Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels), especially after eating. All types of diabetes mellitus share similar symptoms and complications at advanced stages. Hyperglycemia itself can lead to dehydration and ketoacidosis. Longer-term complications include cardiovascular disease (doubled risk), chronic renal failure (it is the main cause for dialysis), retinal damage with eventual blindness, nerve damage and eventual gangrene with risk of amputation of toes, feet, and even legs.
The most important forms of diabetes are due to decreased production of insulin (diabetes mellitus type 1, the first recognized form), or decreased sensitivity of body tissues to insulin (diabetes mellitus type 2, the more common form). The former requires insulin injections, while the latter is generally managed with oral medication and only requires insulin if the tablets are ineffective.
Patient understanding and participation is vital as blood glucose levels change continuously, while successfully keeping blood sugar within normal limits has been compellingly shown to reduce or prevent development of some of the complications of diabetes. Other risk factors that can require addressing to reduce complications are: cessation of smoking, optimizing cholesterol levels, maintaining a stable body weight, controlling high blood pressure and having regular exercise.
In 2004, according to the World Health Organization, more than 150 million people worldwide suffer from diabetes. Its incidence is increasing rapidly, and it is estimated that by the year 2025 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 rate is, however, expected to occur in Asia and Africa, where most of the diabetic patients will be seen by 2025. The increase in incidence of diabetes in the developing countries follows the trend of urbanisation and life style 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 2002 there were about 18.2 million diabetics in the United States alone. 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.
Since insulin is the principal hormone that regulates uptake of glucose into cells (primarily muscle and fat 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 digested 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 in the liver not muscle tissue. Higher insulin level 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 produced 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) nor stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements.
Type 1 diabetes is most commonly diagnosed in children and adolescents, but can occur in adults as well. It is an autoimmune disorder, in which the body's own immune system attacks the beta cells in the Islets of Langerhans of the pancreas, destroying them or damaging them sufficiently to reduce insulin production. The autoimmune attack may be triggered by reaction to an infection, for example by one of the viruses of the Coxsackie virus family. A subtype of type 1 (identifiable by the presence of antibodies against beta cells) develops slowly and so is often confused with Type 2. In addition, a small proportion of type 1 cases has the hereditary condition maturity onset diabetes of the young (MODY).
Some poisons (e.g. certain rat poisons) work by selectively destroying certain types of cells, including pancreatic beta cells, thus producing "artificial" type 1 diabetes. Other pancreatic problems including trauma, pancreatitis or tumors (either malignant or benign) can also lead to loss of insulin production.
Currently, type 1 is treated with insulin injections, lifestyle adjustments, and careful monitoring of blood glucose levels using blood test kits. The treatment must be continued indefinitely. Experimental replacement of beta cells (by transplant) is being investigated in several research programs and may become clinically available in the future.
About 5-10% of all North American 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.
Formerly, type 1 diabetes was called "childhood" or "juvenile" diabetes or "insulin dependent" diabetes. Each term is a misnomer, especially since the obesity epidemic in recent years has led to increased incidence of type 2 diabetes in children and adolescents in the USA, and insulin is used in some type 2 cases.
Type 2 diabetes is characterized by "insulin resistance" as body cells do not respond appropriately when insulin is present. This is a more complex problem than type 1, but is sometimes easier to treat, since insulin is still produced, especially in the initial years. Type 2 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 was formerly known by a variety of partially misleading names, including "adult-onset diabetes", "obesity-related diabetes", "insulin-resistant diabetes", or "non-insulin-dependent diabetes" (NIDDM). It may be caused by a number of diseases, such as hemochromatosis and polycystic ovary syndrome, and can also be caused by certain types of medications (e.g. long-term steroid use). About 90-95% of all North American cases of diabetes are type 2, and about 20% of the population over the age of 65 is a type 2 diabetic. The fraction of type 2 diabetics in other parts of the world varies substantially, almost certainly for environmental and lifestyle reasons. There is also a strong inheritable genetic connection in type 2 diabetes: having relatives (especially first degree) with type 2 is a considerable risk factor for developing type 2 diabetes. The majority of patients with type 2 diabetes mellitus are obese - chronic obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissue is a (recently identified) source of chemical signals (hormones and cytokines). Other research shows that type 2 diabetes causes obesity.12
Type 2 is initially treated by changes in 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 (if these are insufficient) thiazolidinediones. When these have failed, insulin therapy may be necessary to maintain normal glucose levels.
All other specific forms of diabetes, accounting for up to 5% of all diagnosed cases of diabetes, are termed Type 3:
Main article: Gestational diabetes mellitus
Type 4 or 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.
Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by infection, 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 mutation 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. 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 inheriting a tendency toward obesity seems also to contribute. Age is also thought to be a contributing factor, as most type 2 patients in the past were older. The exact reasons for these connections are unknown.
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 irreduceable fatigue. These symptoms may also manifest in Type 2 diabetes in patients who present with frank poorly controlled diabetes.
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.
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 (less than 5 minutes total), inexpensive (materials less than US$1), and can be safely performed by almost anyone with trivial training.
Especially dangerous symptoms in diabetics include the smell of acetone on the patient's breath (a sign of ketoacidosis), 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.
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 less commonly (3) new signs and symptoms attributable to the diabetes.
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of
While not used for diagnosis, an elevated glucose bound to hemoglobin, HbA1c, of 6.0% or higher (2003 revised US standard); is a screening and treatment-tracking test reflecting average blood glucose levels over the preceding 90 days (approximately).
Diabetic ketoacidosis (DKA) is an acute, dangerous complication and is always a medical emergency. Without prompt proper treatment, diabetic ketoacidosis leads to death.
DKA occurs more commonly in type 1 diabetes because the insulin deficiency is more severe, though it can occur rarely in type 2 diabetes. In about a quarter of young people who develop type 1 diabetes, the insulin deficiency and hyperglycemia lead to ketoacidosis before the disease is recognized and treated. This can occur at the onset of type 2 diabetes as well, especially in young people. When a person is known to have diabetes and is being adequately treated, DKA usually results from omission of insulin, mismanagement of acute gastroenteritis (the "flu"), or an overwhelming new health problem (e.g., bacterial infection, myocardial infarction).
Insulin deficiency switches many aspects of metabolic balance in a catabolic direction. The liver becomes a net producer of glucose by way of gluconeogenesis and glycogenolysis. Fat in adipose tissue is reduced to triglycerides and fatty acids by lipolysis. Muscle is degraded to release amino acids for gluconeogenesis. The rise of fatty acid levels is accompanied by a rise of ketones (acetone, acetoacetate and beta-hydroxybutyrate ). As the ketosis worsens, it produces a metabolic acidosis, with anorexia, abdominal distress, and eventually vomiting. The rising level of glucose increases the volume of urine produced by the kidneys (an osmolar diuresis). The high volume of urination (polyuria) also produces increased losses of electrolytes, especially sodium, potassium, chloride, phosphate, and magnesium. Reduced fluid intake from vomiting combined with amplified urination produce dehydration. As the metabolic acidosis worsens, it induces obvious hyperventilation (termed Kussmaul respiration).
On presentation to 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 obtundation may progress to coma. The dehydration can become severe enough to cause shock. Laboratory tests typically show hyperglycemia, metabolic acidosis, normal or elevated potassium, and severe ketosis. Many other tests can be affected.
At this point the patient is urgently in need of intravenous fluids. The basic principles of DKA treatment are
Treatment usually results in full recovery, though death can result from inadequate treatment or a variety of complications.
Hyperosmotic diabetic coma is another acute problem associated with improper management of diabetes mellitus. It has some 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) 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. The osmotic effect of high glucose levels combined with the loss of water will eventually result in such a high serum osmolality that the body's cells may become directly affected as water is drawn out from them. Electrolyte imbalances are also common. This combination of changes, especially if prolonged, will result in symptoms similar to ketoacidosis, including loss of consciousness. As with DKA, urgent medical treatment is necessary. This is the diabetic coma to which type 2 diabetics are prone; it is less common in type 1 diabetics.
Hypoglycemia in diabetic patients almost always arises as a result of poor management 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 death and brain damage. Experienced diabetics can often recognise the symptoms early on - all diabetics should always 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 unnecessary use.
Other ways of treating hypoglycemia include an injection of glucagon which causes the liver to convert its internal stores of glycogen to be released as glucose into the blood. Oral or intravenous dextrose can also be given. In most cases, recovery is rapid and troublefree. Longstanding hypoglycemia may require hospital admission to allow supervised recovery and adjustment of diabetic medications.
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 diseases, 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.
Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, 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 US.
Management of this disease may include lifestyle modifications such as achieving and maintaining proper weight, diet, exercise and foot care. The most important is the hypoglycemic treatment with either oral hypoglycemics and/or insulin therapy. Nowadays, the goal for diabetics is to avoid or minimize chronic diabetic complications, as well as to avoid acute problems of hyperglycemia or hypoglycemia.
Adequate control of diabetes leads to a lower risk of the complications of uncontrolled diabetes which include kidney failure (requiring dialysis or transplant), blindness, heart disease and limb amputation. Recent studies show that use of statins might be needed in primary and secondary prevention of cardiovascular complications and mortality.
Ideal control of hypertension plays a pivotal role in preventing both diabetic nephropathy and cardiovascular disease.
There is emerging solid evidence that full-blown diabetes mellitus type 2 can be evaded in those with only mildly impaired glucose tolerance6.
Patients with type 1 diabetes mellitus require direct injection of insulin as their bodies cannot produce enough (or even any) insulin. As of 2004, there is no other clinically available form of insulin administration other than injection for patients with type 1: injection can be done by insulin pump, by jet injector, or any of several forms of hypodermic needle. There are several insulin application mechanisms under experimental development as of 2004. There have also been proposed vaccines for type I using glutamic acid decarboxylase (GAD), but these are currently not being tested by the pharmaceutical companies that have sublicensed the patents to them.
For type 2 diabetics, diabetic management consists of a combination of diet, exercise, and weight loss, in any achievable combination depending on the patient. Patients who have poor diabetic control after lifestyle modifications are typically placed on oral hypoglycemics. Some Type 2 diabetics eventually fail to respond to these and must proceed to insulin therapy.
Patient education and compliance with treatment is very important in managing the disease. Improper use of medications and insulin can be very dangerous causing hypo- or hyper-glycemic episodes.
Insulin therapy requires close monitoring and a great deal of patient education, as improper administration is quite dangerous. For example, when food intake is reduced, less insulin is required. A previously satisfactory dosing may be too much if less food is consumed causing a hypoglycemic reaction if not intelligently adjusted. In addition, exercise decreases insulin requirements as exercise increases glucose uptake by body cells whose glucose uptake is controlled by insulin. And vice versa. In addition, there are available several types of insulin with varying times of onset and duration of action.
Optimal management of diabetes involves patients measuring and recording their own blood glucose testing at home. By keeping a diary of their own blood glucose measurements and noting the effect of food and exercise, patients can modify their lifestyle to better control their diabetes. For patients on insulin, patient involvement is important in achieving effective dosing and timing.
Relying on their own perceptions of symptoms of hyperglycemia or hypoglycemia is usually unsatisfactory as mild to moderate hyperglycemia causes no obvious symptoms in nearly all patients. Other considerations include the fact that, while food takes several hours to be digested and absorbed, insulin administration can have glucose lowering effects for as little as 2 hours or 24 hours or more (depending on the nature of the insulin preparation used and individual patient reaction). In addition, the onset and duration of the effects of oral hypoglycemic agents vary from type to type and from patient to patient.
A useful test that can be done in a doctor's clinic is the measurement of blood HbA1C levels. This is the ratio of glycosylated red blood cells in relation to the total number of red blood cells. Persistent raised plasma glucose levels causes the proportion of these cells to go up. This is a test that measures the average amount of diabetic control over a period of about 3 months (the average red blood cell lifetime). In the non-diabetic, the HbA1C level ranges from 4.0-6.4%; patients with diabetes mellitus who manage to keep their HbA1C level below 7.0% are considered to have good glycaemic control.
Regular blood testing especially more so in type 1 diabetics is essential to keep a tight reign on the symptoms of the disease. There are many (at least 20+) different types of blood monitoring devices available on the market today, not every meter suits all patients and it is a specific matter of choice for the patient to find a meter that they personally find comfortable to use. The principle of the devices is the virtually the same, a small blood sample is collected by the patient by self-production using a lancing device (a sterile pointed needle) the blood is usually collected at the end point to a test strip. This test strip contains various chemicals which when the blood is applied creates a small electrical charge between two contacts. This charge will vary dependent on the glucose levels within the blood and its effect on the chemicals contained within the strip. In older glucose meters, the drop of blood is placed on top of a strip. A chemical reaction occurs and the strip changes color. The meter then measures the color of the strip optically.
It is this level that is measured and a result in either mg/dL (milligrams per deciliter in the USA) or mmol/L (millimoles per litre in Europe) of blood. The average normal person should have a glucose level of around 4.5 to 7.0 mmol/L (80 to 125 mg/dL). In the diabetic patient, more specifically type 2 patients, it is important to maintain good glucose control, with a before meal level of <6.1 mmol/L (<110 mg/dL) and a level two hours after the start of a meal of <7.8 mmol/L (<140 mg/dL)13.
A level of <3.8 mmol/L (<70 mg/dL) is usually described as a hypoglycaemic attack. Most diabetics 'know' when they're going to go hypo and usually are able to eat some food or drink something sweet to raise levels. It is important to remember though, that a patient who is hyperglycaemic (high glucose) can also have a hypo under certain conditions i.e. not eating regularly, or strenuous exercise, followed by fatigue.
Levels greater than 13-15 mmol/L (230-270 mg/dL) should be monitored closely and the patient is advised to seek urgent medical attention as soon as possible if this continues to rise after 2-3 tests.
Hyperglycaemia is not as easy to detect as hypoglycaemia and usually happens over a period of days rather than hours or minutes. If left untreated this can result in diabetic coma and death.
Prolonged and elevated levels of glucose in the blood, which is left unchecked and untreated will, over time, result in serious diabetic complications and sometimes even death. It is therefore highly important that a diabetic patient checks their blood levels either daily or every few days to see what levels they are achieving over a given period of time. There is also computer software for the PC which is available from blood testing manufacturers which can display results and trends over time. Type 1 patients will have to check on a more regular daily basis due to insulin therapy which is a fine art to master.
These results are especially useful for the diabetic to present to their doctor or physician in the monitoring and control of the disease. Failure to maintain a strict regimen of testing can accelerate symptoms of the condition, and it is therefore imperative that any diabetic patient strictly monitor their glucose levels regularly.
The Declaration of St Vincent was the result of international efforts to improve the care accorded to diabetics. 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.
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 century7.
Until 1922, when insulin was first discovered and made clinically available, a clinical diagnosis of diabetes was an invariable death sentence, more or less quickly. Non-progressing type 2 diabetics almost certainly often went undiagnosed then; many still do.
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 diabetics were deficient in a single chemical that was normally produced by the pancreas - he proposed calling this substance 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 managed to show that they could reverse the induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs8. They 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 did not patent their discovery and insulin therapy rapidly spread around the world.
Other landmark discoveries7 include:
"Diabetes" is a Greek word meaning "a passer through; a siphon". "Mellitus" comes from the Greek word "sweet". Apparently, the Greeks named it thus because the excessive amounts of urine diabetics produce (when blood glucose is too high) attracted flies and bees because of the glucose content. The ancient Chinese tested for diabetes by observing whether ants were attracted to a person's urine; medieval European doctors tested for it by tasting the urine themselves, a scene occasionally depicted in Gothic reliefs.
It is probably important to note that 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.