Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia (high glucose blood sugar), among other signs. The World Health Organization recognizes three main forms of diabetes: type 1, type 2 and gestational diabetes (or type 3, occurring during pregnancy), although these share signs and symptoms but have different causes and population distributions. They are not a single disease or condition. Type 1 is generally due to autoimmune destruction of the insulin-producing cells - pancreatic beta cells - while type 2 is characterized by tissue wide insulin resistance and varies widely. Gestational diabetes is due to a poorly understood interaction between fetal needs and maternal metabolic controls. Type 2 sometimes progresses to loss of beta cell function as well.

Since the first use of insulin (1921) Types 1 and 2 have been incurable, but treatable chronic conditions; gestational diabetes typically resolves with delivery. Aside from acute glucose levels abnormalities, the main risks to health are the characteristic long-term complications. These include cardiovascular disease (doubled risk), chronic renal failure (the main cause of 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 (of several kinds), micro vascular damage (including erectile dysfunction (impotence) and poor healing which can lead to gangrene and even amputation - the leading cause of non-traumatic amputation in developed world adults).

Terminology

The term diabetes was coined by Aretaeus of Cappadocia. It is derived from the Greek word, diabainein that literally means "passing through," or "siphon," a reference to one of diabetes' major symptoms-excessive urine production. In 1675 Thomas Willis added mellitus from the Latin word meaning a sweet taste. This had been noticed long before in ancient times by the Greeks, Chinese, Egyptians, and Indians. In 1776 Matthew Dobson 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" (Madhumeha). The Korean, Chinese, and Japanese words for diabetes are based on the same ideographs and also mean "sweet urine disease." Medieval European doctors tested for it by tasting the urine themselves which was occasionally depicted in Gothic relieves.

While the term, diabetes, usually refers to diabetes mellitus, there are several other, rarer, conditions also named diabetes. The most common of these is diabetes insipidus (unquenchable diabetes) in which the urine is not sweet; it can be caused by either kidney (nephrogenic DI) or pituitary gland (central DI) damage.

The term "type 1 diabetes" has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes. "Type 2 diabetes" has also replaced several older terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes. Beyond these numbers, there is no standard, so a type 2 who has become insulin dependent has sometimes been called type 3, while the same term is also used for gestational diabetes in some cases.

Various sources have defined "type 3 diabetes" as, among others:

• Gestational diabetes (mentioned above)

• Insulin-resistant type 1 diabetes (or "double diabetes")

• Latent autoimmune diabetes of adults (or LADA or "type 1.5" diabetes)

History

Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in various regions since the Middle Ages, and in legend for much longer, pathogenesis of diabetes has only been understood experimentally since about 1900. The discovery of a role for the pancreas in diabetes is generally ascribed to Joseph von Mering and Oskar Minkowski, who in 1889 found that when the pancreases of dogs were removed, the dogs developed all the signs and symptoms of diabetes and died shortly afterward. In 1910, Sir Edward Albert Sharpey-Schafer suggested 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 further clarified until 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski, and went further to demonstrate 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 (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases at the University of Toronto. This led to the availability of an effective treatment-insulin injections-and the first patient was treated in 1922. For this, Banting and laboratory director MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their Prize money with others in the team who were not recognized, in particular Best and Collip. 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 has 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 first clearly made by Sir Harold Percival (Harry) Himsworth in 1935 and was published in January 1936.

Other landmark discoveries include:

• Identification of the first of the sulfonylureas in 1942.

• The determination of the amino acid order of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize).

• The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine).

• The three dimensional structure of insulin.

• Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988.

• Demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose levels approach 'normal' in a large longitudinal study, and also in type 2 diabetics in other large studies.

• Identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990's.

• Self monitoring of glucose in the home via a finger-stick blood sample and a battery powered meter in the 1970s.

Causes and Types

Glucose Metabolism

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.

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 (fructose) 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 (though it is actually many glucoses in long chains) as humans and many animals have no digestive pathway capable of handling it. Insulin is released into the blood by beta cells (β-cells) in the pancreas in response to rising levels of blood glucose (e.g., after a meal). Insulin enables most body cells (about 2/3 is the usual estimate, including muscle cells and adipose tissue) 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 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 ("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. In particular, it is the trigger for entering or leaving ketosis (i.e. the fat burning metabolic phase).

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 will not be handled properly by body cells (about ⅔ 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 Mellitus

Type 1 diabetes mellitus - formerly known as insulin-dependent diabetes (IDDM), childhood diabetes, or juvenile-onset diabetes - is characterized by loss of the insulin-producing beta cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. It should be noted that there is no known preventative measure that can be taken against type 1 diabetes. Most people affected by type 1 diabetes are otherwise healthy and of a healthy weight when onset occurs. Diet and exercise cannot reverse or prevent type 1 diabetes. 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 was traditionally 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.

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 by an pump, which allows continuous infusion of insulin 24 hours a day at preset levels and the ability to program doses (a bolus) of insulin as needed at meal times. It is also possible to deliver insulin with an inhaled powder.

Type 1 treatment must be continued indefinitely. Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication is taken. 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 events. 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. Low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus - previously known as adult-onset diabetes, maturity-onset diabetes, or non-insulin-dependent diabetes mellitus (NIDDM) - is due to a combination of defective insulin secretion and defective responsiveness to insulin (often termed insulin resistance or reduced insulin sensitivity), almost certainly involving the insulin receptor in cell membranes. In early stages, the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. 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. There are numerous theories as to the exact cause and mechanism for this resistance, but central obesity (fat concentrated around the waist in relation to abdominal organs, not it seems, subcutaneous fat) is known to predispose for insulin resistance, possibly due to its secretion of adipokines (a group of hormones) that impair glucose tolerance. Abdominal fat is especially active hormonally. Obesity is found in approximately 90% of developed world patients diagnosed with type 2 diabetes. Other factors may include aging and family history, although in the last decade it has increasingly begun to affect children and adolescents.

Type 2 diabetes may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (e.g., lack of ketoacidotic episodes) and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including renal failure, vascular disease (including coronary artery disease), vision damage, etc.

Type 2 diabetes is usually first treated by changes in physical activity (usually increase), diet (generally decrease carbohydrate intake, especially glucose-generating carbohydrates), 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), most especially when it is in abdominal fat deposits. The next step, if necessary, is treatment with oral anti-diabetic drugs. As insulin production is initially unimpaired, oral medication (often used in combination) can still be used to improve insulin production (e.g. sulfonylurea) and regulate inappropriate release of glucose by the liver (and attenuate insulin resistance to some extent (e.g., metformin), and substantially attenuate insulin resistance (e.g., thiazolidinediones). 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, most particularly and necessarily when taking most of these medications.

Gestational Diabetes

Gestational diabetes 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 20%–50% of women with gestational diabetes develop type 2 diabetes later in life.

Gestational diabetes mellitus (GDM) 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.

Fetal/neonatal risks associated with GDM include congenital anomalies such as cardiac, central nervous system, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental profusion due to vascular impairment. Induction may be indicated with decreased placental function. Cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.

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 (autosomal or mitochondrial)

• Genetically-related insulin resistance, with or without lipo-dystrophy (abnormal body fat deposition)

• Diseases of the pancreas (e.g. chronic pancreatitis, cystic fibrosis)

• 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.

Genetics

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 in a less common group, by stress or environmental factors (such as exposure to certain chemicals or drugs). 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 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 (North American) 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 (frequent urination), polydipsia (increased thirst and consequent increased fluid intake) and polyphagia (increased appetite). 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 more slowly - in type 2. In type 1 there may also be weight loss (despite normal or increased eating) 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 - 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 in 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 1; it should always be suspected in such cases.

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 of many altered state of consciousness or arousal (e.g., hostility and mania or, equally, confusion and lethargy). In severe DKA, coma (unconsciousness) 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 (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-asparagines), and some of the antipsychotic and mood stabilizers (especially phenothiazines and some atypical antipsychotic).

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 (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 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 (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.

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 (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.

Acute

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

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 (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 glucagons (a hormone with the opposite effects of insulin) or an intravenous infusion of glucose is used for treatment, but usually only if the person is unconscious.

Amputation

Persons with poorly controlled diabetes often have a hard time healing even from small cuts or abrasions. In such an event the cut, if left unnoticed or untreated, can result in an infection, and the resulting infection in extreme cases can lead to amputation.

Chronic

Micro Vascular Disease

Chronic elevation of blood glucose level leads to damage of blood vessels. In diabetes, the resultant problems are grouped under "micro vascular disease" (due to damage to small blood vessels) and "macro vascular disease" (due to damage to the arteries).

The damage to small blood vessels leads to a micro angiopathy, 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 micro angiopathy) 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.

Macro Vascular Disease

Macro vascular 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 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 (eg, Certified Diabetes Educators), 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 (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 re-growth of islet cells which are genetically part of the treated individual, thus eliminating the need for immuno-suppressants. However, it has also been hypothesized 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.

A new discovery might have important implications for treatment of diabetes. Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of type 1 diabetes) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes in these mice by 80%, suggesting a link between neuropeptides and the development of diabetes. When the researchers injected the pancreas of the diabetic mice with sensory neuropeptide (sP), they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of type 2 diabetes) was reduced. These research results are in the process of being confirmed, and their applicability in humans will have to be established in the future. Any treatment that could result from this research is probably years away.

Prevention

As little is known on the exact mechanism by which type 1 diabetes develops, there are no preventive measures available for that form of diabetes. Some studies have attributed a protective effect of breastfeeding on the development of type 1 diabetes.

Type 2 diabetes can be prevented in many cases by making changes in diet and increasing physical activity. Some studies have shown delayed progression to diabetes in predisposed patients through the use of metformin or valsartan. Breastfeeding might also be correlated with the prevention of type 2 of the disease in mothers.

As of late 2006, although there are many claims of nutritional cures, there is no reliable proof of their effectiveness. In addition, despite claims by some that vaccinations may cause diabetes, there are no studies proving any such connection.

Individuals with elevated levels of persistent organic pollutants (DDT, dioxins, PCBs and Chlordane, among others) in their body are 38 times more likely to have diabetes than individuals with low levels of these pollutants, according to a Korean study. Among study participants, obesity was associated with diabetes only in people who tested high for these pollutants. These pollutants are accumulated in animal fats, so minimizing consumption of animal fats may reduce the risk of diabetes.

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 programs 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 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 (i.e., dietary) effect, but there is little understanding of the mechanism(s) 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 (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 pre-diabetic. 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. According to the American Diabetes Association, 1 in 3 Americans born after 2000 will develop diabetes in their lifetime.