.
Other landmark discoveries include:
- Dr Gerald Reaven's introduction of the metabolic syndrome in 1988
- Demonstration of the benefit of intensive glycemic control in type 1 diabetes
- identification of thiazolidinediones as effective antidiabetics in the 1990s
Causes and types
Glucose metabolism
Since insulin is the principal hormone that regulates uptake of
glucose into most cells from the blood , deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.
Much of the
carbohydrate in food is converted within a few hours to the
monosaccharide glucose, the principal carbohydrate in blood. Some carbohydrates are not; fruit sugar is usable as cellular fuel but is not converted to glucose and does not participate in the insulin / glucose metabolic regulatory mechanism, nor does the carbohydrate
cellulose as humans and many animals have no digestive pathway capable of handling it. Insulin is released into the blood by beta cells in the pancreas in response to rising levels of blood glucose . 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 to
glycogen for internal storage in liver and muscle cells. Reduced insulin 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, although only glucose thus recovered by the liver re-enters the bloodstream as muscle cells lack the necessary export mechanism.
Higher insulin levels increase many anabolic 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. In particular, it is the trigger for entering or leaving ketosis .
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin , or if the insulin itself is defective, glucose will not be handled properly by body cells 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 mellitus
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the
islets of Langerhans of the pancreas. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. This type comprises up to 10% of total cases in North America and Europe, though this varies by geographical location. This type of diabetes can affect children or adults, but has traditionally been termed "juvenile diabetes" because it represents a majority of cases of diabetes affecting children. The most common cause of beta cell loss leading to type 1 diabetes is autoimmune destruction, accompanied by
antibodies directed against insulin and islet cell
proteins. The principal treatment of type 1 diabetes, even from the earliest stages, is replacement of insulin. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result.
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 ß-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 ß-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 ß-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 . 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 of insulin as needed at meal times. This is at the expense of an indwelling subcutaneous catheter. It is also possible to deliver insulin via an inhaled powder.
Type 1 treatment must be continued indefinitely at present. Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication. The average glucose level for the type 1 patient should be as close to normal as possible. Some physicians suggest up to 140–150 mg/dl for those having trouble with lower values, such as frequent hypoglycemic events. Values above 200 mg/dl are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl usually require immediate treatment and may lead to ketoacidosis. Low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness.
Type 2 diabetes mellitus
Type 2 diabetes mellitus is due to a combination of defective insulin secretion and defective responsiveness to insulin . In early stages, the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. When insulin secretion is affected, the effect is more subtle than in Type 1, and initially involves only the earliest phase of insulin secretion. In the early stages, hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the
liver, but as the disease progresses the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary. Type 2 diabetes is quite common, comprising 90% or more of cases of diabetes, especially in the developed world. There is a strong, but not exclusive, association with
obesity, with aging, and with family history, although in the last decade it has increasingly begun to affect children and adolescents. In the past, this type of diabetes was often termed
adult-onset diabetes,
maturity-onset diabetes, or
non-insulin dependent diabetes mellitus ; each of these terms have been abandoned. .
In
type 2 diabetes insulin levels are initially normal or even elevated, but peripheral tissues lose responsiveness to insulin , almost certainly involving the insulin receptor in cell membranes. There are numerous theories as to the exact cause and mechanism for this resistance, but central obesity is known to predispose for insulin resistance, possibly due to its secretion of adipokines that impair glucose tolerance. Abdominal fat is especially active hormonally. 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 and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including renal failure, vascular disease , vision damage, etc.
Type 2 diabetes is usually first treated by changes in physical activity , diet , and through weight loss. These can restore insulin sensitivity, even when the weight loss is modest, for example, around 5 kg , most especially when it is in abdominal fat deposits. The next step, if necessary, is treatment with oral antidiabetic drugs. As insulin production is initially unimpaired, oral medication can still be used that improves insulin production and regulate inappropriate release of glucose by the liver
Gestational diabetes
Gestational diabetes, Type 3, also involves a combination of inadequate insulin secretion and responsiveness, resembling type 2 diabetes in several respects. It develops during pregnancy and may improve or disappear after delivery. Even though it may be transient, gestational diabetes may damage the health of the fetus or mother, and about 40% of women with gestational diabetes develop type 2 diabetes later in life.
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 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 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, with or without lipodystrophy
- Diseases of the pancreas
- Hormonal defects
- Chemicals or drugs
The tenth version of the International Statistical Classification of Diseases contained a diagnostic entity named "malnutrition-related diabetes mellitus" . 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.
Genetics
Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some infections, or in a less common group, by stress or environmental factors . There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes . 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 .
There is a rather 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 patients diagnosed with this type, so some experts believe that inheriting a tendency toward obesity also contributes.
Diagnosis
Signs and symptoms
The classical triad of diabetes symptoms is polyuria , polydipsia and blurred vision. These symptoms may develop quite fast in type 1, particularly in children , but may be subtle or completely absent - as well as developing much more slowly - in type 2. In type 1 there may also be weight loss , 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. Prolonged high blood glucose causes changes in the shape of the lens in the eye, leading to vision changes. Blurred vision is a common complaint leading to a diagnosis of type 2; it should always be suspected in such cases.
Patients may also present with diabetic ketoacidosis , an extreme state of dysregulation characterized by the smell of
acetone on the patient's breath, Kussmaul breathing , polyuria, nausea, vomiting and abdominal pain and any of many altered state of consciousness or arousal . In severe DKA, coma may follow, progressing to death if untreated. In any form, DKA is a medical emergency and requires expert attention.
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 in regard to water loss.
Diagnostic approach
The diagnosis of type 1 diabetes and many cases of type 2 is usually prompted by recent-onset symptoms of excessive urination and excessive thirst , 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 health screening, detection of hyperglycemia when a doctor is investigating a complication of longstanding, unrecognized diabetes, and 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 .
- 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 , and some of the antipsychotics and mood stabilizers .
- 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.
Diagnostic criteria
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 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 glucose 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 of 6.0% or higher is considered abnormal by most labs; HbA1c is primarily a treatment-tracking test reflecting average blood glucose levels over the preceding 90 days . 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 . People with diabetes that have HbA1c levels within this goal have a significantly lower incidence of complications from diabetes, including retinopathy and diabetic nephropathy.
Complications
The complications are far 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 , elevated cholesterol levels , obesity , high blood pressure, and lack of regular
exercise.
Acute
;Diabetic ketoacidosis
Diabetic ketoacidosis 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 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 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 , 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 , the osmotic effect of high glucose levels combined with the loss of water will eventually result in such a high serum osmolality . 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 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
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 resulting 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 this can be caused by several factors, such as too much or incorrectly timed insulin, too much exercise or incorrectly timed exercise 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 or an
intravenous infusion of glucose is used for treatment, but usually only if the diabetic is unconscious.
Chronic
;Microvascular disease
Chronic elevation of blood glucose level leads to damage of
blood vessels. In diabetes, the resultant problems are grouped under "microvascular disease" and "macrovascular disease" .
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 , which can lead to severe vision loss or blindness. Retinal damage 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 . 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
Macrovascular disease leads to cardiovascular disease, mainly by accelerating
atherosclerosis:
- Coronary artery disease, leading to myocardial infarction or angina
- Stroke
- Peripheral vascular disease, which contributes to intermittent claudication as well as diabetic foot.
- Diabetic myonecrosis
Diabetic foot, often due to a combination of neuropathy and arterial disease, may cause skin
ulcer and infection and, in serious cases, necrosis and gangrene. It is the most common cause of adult amputation, usually of toes and or feet, in the US and other Western countries.
Carotid artery stenosis does not occur more often in diabetes, and there appears to be a lower prevalence of
abdominal aortic aneurysm. However, diabetes does cause higher morbidity, mortality and operative risks with these conditions.
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 share care of a patient in a team approach.
Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, clinical nurse specialists , or nurse practitioners may provide multidisciplinary expertise.
Curing diabetes
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 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 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.
Public health and policy
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 in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most 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. This has suggested an environmental effect, but there is little understanding of the mechanism at present, though there is much speculation, some of it most compellingly presented.
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.
However, the criteria for diagnosing diabetes in the USA means that it is more readily diagnosed than in some 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.
See also
- List of terms associated with diabetes
References
External links
