Insulin: History of a Discovery

Insulin is a hormone that is secreted by pancreas (beta cells). It is made of two polypeptide chains - A and V. Chain A contains 21, and chain V of 30 amino-acids. Polypeptide chains are connected by sulphur links. The main affect of insulin is lowering blood sugar level. Increasing of the glucose level in blood, over the certain level, is a trigger for secreting of insulin. After, insulin accelerates entering of glucose from the blood into the cells of muscles and fat and its further resolution. To explain this more colourfully, glucose in blood searches for the key insulin, so it could bring it along and unlock the door of a cell. This way glucose enters into the cell and is being transformed into the energy. If not, then glucose travels around the body being carried by blood. This way, a cell does not get any energy, sugar level in blood gets higher and causes damages of kidneys (glycosuria), eyes (retinopathy), and nerve-endings (polyneuropathy).

Until the early 1920s a diagnosis of diabetes mellitus amounted to a death sentence. But then a young doctor in Toronto discovered something unusual - the beginning of a success story. Dr. Robin Lawrence knew his time had come: a colleague's diagnosis gave the English doctor a few months to live. He began to plan a journey through Europe as a farewell to this world. The diagnosis that was Lawrence's death sentence was diabetes mellitus. The year was l92l. A quarter of a century later (!), Lawrence spoke at a conference held in honour of an astonishing discovery made in that year, a discovery had saved his life and of millions of others: insulin. That year, l92l, witnessed one of the greatest revolutions in the history of medicine. The discovery of insulin initiated a new era in non-operative medicine and gave fresh hope to many patients. It was breakthrough in the battle against a condition that had long plagued humanity - a battle that doctors of many different cultures had fought in vain for more than 3000 years. Some 1500 years B.C., the Egyptian Ebers Papyrus described a condition that was very likely diabetes. The main symptom, a massive increase in urination, is an unmistakable symptom of the condition, from which is derived its name. The Greek word diabetes means "to pass through" and alludes to the passing of liquids through the body - an insatiable thirst accompanied by polyuria. Around 150 A.D., Aretaeus of Cappadocia set down a remarkably accurate description of the condition: "Diabetes is a strange and not very

common affliction. It consists of a cold, damp transformation of the body into urine, not unlike dropsy. Urination occurs through the usual channels the kidneys and bladder. The patient cannot stop urinating. The illness is chronic, yet the patient does not survive long, for once the disease has broken out in full force, rapid consumption and death soon ensues." To waste away and die - this was to be the fate of people with diabetes for centuries to come. The role of glucose in the pathogenesis of diabetes was fully understood in Europe only in the modern age although an Indian document refers to patients' ''honey-sweet urine" as early as the 4th century B.C. In 1614, Thomas Willis, personal physician to Charles II, also noted the sweet taste of diabetic urine - it was an age in which doctors literally made use of all their senses in the service of diagnosis and medical research. It was not until 1889 that the organ that is the seat of the condition was finally identified. In that year, German research scientists Josef von Mering and Oskar Minkowski observed that removing the pancreas from dogs immediately caused them to develop diabetes. And, scientists saw no connection between this observation and a discovery described by a certain Paul Langerhans in his doctoral dissertation in 1869 the existence in the pancreatic tissue of small, isolated structures, later to be called the islets of Langerhans. Medical science was still a long way from developing an effective treatment for diabetes. The usual therapy was a "starvation diet" of often less than 500 calories per day. This prevented the patient from falling into a diabetic coma and added a few months to his or her life, but was this stay of execution, during which the patient was reduced to a skeleton, plagued by infections, and sunk in lethargy, really a blessing? At the beginning of the 20th century, a new concept entered medical terminology: hormones. It was discovered that a range of organs, whose significance had hitherto been underestimated, secreted powerful substances that decisively influenced essential bodily functions such as metabolism and reproduction and that a reduction or total cessation of this activity generated familiar pathological symptoms. Could it be that the pancreas was such an endocrine gland, and that diabetes was thus a hormonal condition? The answer to this question was found neither in the classical centres of medical learning in the Old World, nor in the burgeoning research centres of the United States. In November I920, a young doctor by the name of Frederick G. Banting asked the director of the Institute of Physiology at the University Of Toronto, Canada, J. J. R. Macleod, for permission to start a new research project. Banting set out to identify in the pancreas that controls the metabolism of glucose and lack of which leads to high blood sugar levels and glycosuria in people with diabetes. Macleod gave Banting and his colleagues, Charles Best and Clark

Noble, a laboratory in which they carried out a series of experiments on dogs. In July l92l, they injected the first dose of an extract of islets of Langerhans into a diabetic laboratory animal. The test was disappointing: after adding a slight drop in blood, sugar level became higher, soon the dog fell into a coma and died. However, as the process of obtaining the extract was refined, results began to improve. On December 30th 1921, the research team, now joined by biochemist James B. Collip, first reported its findings to a scientific colloquium the response was muted, even sceptical. This was to change on January 11th 1922, the day that Banting and Best, together with the patient's physician, administered an intramuscular injection of the extract to 14-year-old Leonhard Thompson. The latter had been subjected to the usual diet for people with diabetes and was on the brink of coma. On this occasion, too, the results were initially not very encouraging. However, within days Collip succeeded in preparing an even purer form of the as yet unnamed extract, which was administered to the patient on January 23rd. Within hours, Thompson's urine was free of sugar and his blood sugar level had fallen from 520 mg/dl to 120mg/dl close to normal. It was an epochal event: for the first time, a case of diabetes had been successfully treated by pharmacological means. The Canadian researchers named the extract "isletin," but it soon changed to "insulin" as news of its success spread around the world. The next time the Toronto team must reported on its findings to colleagues at a conference in Washington in May 1922 the reaction was entirely different: the Canadians were given a standing ovation. Practically overnight, Banting, Best and the colleagues were inundated with request for help. The case of Elisabeth Hughes, the daughter of the U.S. secretary of state, whose life was saved by the new substance, made headlines and largely instrumental in assuring insulins worldwide reputation. With the help of the pharmaceutical industry, it rapidly became possible to produce insulin in large quantities and thus meet the enormous demand for the new miracle drug. However, the breakthrough made by Banting and his colleagues was only the beginning of a long road that was to lead to insulin formulations with different effects, such as the longer-acting insulin developed by the Danish research scientist Hans C. Hagedorn. A further milestone in diabetes research was the deciphering of the insulin molecule by the English biochemist Frederick Sanger, who demonstrated that it consists of two chains of 30 and 21 amino acids respectively, held together by bridges of sulphur atoms. Frederick Sanger received the 1958 Nobel Prize for Chemistry for his work. The first successful insulin preparations came from cows (and later pigs). The pancreatic islets and the insulin protein contained within them were isolated from animals

slaughtered for food in a similar but more complex fashion than was used by our doctor and med-student duo. The bovine (cow) and porcine (pig) insulin were purified, bottled, and sold. In the 1980s, technology had advanced to the point where we could make human insulin. The advantage would be that human insulin would have a much lower chance of inducing a reaction because it is not a foreign protein all humans have the exact same insulin, so we do not "see" this as a foreign protein. The technology which made this approach possible was the development of recombinant DNA techniques. In simple terms, the human gene which codes for the insulin protein was cloned (copied) and then put inside of bacteria. A number of tricks were performed on this gene to make the bacteria want to use it to constantly make insulin. Big vats of bacteria now make tons of human insulin. From this, pharmaceutical companies can isolate pure human insulin. There are many forms of insulin to treat diabetes. They are classified by how fast they start to work and how long their effects last. The types of insulin are: rapidacting, short-acting, intermediate-acting, long-acting and pre-mixed.

The last three of four decades have brought a number of rapid developments in the treatment of diabetes. Beside technological improvements in methods allowing patients to control their blood sugar levels themselves, today a broad range of insulin is available, permitting doctors to fine tune courses of treatment to suit their patients clinical profiles. Todays methods of administering insulin are also many and varied. Instead of a syringe, many patients now use an insulin pump attached to a catheter inserted into the subcutaneous fat of the upper abdomen. Others prefer an insulin pen: very much like a fountain pen in appearance. This device permits a measured dose of the hormone to be administered almost painlessly through an extremely thin needle. And no longer must be the dreaded deterioration of capillary vessels that accompanies diabetes inexorably lead to irreparable damage to nerveends, kidneys and eyes.

Sources: Future The Aventis Magazine 3/2002; pgs 46 49, www.endocrineweb.com/conditions/diabetes/diabetes-what-insulin www.diabetes.webmd.com/diabetes-types-insulin