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Diabetes Overview

Summary

Diabetes exists in two main strains; diabetes mellitus, the more common condition affecting most sufferers, and diabetes insipidus, an extremely rare disease affecting only a very small percentage of the general population (estimated at three in 100,000). In simple terms, diabetes mellitus or ordinary diabetes is a chronic disorder usually caused by a deficient secretion of insulin. The unused sugar accumulates in the blood and acts as a poison which in extreme untreated cases sends the patient into coma and may result in death.

Overview

Diabetes has been known to physicians for thousands of years; one of the first references to it being in the Ebers Papyrus written in Egypt in 1500 BC where the treatment included a mixture of bones and green lead, one not strongly advised today. In the seventeenth century diabetes was known as ‘the pissing evil’ a statement which might still hold true amongst sufferers. However it was not until the nineteenth century that any significant advance was made. In 1889 two German scientists discovered that the removal of the pancreas, a large gland in the abdomen which plays a major part in the condition, gave rise to diabetes. About this time it was also discovered that damage to specific cells in the pancreas, called islets of Langerhans, produced certain forms of diabetes.1)

Derived from the two ancient Greek words; dia meaning through and betes meaning passing, ‘diabetes’ refers to the rapid passing of water through the body from the time of its ingestion to its eventual elimination in the urine. The ‘mellitus’ refers to the fact that the urine is ‘sweet‘ or like ‘honey’, and is the disease known as ‘plain’ diabetes. In the UK it is estimated that around five per cent of the population has diabetes in varying degrees of seriousness (diagnosed or undiagnosed), which amounts to about 3.1 million diabetics (of which 2.9 million people have been diagnosed with diabetes).2) In some peoples, for example the Pima Indians of Arizona in the United States, nearly half the population have the disease.3)

Diabetes mellitus is a disorder characterised by abnormally high concentrations of glucose in the blood (hyperglycaemia) and in the urine. Glucose is a simple sugar needed by all our body cells. It is a relatively small molecule composed of atoms of carbon, hydrogen and oxygen: C6H12O6. After a big meal or one high in carbohydrates, a large amount of glucose enters the bloodstream and is carried around the body. The body, and in particular the brain, is extremely sensitive to the concentration of glucose in the blood and function is impaired when the level of blood sugar rises above or drops below certain limits. After a heavy meal glucose pours into the bloodstream from the small intestine, but this level does not continue to rise indefinitely. In a person without diabetes there is a mechanism to prevent glucose overload.

In response to rising levels of glucose in the blood, certain cells in the pancreas - an endocrine organ (an organ that secretes its products directly into the bloodstream) produces a hormone called insulin. Insulin is able to lower the blood sugar in several important ways; it seems to stimulate cells to increase their uptake of glucose from the blood and body fluids; in the liver and skeletal muscles it stimulates the conversion of glucose to glycogen (a short-term store of energy); it has the effect of increasing the use of glucose for fat synthesis; it also inhibits fat breakdown.

All these mechanisms considerably reduce the level of blood glucose, so that it is maintained within its normal levels of between 4.0 and 7.0 mmol/l in the fasting state.4) There is usually no glucose present in the urine of a healthy person, even after eating a meal high in kilojoule value. Blood glucose level is controlled by insulin and glucose is reabsorbed by the kidney preventing its loss from the body.

The pancreas is an unusual organ because it has a double function. In general, endocrine organs are concerned solely with the production of hormones to regulate the body’s metabolism. Situated in the first loop of the small intestine, the pancreas is ideally located to play its role in regulation of blood sugar through hormonal secretions, as well as to pursue its activities in digestion through the secretion of pancreatic juice. A fine tube called the pancreatic duct connects the pancreas to the small intestine. Scattered throughout the pancreas are small clumps of hormone-producing cells called the islets of Langerhans, being only about two per cent by mass of the pancreas. These islets are composed of two main cell types; the alpha cells (α-cells) and the beta cells (β-cells). The α cells produce glucagon, the hormone responsible for increasing the level of blood sugar, whereas the β cells produce insulin, the hormone responsible for lowering the blood sugar level.

Insulin is held in the form of proinsulin, a large, inactive molecule which can be rapidly converted to insulin where there is demand. Thus both pancreatic hormones, glucagon and insulin, are involved in the regulation of blood sugar levels.

As displayed in the diagram below, the blood sugar level is controlled most importantly through the action of the hormone insulin, produced by the islet cells in the pancreas. Other hormones, such as growth hormone, adrenalin, adrenal steroids (cortisone), adrenocorticotrophic hormone (ACTH) and glucagons also affect the blood glucose level. All of these hormones affect the level of glucose in the blood, but in non-diabetic individuals this level will be controlled by insulin. The amount of glucose in the blood is in itself therefore the affective agent. This level determines the amount of insulin secreted by the islet cells. Diabetes mellitus occurs when one cannot control the level of blood sugar through the action of insulin.

diabetes.jpg

Homeostatic scheme for the control of glucose in the body


Within diabetes mellitus itself there are two different types of diabetes. The distinction between these two major categories was established by Joseph Bornstein, an Australian biochemist who wrote: ‘…there are at least two types of diabetes mellitus, one with no free plasma insulin (Type 1) and the other with apparently normal plasma insulin concentrations (Type 2)’.5)

Abnormality in the β cells of the pancreas can result in the production of little or no insulin; or cells such as muscle or fat cells of some people seem to be resistant to the action of insulin. In either case, such a person is said to be suffering from diabetes mellitus.

Type 1 diabetes

Type 1 diabetes, or Insulin-dependent diabetes mellitus (IDDM), is so called because it can only be treated by insulin administration. Here control of blood sugar is impossible without insulin. IDDM is characterised by symptoms such as thirst, frequent urination, tiredness/general weakness and fatigue, weight loss, slow healing of wounds and itching primarily in the genital area. IDDM tends to occur in young people, with a peak age of onset of between twelve and fourteen years. It is due to damage to and eventual loss of the β cells of the pancreatic islets of Langerhans, with resulting loss of insulin production. The damage may in some cases be due to autoimmunity. The incidence of Addison’s disease, thyroid disease and pernicious anaemia are increased in IDDM.

IDDM is not directly inherited, although individuals may inherit a tendency in that those with certain histocompatibility antigens (HLA) types show increased susceptibility to this type of disease. The treatment involves regular injections of insulin. This hormone was discovered and isolated in 1921 by two Canadian scientists, Frederick Banting and Charles Best, but it wasn’t until 1955 that the question concerning its structure was solved by Frederick Sanger, the English biochemist. It is now known to be a small protein molecule consisting of 51 amino acids, connected in an exact way. It is a two-chain structure of amino-acids bonded together by two chemical ‘bridges’ containing atoms of sulphur. The insulin is extracted from mainly cattle and pigs (bovine and porcine insulins respectively).

Insulins are often classified according to how quickly they remove glucose from the blood; short, long and ultra-long acting and the individual patient in consultation with their doctor will determine this. It is administered by injection into the subcutaneous layer (layer under the skin) where it is easily absorbed into the bloodstream, which transports it around the body so that it can act on the body cells to control the level of glucose.

Type 2 diabetes

Type 2 diabetes, or Non-insulin-dependent diabetes mellitus (NIDDM), affects about 90% of the diabetic population.6) In this condition the pancreas can still produce insulin but not in sufficient amounts to control glucose metabolism, or the person’s cells may be resistant to the action of the insulin. In this case, many of the symptoms are the same as those for IDDM; thirst, frequent urination, slow healing of wounds and increased susceptibility to infection, itching in the genital region, general weakness and fatigue, as well as blurred vision. However, with NIDDM there is usually a gradual onset of symptoms, contrasting with the rather sudden changes that often occur with IDDM.

This form of diabetes usually occurs in those over the age of forty, and is harder to detect as some people may show no symptoms. It is caused by a gene mutation which affects how the body handles glucagon. The gene involved is the one responsible for producing glucagon’s receptor, the molecule to which it binds. In those with the condition, it binds only about a third as strongly to glucogon as it does in healthy people, in turn leading to a decrease in insulin production and therefore high glucose levels and the symptoms of diabetes.

NIDDM is largely associated with obesity and the condition can usually be controlled by an increase in physical activity and a more closely monitored, healthier diet. It is a strongly hereditary condition and women who had large babies or large families are also more prone to develop this type of diabetes later in life, and pass it on.

When the glucose level in the blood exceeds its normal upper limit, the person is said to be suffering from hyperglycaemia. This is known as the ‘high’ - hyperglycaemia - diabetic coma, often characterised by excessive thirst, increased appetite, with weight loss, ‘fruity’ breath (due to the breakdown of fat, producing ketones) and coma. A high blood sugar level takes hours or even days to develop, and may take hours to get back to normal. Treatment involves fluid replacement and insulin injection, and the coma rarely results in death.

Hypoglycaemia, or the ‘low’ - hypoglycaemia -insulin shock, is caused by a low level of blood glucose. The brain responds very quickly to low levels of blood sugar because glucose is its main energy supply. Once affected, typical symptoms include weakness and hunger, trembling, sweating, visual blurring, behavioural changes, mental confusion and possibly coma. This attack can develop in a matter of minutes, and is easily stopped by taking sugar, although if prolonged severe brain damage or death may occur.

Diabetes insipidus (DI)

The other type of diabetes is diabetes insipidus (DI). This is a much rarer form of diabetes, characterised again by excessive thirst and the passing of large volumes of dilute urine with a low specific gravity and containing no abnormal constituents. Unlike diabetes mellitus, it is due to either a lack of the antidiuretic hormone normally produced by the hypothalamus and stored in the posterior pituitary gland in the skull, or to a defect in the renal (kidney) tubules which prevents them responding to the antidiuretic hormone vasopressin. When due to a vasopressin insufficiency, a primary or secondary tumour in the area of the pituitary stalk is responsible for one third of cases. The remainder of cases result from those with no apparent cause, and those from a variety of lesions including trauma, basal meningitis and granulomatous lesions in the pituitary stalk area.

Diabetes insipidus must be differentiated from diabetes mellitus which is an entirely different disease. Little is know concerning the treatment of the condition, although the urine volume can usually be reduced by half by a thiazide diuretic.

Diagnosis

The diagnosis of diabetes must always be established by measuring blood glucose, although glycosuria (the excretion of glucose into the urine) nearly always indicates diabetes. Fasting blood glucose concentrations greater than 7 mmol/L and random blood glucose concentrations greater than 11 mmol/L are diagnostic of diabetes; and fasting values less than 6 mmol/L or random levels less than 7.8 mmol/L exclude diabetes. However these limits are the averages and the threshold varies considerably between individuals and increases with age.

The future for diabetics has improved with more recent developments in methods of taking insulin, and the possibility of being able to stop diabetes before it starts. Techniques for taking insulin are becoming more refined. The numerous daily injections necessary for some patients may be replaced by a constant delivery pump, the insulin entering by needle under the skin. Research identifying the stretch of DNA responsible for IDDM may lead to widespread provision of solutions in addressing a cure for the disease.7) With expert medical attention and determination, sufferers can now lead normal lives.

Further Reading

For an in-depth examination and comparative analysis pertaining to risks and prospective treatment for Type 1 and gestational diabetes mellitus please refer to Diabetes

References

1) Oskar Minkowski and Joseph von Mering, University of Strasbourg
5) Plasma Insulin in Human Diabetes Mellitus, Bornstein and Lawrence, 1951 BMJ Dec 1929
6) http://www.who.int/mediacentre/factsheets/fs312/en/ World Health Organization, Diabetes Fact Sheet

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