Diabetes mellitus is characterized by chronic hyperglycemia and disturbances of carbohydrate, protein and fat metabolism. There are several types of the disease of variable etiology. 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.
According to the World Health Organization, in 2004, more than 150 million people worldwide suffer from some form of diabetes. Even more alarming, by the year 2025 this number is expected to double. Unlike many other diseases, such as malaria, diabetes is prevalent everywhere but more so in economically successful and highly industrialized countries such as the United States. As of 2002, about 18.2 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 change an epidemic. This is a medically and economically important disease, the National Diabetes Information Clearinghouse estimates that in the United States alone diabetes accounts for a total of $132 billion. Diabetes is easily in the top 10 and perhaps in the top 5 most devastating diseases in the developed world, 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 can produce the chronic complications of diabetes mellitus. They include:
- Endothelial damage - manifesting as microvascular or macrovascular damage.
- Proliferative retinopathy can lead to blindness;
- Peripheral neuropathy can lead to foot ulcers leading to necrosis and infection (including gangrene), eventually requiring amputation;
- Nephropathy can cause chronic renal failure requiring dialysis or transplantation.
- Ischemic heart disease, stroke and neuropathy are other possible complications -- probably stemming from blood vessel damage.
- High blood pressure -- which is more common in diabetics.
Diabetes mellitus is the most common cause of adult 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 now be cured (except experimentally in Type 1 diabetics) but it often can be treated effectively and there is emerging solid evidence that diabetes mellitus Type 2 can be evaded in people with impaired glucose tolerance6; that is, in those with 'beginning' Type 2.
Traditionally (after the first use of insulin in 1922), the goal of treatment was prevention of either hyperglycemic or hypoglycemic coma and diabetic ketoacidosis. Lack of sufficiently frequent and sufficiently inexpensive blood glucose monitoring precluded much more nuanced intervention until the late 1970s. The chronic side effects of diabetes were not even recognized as preventable until the last few decades. Until the early 1920s, they couldn't be observed at all -- much less treated -- because patients didn't survive long enough to suffer from them.
Several large, long duration, studies since 1980 have made it clear that the effort needed to keep blood glucose levels as close to normal (ie, fasting levels below 126 mg/dl adn above 60 pr 70 depending on the individual patient) is well worth while, and that it is actually possible in the real world of diabetic patients. The risk of complications is quite clearly inversely proportional to how well controlled blood glucose levels are kept. Several studies have recently shown that the beneficial effect of close control is a long term one as well. More recent studies in Type 2 diabetes also stress the need for stringent blood pressure and cholesterol 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 - probably due to insulin resistance or renal failure / damage or both.
The clinical goal 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 1 diabetics, this means injecting insulin; for Type 2 diabetics, this means diet, exercise, and weight loss, in any possible combination depending on the patient, followed by medication (usually oral, but possibly insulin as well).
The management of diabetes is almost always a major ongoing presence in patients' lives and activities. It need not be more than 'merely' annoying for most; however, patient participation is so important to diabetes management that patient education is required for diabetes. Many treatments are potentially damaging (if not deadly) when administered improperly. Moreover, there are (and appear to have long been) a large number of "alternative" treatments for diabetes; some are dangerous and occasionally deadly in themselves and/or by supplanting more conventional treatments.
"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 applied to many of them. The most common are diabetes insipidus and diabetes mellitus.
Until 1922, when insulin was first discovered and made clinically available, a clinical diagnosis of diabetes was an invariable death sentence, more or less promptly. Non-progressing Type 2 diabetics almost certainly often went undiagnosed then; many still do.
The discovery of the role of the pancreas in diabetes is generally credited to Joseph Von Mering and Oskar Minkowski, two European researchers who, in 1889, found that when they completely removed the pancreas of dogs, the dogs developed all the signs and symptoms of diabetes and died shortly afterward. In 1910, Sir Edward Albert Sharpey-Schafer in Edinburgh suggested that diabetics were deficient in a single chemical that was normally produced by the pancreas - he proposed calling this substance insulin.
The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not fully clarified until 1921, when Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski but went a step further and managed to show that they could reverse the induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs. They went on to isolate the hormone insulin from bovine pancreases at the University of Toronto in Canada.
This led to the availability of an effective treatment - insulin injections - and the first clinical patient was treated in 1922. For this, Banting, et al, received the Nobel Prize in Medicine in 1923. The two researchers did not patent their discovery and the therapy rapidly spread around the world.
Causes and types
The role of insulin
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 very small 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. Hyperglycemia has 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 and even in some Type 1)
Type 1 diabetes is most commonly diagnosed in children and adolescents. It is an autoimmune disorder, in which the body's own immune system attacks the glutamate decarboxylase enzyme in the hormone-producing beta cells of the Islets of Langerhans in the pancreas, preventing them from producing enough (or any) insulin. The autoimmune attack is generally triggered by an infection, often by one of the Coxsackie virus family (group B). The Coxsackie virus expresses the protein P2-C, which is similar in structure to glutamate decarboxylase and lead to molecular mimicry.
Some poisons work by selectively destroying the beta cells, thus producing 'artificial' Type 1 diabetes. Pancreatic trauma or tumor can also do so.
Currently, Type 1 is almost always treated with insulin injections, usually using intensive insulinotherapy on a sliding dose scale. Doses must be fitted to the individual patient's responses, and adjusted thereafter as required.
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 differs; this is likely due to both differences in the rate of Type 1 and differences in the rate of other Types, most prominently Type 2. Most of this difference is not currently understood.
Formerly Type 1 diabetes was called "childhood" or "juvenile" diabetes or and "insulin dependent" (IDDM) diabetes. All are misnomers, especially since the obesity epidemic of recent years has lead to increased incidence of Type 2 diabetes in children and adolescents.
Type 2 diabetes is characterized by resistant to insulin in those body cells requiring insulin to permit uptake of glucose from the blood; about 2/3 of body cells do. The four main characteristics of this disease ("the disharmonious quartet") are: (1) decreased insulin secretion, (2) increased lipolysis, (3) increased hepatic glucose production (gluconeogenesis), and (4) decreased muscular glucose uptake. All contribute to the development of hyperglycemia, which often goes unnoticed for years and may lead to complications (see below) by which it is finally detected. Type 2 often develops later in life, and is often accompanied by central obesity, hypertension and combined dyslipidemia (together termed Metabolic Syndrome X. However, it is currently believed that obesity is the most significant risk factor. A person's chances of developing Type 2 diabetes increases by 4 percent for every pound of excess weight.
It was formerly called any of 'adult-onset' diabetes, 'obesity related'-diabetes, 'insulin resistant'-diabetes, or 'non-insulin dependent' (NIDDM) diabetes.
Type 2 diabetes can be secondary to a number of diseases (e.g. hemochromatosis and polycystic ovary syndrome) and certain types of medication (e.g. as a side effect of long-term steroid use). About 90-95% of all North American cases of diabetes are Type 2, and about 20% of the population over the age of 65 suffer from it. The fraction of Type 2 diabetics in other parts of the world varies substantially, almost certainly for environmental reasons (probably lifestyle differences). There is a very strong inheritable genetic connection in Type 2 diabetes. For example, in late 2000 researchers found that a variation of the gene Caplain-10, is associated with the development of Type 2 diabetes. Relatives, especially close ones, with Type 2 are a considerable risk factor.
Type 2 is initially treated with weight loss, which can restore insulin sensitivity even when the weight lost is modest. Often, the next step is treatment with oral antidiabetic drugs (sulphonylureas, metformin, or thiazolidinediones). When a combination of the above has failed, insulin therapy may be necessary.
Other specific forms of diabetes, accounting for up to 5% of all diagnosed cases of diabetes:
- Genetic defect in beta cells.
- Genetically related insulin resistance.
- Diseases of the pancreas.
- Caused by hormonal defects.
- Caused by chemicals or drugs.
- Gestational diabetes mellitus appears in about 2-5% of all pregnancies. About 20-50% of these women go on to develop Type 2 diabetes.
Both Type 1 and Type 2 diabetes have genetic linkages. 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. Even with the susceptibility, Type 1 does not apparently occur without an environmental trigger. 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 reasons for these connections are 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: sufficient excess glucose (above the 'renal threshold') from the blood is eventually excreted by the kidneys but this causes fluid loss, which must be replaced.
Acute danger signs for diabetics 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 altered consciousness is the so-called "diabetic coma". Early symptoms of impending diabetic coma are polyuria, nausea, vomiting and abdominal pain, with lethargy and somnolence a later development, progressing to unconsciousness and coma and death if continued and untreated.
Diabetic ketoacidosis and coma
See also the main article diabetic ketoacidosis and diabetic coma
Diabetic ketoacidosis (DKA) is an acute, dangerous complication diabetes and always is a medical emergency. If left without prompt proper treatment diabetic ketoacidosis has substantial mortality.
Pathophysiology of diabetic ketoacidosis
It arises from incomplete fat breakdown. Production of [[fatty acid]]s from stored lipids is entirely normal during metabolic ketosis, and is begun when insulin levels are low. It is therefore indirectly controlled by the blood glucose level (in non-diabetics) and so ultimately, though still more indirectly, controlled by carbohydrates in the diet. When glucose is persistently low or absent (and so when fat is being taken from body stores and converted to fatty acids for energy use, ie ketosis), glucose is produced from some amino acids after protein degradation. During glucose production from protein, fat metabolism (ie, ketosis) becomes abnormal because of competitive interference between the two processes. Under those conditions, the liver converts the metabolic chemical acetyl-CoA (an intermediate in ketosis) to ketone bodies without completing fat processing; these are together quite acidic, and if present in too high quantities cannot be removed from the blood fast enough to prevent acidosis. DKA is more common in Type 1 diabetics, probably because they do not secrete significant amounts of their own insulin. It is much rarer in Type 2 diabetics.
The brain (and a few other tissues, including parts of the kidneys) uses glucose from the blood regardless of diabetic status (ie, insulin insufficiency or cellular resistance) as nerve cells do not require insulin to absorb glucose; but neither it nor most of the rest of the body is able 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; the name survives from a time when the biochemistry was poorly understood.
DKA is usually accompanied by hyperglycemia which also causes osmotic diuresis, leading to excessive losses of water, sodium and potassium. These electrolyte imbalances are also dangerous and can cause problems up to and including death.
A patient with DKA is always acidotic, almost always dehydrated, and nearly always hyperglycaemic. All are very dangerous conditions and together are no less so. The patient urgently requires IV fluids and, almost always, insulin -- typically intravenously. A bicarbonate infusion may be necessary if the pH of the blood is sufficiently low. DKA is a medical emergency and requires immediate skilled treatment, supplies, and facilities; it cannot be adequately handled at home on a 'first aid' basis.
Hyperosmotic diabetic coma
Hyperosmotic diabetic coma has some 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. The osmotic effect of the high glucose levels combined with the (excessive) loss of water will eventually result in raised serum osmolality. Electrolyte imbalances often also occur. The combination of changes, if prolonged, will result in symptoms similar to ketoacidosis, including loss of consciousness. As with DKA, urgent medical treatment is necessary. It is the diabetic coma to which Type 2 diabetics are prone.
A complication of treatment (primarily, insulin and sulphonylureas) is hypoglycemia, meaning excessively low blood sugar levels. The patient is often agitated (sometimes irrational), sweaty and has all the features of sympathetic activation of the autonomic nervous system. Consciousness drops in extreme cases, leading to coma and seizures. A diabetic, particularly an experienced one, can sometimes recognise the symptoms early (that is, if no hypoglycemia unawareness is present) and should always carry something sugary to eat or drink, which can reduce the symptoms rapidly. If this opportunity has been missed, oral or intravenous dextrose administration will reverse the symptoms very quickly. Longstanding hypoglycemia might require hospital admission.
See lab diagnosis of diabetes
The need for treatment
Diabetes is a chronic disease (the most common such disease) and, as there is no cure, it can only be managed symptomatically, often by life-long treatment with medication. Moreover, it can lead to several serious acute or chronic complications that can make a patient dependent on dialysis, blind and wheelchair-bound if not managed adequately and systematically.
Diabetes mellitus requires complex therapy, education and life-style modifications to minimize bad outcomes. The goals of diabetes management are several: not only near-normal glycemic control (and so avoidance of both acute and chronic hyperglycemia), 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 and beyond reasonable doubt, that keeping blood glucose levels as close as possible to 'normal', nondiabetic, values really does prevent, or delay, chronic diabetic complications1,2:
- Diabetic retinopathy
- Microangiopathic and macroangiopathic damage (atherosclerosis)
Close glucose control should be undertaken with care, as keeping blood glucose levels 'normally' low in diabetics leaves less room for medication / diet / exercise error and so increases the possibility of a (possibly dangerous) hypoglycemic episode (see above).
Treatment depends on the type of diabetes:
Type 1 is generally treated with insulin as a first-line therapy, sometimes proceeding to an insulin pump. There is no oral treatment for Type 1 diabetes. Islet transplants are still in their experimental stage.
Type 2 can usually be managed with: a diet and medication. Common antidiabetic drugs include the biguanides (mainly metformin), the sulfonylureas (e.g. Orinase®, Diabinase®, and Tolinase® among many others) and the newer thiazolidinediones (rosiglitazone and pioglitazone). Some Type 2 diabetics require insulin therapy when diet, exercise, weight control, and combinations of antidiabetic drugs have failed to bring the glucose levels down (or have caused intolerable side effects).
Insulin therapy requires close monitoring and a great deal of patient education. For example, when food intake is reduced, less insulin is required. The previously satisfactory doseing may now be too much and cause a hypoglycemic reaction. More exercise decreases insulin requirements, and vice versa: exercise increases 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 (including individual patient variations), 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 an attainable goal for the average patient, but it is not simple, nor trivially safe either. The consequences of making an error include death, and so great caution, and expert advice (especially when beginning drug therapy), 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 (eg, several of the stress hormones force increases in 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. for that particular patient.
Other risk factors
The presence of hyperglycemia should prompt the search for other risk factors that can lead to cardiovascular disease, mainly hypertension and hypercholesterolemia. In both conditions, the presence of diabetes is an additional reason to intensify treatment.
Results from an important study5 in the journal Lancet suggest that diabetics should be treated with a statin drug (simvastatin 40 mg or equivalent), irrespective of their cholesterol levels. The treatment seems to reduce (by 24-27%) the rate of myocardial infarction, coronary death, and stroke, as well as the need for peripheral arterial revascularization procedures. The reason is thought to be an anti-inflammatory reaction, and not just the modification of cholesterol levels. The effect seems clear, but the mechanism remains obscure.
Monitoring of blood glucose levels
a simple blood glucose meter Sensible management of diabetes depends almost entirely on blood glucose testing. This is because mild to moderate hyperglycemia causes no obvious symptoms in most patients. Other complicating factors include the fact that, while food takes several hours to be digested and absorbed, insulin can have glucose lowering effects for as little as 2 hours or 24 hours or more (depending on the nature of the insulin preparation used and individual patient reaction). And, the onset time and duration of the effects of oral hypoglycemic agents (nearly always pills) vary from type to type and from patient to patient.
Since blood glucose levels change regularly and rapidly (within hours and less), portable meters are effectively the only reasonable choice. Testing only during visits to a clinic, at a doctor's office, or in hospital is entirely inadequate as a basis for almost every decision about food, exercise, drug dosage and timing a diabetic patient is obliged to make.
Regular urine glucose testing is only slightly more useful, except perhaps for detecting ketones in the early stages of ketoacidosis. It reflects all glucose levels since the last urination, not only what they are now. Even in an emergency, this is not likely to be of much help.
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, where it can be taken (from a finger, or a forearm, or ...), 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, the underlying detection technique (optical reflectance or electrochemical are the usual techniques), and compatibility with computer programs for keeping records of readings and other information. Cost also varies, but not for inherent technical reasons; these are all machines of quite similar complexity and inherent cost.
a blood test strip The cost per test strip varies quite substantially -- cost differences of more than 3x are found in the US as this is written. Thus, strips for one meter model may be as much as 1/3 the cost for strips for another. Cumulative strip costs, over even short periods, completely swamp all other meter cost issues. Strip cost should be a major (probably the most important) contributor in the decision of which meter to choose. How often to test, and what to do with/about the results should be closely coordinated with medication schedules (especially for insulin), food, and exercise. At least when beginning to test, medical supervision is a very sensible, and in many cases necessary.
A useful laboratory test of long term diabetic glucose control is the glycated haemoglobin level (aka, "HbA1c"). Non-diabetics typically have an HbA1c level of less than 7%. This is a good target for most (but not all) diabetics; since diabetic situations differ, determining an HbA1c target should be determined in cooperation with a physician. HbA1c levels indicate average glucose levels in the recent past (around 3 months in most people as the lifetime of a red blood cell usually averages 120 days), and so less 'close' blood glucose control. What HbA1c level indicates poor diabetic control will vary with each patient. There is now a commercial test kit (in the US, anyway) for doing this at home.
Short term (acute) problems
Since insulin became available, short term benefits of its sensible use have been, on the whole, excellent. At the very least, they didn't inevitably die in the short term as they had inevitably done previously. Impurities in insulin preparations have been decreasing steadily since 1922, and allergic reactions have decreased with them. Insulin has never been purer, by and large, than it is now. Insulin use has not become trivial and side effect reactions to commercial insulin products have not disappeared, but the situation is better now than it has ever been. 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, or behave sensibly, 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 autonomic nervous systems (diabetic neuropathy). Each of these causes its own symptoms, most of them unfortunate.
Distinct forms of microangiopathy include damage to the retina of the eye (diabetic retinopathy) and damage to the kidneys (nephropathy). The damage in both cases seems to be primarily due to high glucose levels, probably via assorted reactions between glucose and various proteins which thereupon change 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 sensory neuropathy affects sensation at first, and primarily, in the feet and lower legs, and eventually even fingers and hands. Feeling decreases and with it protective reaction to damage, eg from thumb tacks, blisters, ill fitting shoes, .... Combined with vascular damage leading to slower healing, the effect is to greatly increase the risk of trauma (eg, can't feel the pebble or pin or developing blister), and the risk of spread of serious infection (eg, infection not noticed (no or reduced pain) and no measures taken until 'too late'). Autonomic neuropathy can cause problems with balance, with intestinal operations (ie, digestion), with balance and coordination, with sexual responses and other reflexes, and indeed, 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'. Blood glucose testing is important if only because it helps with this.
Other investigations include urinanalysis for glucose, ketones and protein; full blood count; electrolytes; kidney function tests; blood cholesterol and triglycerides.