Diabetes past and present

Our understanding of diabetes progressed from the sweet taste of the urine to the measurement of glucose in the blood, and from there to an appreciation of the overproduction of glucose by the liver. Insulin was, after a long search, identified as the key to an understanding of diabetes and of the metabolic economy of the body. A further long quest led to the understanding that there are two types of diabetes. Predisposition to both types of diabetes is conferred by the interplay of multiple genes, but the importance of environmental factors is shown by the rapidly rising incidence of both type 1 and type 2 diabetes. Two observations have been of key importance in directing the treatment of diabetes. The first is the observation that complications affecting the small blood vessels can be prevented by careful control of blood glucose levels, and the second is the observation that cardiovascular disease is 2-3 times as common in those with diabetes as in those without. Good glucose control is not enough; there has to be careful attention to all cardiovascular risk factors. These considerations have guided modern therapy, which relies on good organization and early intervention to prevent diabetes from progressing from risk factor to disease.

Background

Diabetes mellitus, the "sweet-tasting urine" disease was so named to distinguish it from diabetes insipidus, the "tasteless urine" disease, a distinction which was only recognised in the eighteenth century. There is no connection between the two conditions. Diabetes mellitus was generally considered to be a disease of the kidneys before the nineteenth century, when it was appreciated that the condition is due to raised levels of glucose in the blood which then spill over into the urine. (See History to 1900 for further details of the early history of diabetes).

The cause of diabetes mellitus (hereafter just called "diabetes") remained a mystery throughout most of the nineteenth century, until it was shown (by accident) in 1889 that a dog develops diabetes when the pancreas is surgically removed. It took a further thirty years to puzzle out the explanation, which is that the pancreas produces insulin, the hormone that in health regulates the flow of glucose from the liver and its uptake into other tissues including muscle and fat. Further research showed that insulin also controls important aspects of fat and protein metabolism, and is therefore much more than a "sugar hormone". (See History 1900 to 1950 for this part of the story).

Different types of diabetes

Early clinicians often noted the difference between young thin patients whose live expectancy was short before the introduction of insulin, and older patients, often overweight, who could survive in the absence of insulin. By the 1930s it was appreciated that diabetes could arise either because the body no longer produced insulin, or because it has become resistant to its action. It was not until the 1970s that this distinction was formalized into our current classification of type 1 and type 2 diabetes (see the Discovery of type 1 diabetes). It should however be appreciated that there is some overlap between the two, in that some people with insulin deficiency are also insulin resistant, and that insulin resistance only ends in diabetes when there is an element of insulin deficiency.

Causes of diabetes

The causes of type 1 and type 2 diabetes are poorly understood, although type 1 diabetes is known to result from activation of the immune system, which then "rejects" the insulin producing islet cells of the pancreas as if they were alien to the body. Multiple genes predispose to diabetes, with different genes for type 1 and type 2, and your risk increases in proportion to the number of risk genes that you carry. These genes show that individuals have an increased predisposition to diabetes, but do not in themselves cause the disease, as can be seen in the fact that most people who carry even high risk combinations of these genes will not develop diabetes. This clearly shows that environment and lifestyle play an important role in its causation. See Historical aspects of type 1 diabetes and Historical aspects of type 2 diabetes for further details.

Diabetes may also arise as a secondary consequence of other diseases which damage the pancreas or cause an increased requirement for insulin. These are described under Other types of diabetes mellitus, and include Pancreatic disorders, Endocrine disorders - diseases resulting from overproduction of other hormones which antagonize the action of insulin, Drug-induced diabetes, and a variety of inherited conditions due either to a single gene (Monogenic diabetes) or in association with Genetic syndromes.

What goes wrong in diabetes

An introduction to glucose

The body derives energy from three basic sources: carbohydrate (e.g. glucose), fat and protein. Insulin is the most important hormone influencing the fuel economy of the body. When insulin levels are high, as after meals, the balance tilts towards storage; when insulin levels are low, and in concert with many other hormones, insulin helps to determine the rate and pattern at which body fuels are released into the circulation and metabolised by the body. Insulin is thus the conductor of the metabolic orchestra, and lack of insulin results in alterations affecting every aspect of metabolism, and not just glucose.

Glucose is an essential body fuel which supplies the energy requirements of the brain, and this rapidly begins to malfunction if deprived of a steady supply of glucose. Low blood glucose (and the clinical condition that results) is referred to as hypoglycaemia, as against hyperglycaemia for high blood glucose.

Glucose is less essential for other major organs and tissues, but it provides a convenient and readily accessible source of energy. Insulin is the signal that allows surplus glucose to be stored in liver or muscle as glycogen, or converted into fat.

Glucose reaches the circulation by two main routes. The first is the food we eat, and the second is glucose production by the liver. The role of the liver is to "top up" circulating levels of glucose between meals or during fasts, thus ensuring an uninterrupted flow of glucose to the brain. In diabetes, the liver "sees" too little insulin, and (in the absence of this signal) overproduces glucose.

When glucose levels rise above the normal range there are no immediately harmful consequences for the brain or other tissues. There is however a point (known as the renal threshold for glucose) at which the kidney is no longer able to recover all the glucose it filters. When this happens, glucose appears in the urine. This sucks salt and other electrolytes into the urine by osmosis, and results in excessive urine production, dehydration and thirst - cardinal symptoms of diabetes.

Treating diabetes: an Introduction

Diet: It has been known for 200 hundred years that weight loss can be an effective treatment for type 2 diabetes, and the incidence of diabetes falls rapidly when whole populations are forced to live on a spare diet, as in times of war. Many diet and lifestyle regimens have been developed over the years, and each has its advocates. A common factor in success has tended to be acceptability and sustainability.

Insulin: Insulin was initially made from beef pancreas, but pork insulin more closely resembles human insulin and is less likely to cause allergic reactions; it became more popular in the 1970s. Genetically engineered (biosynthetic) insulin was introduced in the 1980s, and analogue insulins came in towards the end of the century. These are "designer" insulins modified to reach their target tissues more quickly or more smoothly over many hours.

Tablets: The first tablet preparations were introduced in the 1950s. These were the sulfonylureas, which act by promoting insulin secretion. These were followed in the 1960s by metformin, an insulin sensitizer which remains the first line drug of choice for type 2 diabetes. Metformin did not reach the USA until 1995. The thiazolidinediones (TZDs or glitazones) were introduced toward the end of the century, but their use is currently limited by their adverse effect profile. These and other classes of tablets for the treatment of diabetes are described further in the section on Non-insulin drugs.

GLP-1 based therapies: Glucagon-like peptide or GLP-1 is a hormone produced by cells in the gut wall which stimulates insulin secretion by the pancreas, delays gastric emptying and has other potentially useful properties for the treatment of diabetes. The native hormone is rapidly broken down by enzymes of the DPP-4 class, and thus has a very short half-life in the circulation. This can be prolonged by use of DPP-4 inhibitor tablets. Alternatively, GLP-1 analogues (molecules modified to be resistant to breakdown while retaining the biological actions of GLP-1) are also widely used. There is some controversy as to the safety of these agents.

New technologies

Although insulin deficiency (relative or absolute) affects all aspects of metabolism, clinical experience has shown that most - but not all - of the resulting metabolic abnormalities can be returned towards normal by correcting glucose levels, and that late complications of diabetes can be prevented or delayed by so doing. Glucose is thus a useful marker of metabolic status and a logical benchmark for treatment.

Newer technologies have aimed at better ways of insulin delivery, for example by pumps rather than injections, and investigators have explored other routes and modes of insulin delivery, for example into the portal (liver) circulation, as nature intended, rather than into the systemic circulation. A parallel quest has led to better and more accurate ways of providing feedback about changes in glucose levels, most recently obtained via implantable sensors. The ultimate dream of many investigators is to "close the loop"; i.e. link automated glucose measurement to automated insulin delivery. At present this is only achievable over short periods of time and at considerable expense, and there are still many challenges to be overcome.

Other possible ways of replacing insulin are described in Future prospects for the management of type 1 diabetes.

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