The Background To Diabetes

Diabetes mellitus is most correctly defined as a series of disorders or a syndrome in which the body is unable to properly regulate the processing, or metabolism, of carbohydrates, fats and proteins. It is caused by an absolute or partial deficiency of the important hormone insulin, which is produced and released by specialized cells (known as beta cells) located in the pancreas. The pancreas itself is a gland that is situated between the duodenum and the spleen and behind the stomach and is about 15 cm in length. It contains two main types of cells both of which produce secretions. The first group secretes digestive enzymes involved in the breakdown of food, and the second comprises clusters of cells called the islets of Langerhans, which produce hormones. As noted above, the beta cells are the ones that produce and release insulin but others, the alpha cells, secrete a different hormone called glucagon which is also involved in the regulation of blood glucose levels. Glucagon acts principally upon processes that occur in the liver (see below) and has an important role in preventing hypoglycaemia. Hypoglycaemia is one of the main features of the form of diabetes.

The function of insulin is to regulate the levels of glucose (the body's energy source) in the blood in order to ensure that enough is made available at all times to all the various tissues and organs, so that vital life-processes can continue. Glucose is the simplest form of sugar molecule, being the end product of carbohydrate digestion and the form in which carbohydrate is absorbed from the gut into the bloodstream. Hence the main and ultimate source of glucose is carbohydrate taken in as food, but the body does not rely on this alone. When dietary glucose is in short supply, the body turns to alternative sources and processes. An understanding of the regulatory mechanisms involving insulin is important in order to comprehend what happens in diabetes, and so it is useful to look briefly at these in a little more detail. Insulin has short-term (metabolic) and longer-term activity within the body, both of which affect other processes important to health. Returning to the analogy of ripples in a pool, when something goes wrong with the activity of insulin, as in diabetes, the effects can be far-reaching and at first sight, perhaps somewhat surprising.

Insulin is released from the beta cells in response to certain triggers, in particular, the presence of glucose in the blood which rises following digestion of meals containing carbohydrate. Other triggers are the presence of amino acids (the end products of protein digestion) and certain hormones, including glucagon, released from the pancreatic alpha cells. Release of insulin is inhibited by the presence of certain other hormones, especially adrenaline and noradrenaline, produced by the adrenal glands, which are also known as catecholamines, and also somatostatin. Adrenaline is the hormone that prepares the body for 'fright, flight or fight' and is sometimes called the stress hormone, while somatostatin is produced by a third type of islet of Langerhans cells, the delta cells. In addition, it is possible that a high release of insulin may itself inhibit further secretion of the hormone.

Once released, insulin carries out its effects by acting within cells. The insulin molecules do this by each attaching to a specialized receptor site located in the cell membrane that is tailor-made to receive it. All human cells contain a number of insulin receptors but some have a particular affinity for the hormone. These are: adipocytes (fat cells); hepatocytes (liver cells); skeletal myocytes (voluntary muscle cells, i.e. those attached to bones and joints). The affinity of these target cells for insulin becomes more meaningful when the overall regulatory activity of the hormone is understood, and this is described below. The effects of insulin take place by means of a whole series of biochemical events that begin to be activated once the insulin molecules are locked into place on their receptors. These are known as post-binding or post-receptor events (because they occur after the insulin molecules are bound to their receptors). They take place within cells, that is, on the inner side of the cell membrane. They are highly complex biochemical reactions involving enzymes, transport mechanisms and even, ultimately, the expression or working of certain genes (one of the longer-term effects of insulin). While it is not necessary to know how these reactions work, a knowledge of their existence and that of insulin receptors is quite important in understanding diabetes.

Insulin is the principal regulator of blood glucose and this is achieved through its actions being subjected to certain checks and balances, producing a system which in normal health is very finely tuned and controlled. The checks and balances operate mainly at post-receptor level, that is, within cells and they mainly involve counter-regulatory hormones which act antagonistically (i.e. against) the effects of insulin. The most important of these is glucagon, and also significant is growth hormone, secreted by the thyroid gland.

In normal health, insulin is produced at a low level throughout any 24-hour period, accounting for about half of the total amount released. However, as mentioned above, this increases markedly when blood glucose levels rise following digestion of a carbohydrate-containing meal, and insulin then goes to work to remove this from the circulation. It does this by promoting the uptake of glucose by all cells to fulfil their immediate energy needs. Also, and most important, it promotes the removal of glucose to liver and skeletal muscle cells, where it is converted to glycogen. Glycogen or animal starch is a complex carbohydrate molecule and is the body's main reserve energy store, which can be drawn upon in times of need.

Additionally, insulin stimulates the uptake of surplus glucose by fatty tissue where it is converted to triglyceride (a type of fat) molecules and stored. Insulin has other effects as well but in order to understand these, it is necessary to look at what happens in the liver. We also need to examine the chain of events that occurs when carbohydrate and food in general are in short supply. If food is unavailable, there is no need for high levels of insulin to be released, but the body still requires glucose to supply its energy needs. In these circumstances, for example after the nightly fast, a process called glycogenosis takes place in the liver in which glycogen is broken down into glucose and released into the circulation. The hormone which stimulates this process is glucagon.

In addition, and especially when glycogen stores have themselves been depleted and there is still a lack of food, another mechanism called gluconeogenesis is activated. In this process, stored fats and eventually proteins are broken down and the molecules released are used by the liver to manufacture glucose. Breakdown (or lipolysis) of triglycerides also takes place in fatty tissues and releases fatty acids. In the liver these are utilized to make glucose, but another process called ketogenesis (which has potentially serious consequences in diabetes) also occurs as a result of this process. Ketogenesis produces molecules called ketone bodies or ketones which, in normal conditions as described above, provide energy for outlying tissues such as muscles. A familiar ketone body and one which is important in diabetes, is acetone, which has a characteristic 'fruity', 'pear-drops' aroma. One of the most important functions of insulin, and one which is critical in diabetes, is to suppress both the breakdown of triglycerides and ketogenesis.

The body's normal energy stores - glycogen and then triglycerides -are used first when food is unavailable. But if fasting continues, proteins derived from tissues such as the muscles eventually have to be utilized and converted, by gluconeogenesis, into glucose. Glycogenolysis and gluconeogenesis occur when insulin levels are low because the body has not received an intake of food. In normal circumstances, the body has enough reserves of stored energy to 'fuel' its daily activity, and protein does not need to be utilized for this purpose. Any protein eaten can therefore be used for its normal purposes of tissue growth and repair. Insulin indirectly regulates the fate of protein through its effects upon carbohydrates and fats. The processes described above determine what happens when a person embarks upon a weight-loss diet or a 'fad' diet such as a protein-only regime and, as we shall see, are highly significant in diabetes. In normal health, insulin and its counter-regulatory system are so finely tuned that they maintain blood glucose levels within an extremely narrow range of 3-8 mmol/1 (millimols per litre).

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