Diabetes mellitus

Diabetes mellitus is a name for any condition that is characterized by chronic hyperglycemia and disturbances of carbohydrate, protein and fat metabolism. There are several types of the disease of variable aetiology. In recent decades, understanding of underlying causes and pathological mechanisms leading to diabetes mellitus has progressed considerably. It has become possible to distinguish clearly among the different forms of the disease, sometimes tracing the cause to a single defective gene.

As of 2002, about 17 million United States nationals suffer from diabetes. For at least 20 years, diabetes rates in North America have been increasing substantially. The Centers for Disease Control has termed the changes an epidemic. This is a medically and economically important disease, well in the top 10 and perhaps in the top 5, and is becoming rapidly more so (see big killers).

Long-term diabetes mellitus can have detrimental effects on numerous organs of the body. Prolonged high blood glucose levels lead to endothelial damage - manifesting as microvascular or macrovascular damage. This can lead to the chronic complications of diabetes mellitus. They include:

• proliferative retinopathy can lead to blindness;
• peripheral neuropathy can lead to foot ulcers leading to necrosis and infection (gangrene), eventually requiring amputation;
• nephropathy can cause chronic renal failure requiring dialysis or transplantation.
• ischemic heart disease, stroke and neuropathy are other possible complications.

Diabetes mellitus is the most common cause of renal failure worldwide. It is the most common non-accidental cause of amputation in the US. It is the most common cause of blindness among non-elderly adults in the US.

Generally diabetes cannot currently be cured (except experimentally in some Type 1 diabetics) but it often can be treated effectively and there is emerging solid evidence that diabetes mellitus Type 2 can be prevented in people with impaired glucose tolerance⁶.

Traditionally the goal of treatment was prevention of either hyperglycemic or hypoglycemic coma and diabetic ketoacidosis.

Several large studies have made it clear that the effort needed to keep blood glucose levels as close to normal (fasting levels below 126 mg/dl) as possible is well worth while. The risk of complications is inversely proportional to how well controlled blood glucose levels are kept. Studies have recently shown that the effect of close control is a long term one as well. More recent studies of Type 2 diabetes also stress the need for stringent blood pressure control. Much of the vascular damage that is associated with diabetes mellitus seems to be due, in large part, to prolonged uncontrolled high blood pressure, which is common in diabetics.

The aim today is to avoid or minimize chronic diabetic complications as well as to avoid acute problems due to too high or too low blood glucose. For Type I diabetics, the chief tool is external insulin (in one or more types), usually injected. For Type 2 diabetics, treatment usually begins with diet, exercise, and weight reduction. Many patients require some form of oral hypoglycemic agents but a substantial fraction of them eventually require insulin as well since there is a considerable number of patients who eventually fail to respond to the currently available oral hypoglycemic agents. In all cases, regular patient self-monitoring of blood glucose levels is desirable.

The management of diabetes is usually a major ongoing influence on patients' lives and activities.

Table of contents

1 Etymology 2 Causes and types 3 Presentation (signs and symptoms) 3.1 Diabetic ketoacidosis 3.2 Diabetic coma 4 Diabetes Treatment 4.3 Monitoring of blood glucose levels 5 Prognosis 5.4 short term -- acute problems 5.5 long term -- chronic problems 6 Public Health, Policy and Health Economics 7 History 8 References

Etymology

"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 that a diabetic (when in a hyperglycemic state) would excrete attracted flies and bees because of the glucose content. The ancient Chinese would test for diabetes by observing whether ants were attracted to a person's urine.

Passing abnormal amounts of urine can be a symptom of several diseases (most commonly of the kidneys), and the word diabetes is connected with many diseases. The most common are diabetes insipidus and diabetes mellitus.

Causes and types

Insulin is a hormone that enables blood glucose molecules to enter about 2/3 of the cells of the body (primarily muscle and fat cells). It also controls many other body mechanisms, from fat processing (in liver and fat cells), protein synthesis (by controlling amino acid uptake in cells), and electrolyte balance (by controlling potassium uptake in cells). It is the central hormone involved in controlling metabolism. It is produced in the endocrine part of the pancreas, which consists of clumps of specialised cells scattered throughout that organ (the 'Islets of Langerhans'). Hyperglycemia (too high blood glucose levels) results if the amount of insulin is not sufficient to cause the cells to take up the glucose from the blood, or if those cells which require insulin to absorb glucose no longer respond adequately to it. This can have two major causes, which may occur together:

• not enough insulin is produced by the pancreas (in Type 1, and in some Type 2)
• the cells of the body have become resistant to insulin action (in Type 2)

There are several types of diabetes mellitus:

• Type 1, most commonly first diagnosed in children and adolescents, an autoimmune disorder in which the body's own immune system attacks the hormone producing beta cells of the islets of Langerhans in the pancreas, preventing it from producing enough (or any) insulin. The autoimmune attack is generally triggered by an infection, often by one of the Coxsackie virus family. Some types of poisons work by selectively destroying the beta cells, producing Type 1 diabetes. Pancreatic trauma or tumor can do so as well. Type 1 is almost always treated with insulin injections, usually utilizing intensive insulinotherapy. About 5-10% of all North American cases of diabetes are Type 1. The fraction of Type 1 diabetics in other parts of the world varies. Formerly called 'childhood' or 'juvenile' diabetes.

• Type 2, in which the body's cells become resistant to insulin. Eventually, the amount of insulin is insufficient to cause enough absorption of blood glucose, resulting in hyperglycemia and finally in glucose being dumped by the kidneys into the urine. Type 2 often develops later in life, and is often accompanied by overweight. There is a strong genetic connection to Type 2 diabetes. Relatives with Type 2 are a considerable risk factor. Type 2 can be treated with drugs, diet and exercise. Several drugs and other conditions, however, can cause this type of diabetes. For instance, diabetes is a common side effect of long-term steroid use, and is often the result of untreated hemochromatosis (a defect in handling of body iron stores, often inherited and the most common genetic disease among Northern Europeans). About 90-95% of all North American cases of diabetes are Type 2, and about 20% of the population over the age of 65 suffer from it. See also Diabetes mellitus type 2. The fraction of Type 2 diabetics in other parts of the world varies.

• Type 3 All other specific forms, accounting for up to 5% of all diagnosed cases of diabetes:
  • 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 or Gestational diabetes mellitus appears in about 2-5% of all pregnancies. About 20-50% of these women go on to develop Type 2 diabetes.

The older names, juvenile or insulin-dependent (IDDM) for Type 1, and adult-onset, or non-insulin dependent (NIDDM), or obesity-related, for Type 2 diabetes, are discouraged as they are misleading. Type 2 diabetes sometimes requires treatment with insulin, and is increasingly diagnosed among juveniles. Many Type 2 diabetics have reduced insulin production even though they are not likely to have the classic autoimmune caused by Type 1.

Both Type 1 and Type 2 diabetes are genetically linked. Type 1 diabetes may be triggered by infection, stress, or environmental factors (eg, substances of one kind or another). There is clearly a genetic element in the susceptibility of individuals to some of these triggers; it has been traced to particular HLA genotypes. There is an even stronger genetic link in 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. Age is also thought to be a contributing factor, as most Type 2 patients in the past were older. The exact reason for this is unknown.

Presentation (signs and symptoms)

In Type 2 diabetes there is almost always a slow onset (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 concomitant increased fluid intake). There may also be weight loss despite normal or increased eating, increased appetite, and unreduceable fatigue. These may also be symptoms of Type 2, though usually not until a later, more 'severe' stage.

Thirst develops because of osmotic effects - excess glucose from the blood is eventually excreted by the kidneys but this causes fluid loss, which must be replaced.

Dangerous signs to watch out for include the smell of acetone on the patient's breath (a sign of ketoacidosis), Kussmaul breathing (rapid, deep breathing), and any altered state of consciousness or arousal (hostility and mania are both possible, as is confusion), the worst form of which is the so-called "diabetic coma". Early symptoms are polyuria, nausea, vomiting and abdominal pain, with lethargy and somnolence a later development, progressing to unconsciousness and coma if untreated.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is a complication of diabetes, particularly of Type I diabetes and is an absolute medical emergency. It arises from excess fat breakdown and the production of fatty acids and acetyl CoA. The liver converts the latter to ketone bodies, particularly acetoacetate. DKA is an extremely dangerous and often fatal condition. Today, in diabetics, reduced cellular uptake of glucose is typically due to insufficient insulin production. DKA is more common in Type I diabetics because they do not secrete significant amounts of their own insulin. It is uncommon in Type II diabetics, even in those who require insulin due to partial or complete failure of their beta cells. Type 2 diabetics have their own similar, and equally dangerous, problem called hyperosmotic diabetic coma.

The brain continues to use glucose from the blood (nerve cells do not require insulin to absorb glucose), and can use ketone bodies themselves when present, but is unable to survive acidosis if it is too severe or continues too long. The ketone bodies are acetone, acetoacetate and beta-hydroxybutyrate. Oddly, only two are, chemically, ketones. DKA is usually accompanied by hyperglycemia which also causes osmotic diuresis, leading to excessive losses of water, sodium and potassium. These are also dangerous and can cause problems up to and including death.

A patient with DKA is almost always dehydrated, acidotic, and hyperglycaemic. The patient urgently requires IV fluids and, almost always, insulin. A bicarbonate infusion may be necessary if the pH of the blood is suffieintly low. DKA is an urgent medical emergency.

Hyperosmotic diabetic coma has similar symptoms, but a different cause. 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 be dumping glucose, and the water necessary to carry it, from the blood. that water will, eventually come from within cells, and if continued, will eventually cause death. Electrolytes (potassium ion, sodium ion, etc) will be lost also. The combination of changes, if prolonged, will cause symptoms similar to keotacidosis, including loss of consciousness. As with DKA, treatment is medically urgent and must be carefully done. Such patients are in crisis.

Diabetic coma

The brain requires many things to function correctly, but two things are critically important at all times: oxygen and glucose. Breathing (lungs) and blood circulation (heart and blood vessels) supply the oxygen, without which brain cells very quickly (minutes) die. Blood circulation also supplies glucose, without which brain cells starve (they maintain very little internal glucose stores) and brain function is immediately (also minutes) impaired. The level of consciousness is altered, physiological functions are impaired, and ultimately the patient with hypoglycemia (too little blood glucose) will die if untreated.

Patients with hyperglycemia (too much blood glucose) also will eventually (months, up to a few years) die without treatment for the same basic reason: cell starvation as glucose (fuel) cannot get into about 2/3 of the cells. Protein will be used for fuel production (catabolism) regardless of the damage caused. Muscle cells are prominently affected and muscle wasting follows.

The treatment in one case is to raise blood glucose levels, and in the other to adjust blood chemistry values back to something more nearly normal, including lowering glucose levels. In hypoglycemia, if patient is conscious, feeding with some simple carbohydrate may be sufficient to normalize blood glucose. Unconscious patients cannot swallow and may choke; medical intervention will usually be needed. In severe hyperglycemia, medical treatment is generally required because of its complex, interconnected, and quite dangerous biochemical disturbances.

Diabetes Treatment

Diabetes is currently a life-long disease -- with several possible serious complications -- which requires complex therapy, education and life-style modifications to minimize bad outcomes. At this writing, there is no cure for either Type 1 or 2 diabetes and treatment is a longterm continuous effort. The goals of the management of diabetes are several: not only near-normal glycemic control, but also prevention of hypoglycemia episodes, thus reducing the risk of long-term complications and preserving quality of life for patients.

Several major studies (involving very large numbers of patients) have shown, clearly and convincingly, that keeping blood glucose levels as close as possible to the normal, nondiabetic, range really does prevent, slow, and delay chronic diabetic complications: diabetic retinopathy, nephropathy, microangiopathic and macroangiopathic damage as well as neuropathy^1,2. Close control should be undertaken with care, as keeping blood glucose levels 'normally' low leaves less room for medication error and so increases the possibility of a (possibly dangerous) hypoglycemic episode.

There are several different ways of delivering drugs for treating Type 2 diabetes: insulin injections, insulin pumps, pills, and implants. Common drugs in pill form (for Type 2 ONLY) include metformin, and the sulfonylureas (e.g, Orinase, Diabinase, and Tolinase among many others).

Hypoglycemia means an excessively low blood glucose level. It arises in diabetics who have too much insulin (from injections or from insulin release stimulating drugs -- usually pills) for the amount of food they eat and exercise they get. On days when, for whatever reason, less food is taken, less insulin will be required; the previously satisfactory amount may now be too much and cause a hypoglycemic reaction. When more exercise is gotten, less insulin will be required, and vice versa; exercise increase glucose uptake by body cells nominally under insulin control for glucose uptake. Since there are many different insulin preparations, since foods vary in their effect on blood glucose levels (even if they have exactly the same calories), and since the 'glucose absorption' effect of exercise varies depending on many factors, getting the right amount and timing of diabetic medication (most particularly insulin) is not trivial. For most diabetics, it takes time and effort to 'get the hang of it'. Adjusting insulin and other diabetic drugs is hardly impossible, but it is not simple, nor trivially safe either. The consequences of making a error include death (from coma), and so great caution, and useful expert advice, are both mandatory. Especially for newly diagnosed diabetics, medication changes should be done only in consultation with a physician.

Illness, surgery, and stress also affect glucose levels, so all diabetics should be aware that their insulin and other drug routines may have to change if any of these occur. Previously prepared "sick day rules" may be a reasonable approach, but must actually be suitable to the diabetic situation during illness, stress, etc.

Monitoring of blood glucose levels

Sensible treatment of diabetes depends almost entirely on blood glucose testing, since grossly observable signs and symptoms almost never appear immediately and urine tests only summarize high blood glucose levels since the last urination. The food you ate hours ago is still being digested and absorbed, the insulin you injected can have glucose lowering effects for as long as 24+ hours or can be over as quickly as 2 hours(depending on the nature of the insulin preparation), and the timing of insulin pill effects also varies. And, since blood glucose levels change regularly and rapidly (hours or so), portable meters are a very good choice. Testing only during visits to a clinic, doctor's office, or hospital is entirely inadequate as a basis for almost every decision about food, exercise, drug dosage and timing.

Regular urine glucose testing is only slightly more useful, except perhaps in an emergency. It reflects all glucose levels since the last urination, not only what they are now.

There are multiple suppliers of blood glucose meters (all of which must be approved by the FDA in the US). Differences among them include size of the blood droplet required, whether the blood sample may be applied to a test strip before or after it is inserted in the meter, length of delay until results are available, size and packaging of the disposable test strips and compatibility with computer programs for keeping records of readings and other information.

The difference in cost for each test strip varies substantially - cumulative strip costs over even short periods completely swamp all other factors in meter cost. How often to test, and what to do with the results should be closely connected with medication schedules (especially for insulin), food, and exercise.

A useful laboratory test of long term diabetic glucose control is to measure the patient's blood level of glycosylated haemoglobin (ie, "HbA1c"). Non-diabetics have an HbA1c level of less than 7%; it's a good target for diabetics. Higher HbA1c levels indicate poorer glucose level control in the recent past (up to 3 months in most people); the higher, the poorer. But an HbA1c reading is not at all useful for checking the need for medication, food, or exercise just now, which is when you must make the decision(s). There is now a commercial test kit for doing this at home.

Results from a significant study in the journal Lancet⁵ suggest that diabetics should be treated with a statin drug irrespective of their cholesterol levels. The treatment seems to reduce, by 24-27%, the rate of myocardial infarction, coronary death, stroke, as well as the need for peripheral arterial revascularization procedures. At this writing, the reason is thought to be an anti-inflammatory effect and possibly other factors operating independent of the hypolipemic effect.

Prognosis

short term -- acute problems

Since insulin became available, short term results have been excellent for diabetics. Impurities in insulin preparations have been decreasing steadily since 1922, and allergic reactions with them. Insulin has never been purer, by and large, than it is now. The acute problems of diabetes mellitus, such as DKA, are fully treatable today. They are not always treated properly, in part because many people don't pay sufficient attention to their diabetes, and in part because some care givers have not taken into account the discoveries of the past few years about best treatments for diabetics.

long term -- chronic problems

The long-term consequences of diabetes mellitus are another story. Long term complications of diabetes mellitus include damage to small blood vessels (microangiopathy), larger blood vessels (macroangiopathy), kidneys nephropathy, and to the peripheral and autonomous nervous system (diabetic neuropathy). Each of these causes its own symptoms, most of them unfortunate.

Distinct forms of microangiopathy are damage to the retina of the eye (diabetic retinopathy) and damage to the kidneys (nephropathy). The damage seems to be primarily due to high glucose levels, probably via assorted reactions between glucose and assorted proteins which changes their behaviour and so the behaviour of the tissue in which the protein is found (eg, small blood vessel walls). Keeping glucose levels at or near 'normal' reduces the risk of any of these complications of diabetes mellitus without any question. There are distinct forms of neuropathy as well. Peripheral neuropathy affects the feet and lower legs, and eventually fingers and hands with numbness. Combined with vascular damage leading to slower healing, the effect is to greatly increase the risk of trauma (can't feel the pebble or pin or developing blister) and the risk of spread of serious infection. Autonomic neuropathy can cause problems with balance, with intestinal coordination, with automatic compensating adjustments of many kinds.

Several studies have demonstrated that, for both types of diabetes mellitus, the rate and severity of these long term complication is substantially reduced, or eliminated, by keeping blood glucose levels at or near 'normal'. Testing is important.

Public Health, Policy and Health Economics

The Declaration of St Vincent was the result of international efforts to improve the care accorded to diabetics. 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 (from kidney failure).

Work in the Puget Sound area of N. America (by the heath organization Group Health) shows that, over its large and varied patient population, specially retaining information for 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 his 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.

History

Until 1922, when insulin was first discovered and made available, a clinical diagnosis of diabetes was an invariable death sentence. Non-progressing Type II diabetics almost certainly often went undiagnosed then. Many still do.

The endocrine role of the pancreas and of insulin in metabolism was not fully clarified until 1921, when Frederick Grant Banting and Charles Herbert Best managed to isolate a preparation of the hormone insulin at the University of Toronto in Canada. This led to the development of an effective treatment - insulin injections - in 1922. For this, Banting received the Nobel Prize in Medicine in 1923. The two researchers did not patent their discovery and the therapy rapidly spread around the world.

References

1. "Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus." N Engl J Med 329:977-986, 1993 (abstract)
2. "World Health Organisation, Department of Noncommunicable Disease Surveillance. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications." Geneva: WHO; 1999. Available in PDF
3. "UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)." Lancet 352:837-853, 1998
4. "Conditions in Occupational Therapy: effect on occupational performance." ed. Ruth A. Hansen and Ben Atchison (Baltimore: Lippincott Williams & Williams, 2000), 298-309. ISBN 0-683-30417-8
5. "Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial." Lancet 2003 Jun 14;361(9374):2005-2016
6. "Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M : Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance." N Engl J Med 2001 May 3;344(18):1343-50

See also: diabetes dictionary, endocrinology, diabetes insipidus, diabetic coma, List of Celebrities With Diabetes.