Diabetes

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 sensitivit 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 engaging in regular exercise.

Statistics

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.

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.

Causes and types

The role of insulin

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 mellitus

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.

As of 2004, type 1 is treated with insulin injections, lifestyle adjustments, and careful monitoring of blood glucose levels using blood test kits. Insulin delivery is also available by an insulin pump, which allows the infusion of insulin 24 hours a day at preset levels, and the ability to program push doses (bolus) of insulin as needed at meal times. 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 mellitus

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.

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.

Type 3 diabetes mellitus

All other specific forms of diabetes, accounting for up to 5% of all diagnosed cases of diabetes, are termed Type 3:

• Type 3A: genetic defect in beta cells.
• Type 3B: genetically related insulin resistance.
• Type 3C: diseases of the pancreas.
• Type 3D: caused by hormonal defects.
• Type 3E: caused by chemicals or drugs.

Type 4 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.

Genetics

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.

Diagnosis

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 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 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.

Diagnosis

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.

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 2 hours after 75 g of glucose, or a formal glucose tolerance test. Many health care recommendations for adults recommend universal screening at age 40 or 50 years, 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.

Criteria for diagnosis

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of

1. two fasting plasma glucose levels above 7 mmol/l (125 mg/dl) on different days;
2. plasma glucose above 11.1 mmol/l (200 mg/dl) two hours after a 75 g glucose load; or
3. symptoms of diabetes and a random glucose above 11 mmol/l (200 mg/dl).

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 and coma

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

1. Rapid restoration of adequate circulation and perfusion with isotonic intravenous fluids
2. Gradual rehydration and restoration of depleted electrolytes (especially sodium and potassium)
3. Insulin to reverse the ketosis and lower the glucose
4. Careful monitoring to detect and treat complications

Treatment usually results in full recovery, though death can result from inadequate treatment or a variety of complications.

Hyperosmotic diabetic coma

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

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.

External links

• MedlinePlus Diabetes from the U.S. National Library of Medicine
• Children with Diabetes
• MyWebMD Diabetes Section
• Canadian Diabetes Association
• Juvenile Diabetes Research Foundation
• American Diabetes Association
• International Diabetes Federation
• Health Canada Diabetes Type 2 Risk Evaluation
• Center for Disease Control Diabetes Section