Diabetes Mellitus. History of the Discovery of the Disease

The disorder called diabetes mellitus, translated from the Greek, means ‘‘flow of urine like honey.’’ In the second century AD Aretaeus the Cappadocian (or more likely one of his assistants) made the diagnosis by dipping a finger in urine and tasting the sweetness. By 1889 Josef von Mering had shown that diabetes could be produced in animals by removing the pancreas. It was known that the pancreas secreted a substance into the duodenum that was essential for absorption of food.

Additionally, it was postulated that the pancreas had a function related to glucose control. By 1916 the substance that the pancreas released into the blood stream and that was central to control of blood glucose levels was named insulin although it had never been isolated. Frederick Banting and Charles Best were the first to produce a pancreatic extract that lowered blood sugar in 1922, and they received a well-deserved Nobel Prize for their discovery.

The first patient to be treated was a 14-year-old girl in Toronto. Prior to this, what we now call type I diabetes had a mortality rate of 100 percent within two years. Few would dispute that the discovery of insulin was one of the outstanding achievements of the twentieth century.

Insulin is a pancreatic hormone that facilitates the uptake and metabolism of glucose from the blood into muscle where it is essential for energy requirements. Without insulin, blood sugar levels rise, and fat has to be used to supply the body’s energy requirements. The end products of fat metabolism are highly acidic, and when the blood becomes acidic, coma and death ensue.

The original pancreatic extracts were crude and short acting, and they contained many impurities. Insulin was crystallized in 1926, and in the 1930s it was combined with zinc, protamine, or globin in various proportions to achieve different lengths of action. Protein purification procedures were developed in the late 1960s to produce monocomponent insulins.

Between 1951 and 1971 Frederick Sanger and Dorothy C. Hodgkin worked on determining the structure of insulin, and their work laid the foundation for the next major development. A report in 1978 of an anticipated shortage of animal insulin led to the development of synthesized human insulin. The two ways of doing this were either by enzymatic conversion of porcine insulin or by recombinant DNA technology.

Human genes are synthesized for the insulin molecules A or B chains then joined by recombinant methods with sequences coding for ß-galactosidase. Plasmids containing the modified genes are inserted into a special strain of the bacteria E. Coli, which after fermentation produce the insulin that is cleaved from the bacterial proteins and purified. Both these techniques produced a peptide indistinguishable from pancreatic human insulin.

By the late 1980s, completely synthetic insulins were available that were characterized by manipulation of the insulin molecule to modify its pharmacokinetics (speed of onset and duration of action). These products were termed insulin analogs (1992) and could equally well be described as ‘‘designer’’ insulins.

A series of studies in the 1980s showed that tight control reduced the microvascular complications of diabetes. Thus, physicians were at last able to achieve good 24-hour control of blood sugar levels by using different types of insulin and multiple injection techniques to mimic the normal pattern of insulin secretion according to the patient’s eating, sleeping, and exercise habits.

The treatment of type II diabetes (which afflicts older, overweight people) was difficult because of insulin resistance, a key feature of this type of diabetes, which made injected insulin less satisfactory. In 1942, during a typhoid epidemic in occupied Europe, researchers in a trial for a new compound of the sulfonamides (antimicrobial agents introduced in the 1930s) noted severe hypoglycemia (low blood sugar) in the subjects.

The sulfonylurea group of drugs, which stimulate the pancreas to produce more insulin, were the result of further research; examples include tolbutamide, glibenclamide, and gliclizide. The digua- nides were rather more physiological; their mode of action was to increase glucose uptake, but they were not free of side effects.

The thiazolidinediones, introduced in 1996 (rosiglitazone and pioglitazone), also reduce insulin resistance and increase the uptake of insulin from the blood into the cells. As with the diguanides, this is a more physiological approach. By 2000 they had not been in use long enough to be assessed.

The first successful pancreas transplant was performed in 1967 by Dr. Richard C. Lillehei at the University of Minnesota, and is now usually performed at the same time as a kidney transplant for Type I diabetes patients with severe complications. Islet cell transplants are still experimental, although pig islet cells have been transplanted into immunodeficient mice and dogs, with rejection prevented by immune-suppressing drugs.

At the end of the twentieth century, diabetes was the prime example of self-management of a serious disease. Patients inject themselves with insulin, using disposable ‘‘dial-a-dose’’ syringes. They determine the dose by measuring their own blood glucose levels. This can be done by using a spring-loaded lancet to prick the finger and produce a drop of blood that is applied to a strip impregnated with a reagent area containing glucose oxidase.

The resulting color change is measured by a small reflectance meter. This gives a blood sugar reading in millimoles per liter within 15 seconds. When these systems were introduced in 1978, there was some skepticism as to whether patients could cope, but they have proved highly adaptable with even five-year-olds rapidly becoming competent in measuring their sugar levels and taking the appropriate dose of insulin. Later developments included digital devices that were even easier to use.

The decrease in the complications of diabetes during the century has been due to several therapeutic advances. Renal damage and hypertension (high blood pressure) have been reduced by the use of the angiotensin-converting enzyme (ACE) inhibitors, which are effective in protecting the kidney and controlling blood pressure and thereby further reducing the risk of heart disease.

Until the 1980s renal dialysis was not considered an appropriate treatment for the kidney failure of diabetics, but, fortunately, that rigid and inflexible attitude no longer applies. Erectile failure is a problem for diabetics, but even the U.K. government accepted that diabetics were allowed to have sildenafil (Viagra), which enhances penile blood flow, on National Health Service prescriptions. Laser photocoagulation of diabetic retinopathy was introduced in 1984.

As a result of retinal screening and laser treatment, blindness is now rare in diabetic clinics. Finally, the pioneering work of D. Hockaday and K.G. Alberti in 1972 pointed to a physiological approach to diabetic coma using frequent very low doses of insulin, and mortality was reduced drastically.