Diabetes

Diabetes mellitus

Diabetes mellitus is a disorder of carbohydrate metabolism. It is a disease characterized by persistent hyperglycemia (high blood sugar levels). 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 (or type 3, occurring during pregnancy)[1], 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. Type 2 may progress to destruction of the insulin producing cells of the pancreas, but is still considered Type 2, even though insulin administration may be required..
Since the first therapeutic use of insulin (1921) diabetes has been a treatable but chronic condition, and the main risks to health are its characteristic long-term complications. These include cardiovascular disease (doubled risk), chronic renal failure (it is the main cause for dialysis in developed world adults), retinal damage which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world, nerve damage, erectile dysfunction (impotence), to gangrene with risk of amputation of toes, feet, and even legs.
The term diabetes was coined by Aretaeus of Cappadocia. It is derived from the Greek diabaínein 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 for honey (mel in the sense of "honey sweet") 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.[citation needed]
The ancient Indians tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (Madhumehalai); medieval European doctors tested for it by tasting the urine themselves, a scene which was occasionally depicted in Gothic reliefs.
While the term diabetes without a modifier usually refers to diabetes mellitus, there is another, rarer condition named diabetes insipidus (unquenchable diabetes) in which the urine is not sweet; it can be caused by either kidney (nephrogenic DI) or pituitary gland (central DI) damage.
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, 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 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 (particularly the chemist Collip) 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 and 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 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.
Glucose metabolism
Mechanism of insulin release in normal pancreatic beta cells (that is, glucose dependence). Insulin secretion does not depend on blood glucose levels; it is stored pending release which does depend on blood glucose levels. 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 (ie, 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. 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.
Currently, type 1 diabetes can be treated only with insulin, with careful monitoring of blood glucose levels using blood testing monitors. Emphasis is also placed on lifestyle adjustments (diet and exercise). Apart from the common subcutaneous injections, it is also possible to deliver insulin via a pump, which allows infusion of insulin 24 hours a day at preset levels, and the ability to program a push dose (a bolus) of insulin as needed at meal times. This is at the expense of an indwelling subcutaneous catheter. 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 (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 (eg, 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 antidiabetic drugs. As insulin production is initially unimpaired, oral medication (often used in combination) can still be used that improves insulin production (eg, sulfonylureas) and regulate inappropriate release of glucose by the liver (and attenuate insulin resistance to some extent (eg, metformin), and substantially attenuate insulin resistance (eg, 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, 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 20%–50% 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 (high birth weight) of the child. It requires careful medical supervision during the pregnancy.
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 lipodystrophy (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.[citation needed]
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), increased appetite, and irreducible fatigue. These symptoms may also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.
Thirst develops because of osmotic effects—sufficiently high glucose (above the "renal threshold") in the blood is excreted by the kidneys, but this requires water to carry it and causes increased fluid loss, which must be replaced. The lost blood volume will be replaced from water held inside body cells, causing dehydration. Prolonged high blood glucose causes changes in the shape of the lens in the eye, leading to 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 (eg, 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.
(3) new signs and symptoms attributable to the diabetes.
Diabetes screening is recommended for many types of people at various stages of life or with several different risk factors. The screening test varies according to circumstances and local policy and may be a random glucose, a fasting glucose and insulin, a glucose two hours after 75 g of glucose, or a formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and sometimes occasionally thereafter. Earlier screening is recommended for those with risk factors such as obesity, family history of diabetes, high-risk ethnicity (Hispanic/Latin American, American Indian, African American, Pacific Island, and South Asian ancestry).
Many medical conditions are associated with a higher risk of various types of diabetes and warrant screening. A partial list includes: high blood pressure, elevated cholesterol levels, coronary artery disease, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, fatty liver, hemochromatosis, cystic fibrosis, several mitochondrial neuropathies and myopathies, myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal hyperinsulinism, and many others. Risk of diabetes is higher with chronic use of several medications, including high-dose glucocorticoids, some chemotherapy agents (especially L-asparaginase), and some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics). Diabetes is often detected when a person suffers a problem frequently caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia.
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 Problems.
Diabetic ketoacidosis , Nonketotic hyperosmolar coma , Hypoglycemia , and Diabetic coma.
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 glucagon (a hormone with the opposite effects of insulin) or an intravenous infusion of glucose is used for treatment, but usually only if the diabetic is unconscious.
Chronic problems.
Microvascular disease
Chronic elevation of blood glucose level leads to damage of blood vessels. In diabetes, the resultant problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).
The damage to small blood vessels leads to a microangiopathy, which causes the following organ-related problems:
Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
Diabetic neuropathy, abnormal and decreased sensation, usually in a stocking distribution starting at the feet but potentially in other nerves. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy.
Diabetic nephropathy, damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide.
Macrovascular disease
Macrovascular disease leads to cardiovascular disease, mainly by accelerating atherosclerosis:
Coronary artery disease, leading to myocardial infarction ("heart attack") or angina
Stroke (mainly ischemic type)
Peripheral vascular disease, which contributes to intermittent claudication (exertion-related foot pain) as well as diabetic foot.
Diabetic 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 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.