About Diabetes
The Story of Diabetes?
Diabetes is a disease known from ancient times. Ayurveda recognised twenty varieties of Prameha or disordered urination, one of which was Madhumeha or honey-urine. Sweetness of urine, weakness, boils, gangrene and drowsiness were described as features of Madhumeha in Ayurveda. Ayurveda had enlightened views on the diet of a person afflicted with diabetes. A restricted diet was recommended to fat patients, while a liberal diet was prescribed for the lean. References to a disease characterised by intense thirst and excessive and sweet urine are also found in ancient Egyptian, Chinese and Arabic medical works.
Araetius of Cappadocia (now in Central Turkey, 2nd Century C.E.) was the first European to give a fairly complete description of the disease. He named it diabetes, a term derived from a Greek word, diabetos, meaning a siphon, because in this malady fluids are not retained in the body. The word 'mellitus' meaning 'honeyed' was added by John Rollo, a British surgeon, in late eighteenth century.
Although it was known for centuries that the urine of a patient with diabetes was sweet, it was left to Mathew Dobson of Liverpool, to prove in 1766, that the sweetness was due to sugar. He evaporated the urine of a diabetic and obtained a white cake which he showed to be sugar. In another experiment, he took the blood of a diabetic and noted that the serum was sweet. He concluded that the sweet substance first appeared in the serum and later in the urine. Michele Chevreul, a French chemist, showed in 1815 that the sugar in diabetic urine was glucose or grape sugar.
In the eighteenth and the nineteenth centuries, many suggestions such as disorder cf kidney, stomach or nervous system, consumption of alcohol and fatigue, were put forward as the cause of diabetes. In 1788, Thomas Cawley reported a case of diabetes due to stones in pancreas or sweetbread. He made a remarkable suggestion that diabetes could occur due to damage to the pancreas.
The digestive function of the pancreas was studied by the middle of the nineteenth century. While studying the structure of the pancreas, Paul Langherhans, a twenty-one year old student, observed in 1869, some clusters of cells, which were subsequently named after him. Another important milestone in the study of diabetes, was an experiment conducted by Minkowski and Mering of Strassburg. In 1869, they observed that a dog became diabetic if its pancreas was completely removed. Minkowski later noted that the dog did not develop diabetes if a portion of the pancreas was left behind. He also observed that the pancreas of a dog shrivelled if its duct (a tube like structure carrying the digestive juice) was tied but such a dog did not develop diabetes. By the end of the nineteenth century, many research workers had suspected that the pancreas produced an internal secretion, which mixes directly with the blood and which is not carried by a tube. By 1920, many of them had come very close to isolating the suspected internal secretion of pancreas.
Life was miserable for people with diabetes before the discovery of insulin. Overweight middle aged diabetics could carry on with a markedly restricted diet. Young diabetics barely survived for a couple of years before finally succumbing to diabetic coma or some infection. A diabetic woman rarely conceived and if lucky to do so, often had a stillbirth. Surgery in a diabetic was disastrous.
Discovery of insulin
Discovery of insulin by Banting and Best ushered in a new era in medicine. (P1. I) In 1920, Frederick G Banting, a young Canadian orthopaedic surgeon came across an article by Dr. M. Barron on "The relation of islets of Langerhans to diabetes". Dr. Barron suggested that the secretion of the pancreas could be isolated if the experiments of Minkowski and Mering were carried further. Excited by this idea, Banting went to Toronto to seek the help of J. G. Macleod, the professor of Physiology. In the beginning, Macleod was not impressed with Banting's idea. After all, several research workers before Banting had tried to isolate the secretion and had failed. However, after some persuasion, Macleod allowed Banting to use his laboratory during the summer vacation of 1921. Banting did not have any background of chemistry. Charles Best, a twenty-one year old physiology student, chosen by a toss of coin, volunteered to help Banting in this venture. After reviewing the literature, they set out to experiment. Macleod, a recognised authority on carbohydrates, gave general guidance in this project.
In the beginning, they made dogs diabetic by removing their pancreas. In some dogs, they tied the duct of the pancreas and destroyed that part of the pancreas which produced its digestive juice. The remaining part of the pancreas contained the islets of Langerhans, which Banting and Best thought were producing the internal secretion. Subsequently they observed that prior tying up of the pancreatic duct was not necessary. They removed the pancreas, and ground it at a low temperature in an acidic solution.
On July 30, 1921, they injected this extract into a dog that was made diabetic and observed that its blood sugar dropped from 0.2 g. per cent to 0.12 g. per cent. Later they found that a larger dose of the extract brought down the blood sugar to a very low level. Since the extract was obtained from islets of Langerhans, Banting and Best named it "isletin". On November 14, 1921, Banting and Best reported their discovery to the Physiology Journal Club of the University of Toronto. The term "isletin" was later dropped in favour of the term, "insulin" coined by Macleod, who was not aware that de Mayer, had suggested, in 1909, the name. "insuline" for this hypothetical active principle. James Collip, a young research worker, joined the "isletin" team and lent his chemistry expertise. Banting and Macleod were jointly awarded the Nobel prize in 1923 for their discovery. Banting split his share of the prize with Best and Macleod with Collip.
The efficiency of insulin even in critically ill diabetics was soon established. The production of insulin on a large scale, difficult initially, was achieved by 1923. The original extract, a yellow liquid, had to be injected in the doses of five to ten ml. This resulted in sterile abscesses. Production of insulin was soon achieved with the help of Connaught Laboratories and Eli Lily and Company. The extract that was available then was in a crude form.
Different preparations of insulin
J.J.Abel, an American scientist, prepared crystalline insulin in 1926. Crystalline insulin produced less irritation at the site of injection than the original crude insulin, and it had a quick but shorter action. Hence, to control diabetes, two or three injections of crystalline insulin per day were necessary. In 1936, Hagedorn and others from Denmark reported that the action of insulin could be prolonged, if a small amount of protamine, a fish protein, was added to it. In 1937, Scott showed that an addition of zinc made this combination (protamine zinc insulin) more stable. Globin insulin and the neutral protamine Hagedorn (NPH or isophane) were introduced in 1939 and 1946 respectively. These preparations of insulin could give rise to allergic reactions because they contained a foreign protein. Other preparations of insulin namely, insulin zinc suspensions (semi lente, lente and ultra lente) were available by 1952. These insulin preparations did not contain a foreign protein and were less likely to produce allergic reactions than the earlier preparations.
The amino acid sequence of insulin was reported by F. Sanger in 1955 and the three dimensional structure of insulin by Dorothy Hodgkin in 1969. Both these British scientists were awarded Nobel Prize. The complete insulin molecule was synthesized from amino acids, by Chinese scientists, in Shanghai, in 1965.
The chemical structure of insulin of many animal species has now been established and pork insulin has been shown to be more akin to human insulin than bovine insulin. Contrary to popular misconception, human insulin is not obtained from cadavers. It is prepared by a bio engineering technique.
Berson and Yalow developed the technique of estimating very minute levels of insulin in the blood by using radioisotopes for which they were awarded Nobel prize. Yalow alone received the Nobel Prize because Berson predeceased the award ceremony.
Although relatively pure, the conventional insulin preparations still contained impurities like proinsulin (precursor of insulin) and peptides in minute quantities. Very pure insulins (monocomponent insulins) are now being prepared and marketed. The plastic disposable syringes were introduced in the eighties and the 'insulin pen' in 1981.
Insulin analogues (Link to __)
New Insulin Delivery Systems (Link to __)
Role of other endocrine glands
There are many glands in the body like the pituitary, thyroid, and adrenal whose secretions enter the blood stream and control diverse functions of the body. These glands are also concerned with the regulation of blood glucose level. Bernardo Houssay, the Nobel Prize winner from Argentina made a signal contribution to this field. He made animals diabetic by removing their pancreas. He then removed their pituitary gland and noted that their diabetes became very mild. In another experiment, he produced diabetes in animals by injecting a pituitary extract.
Oral drugs
Although insulin is a remarkably useful drug, it cannot be given orally. The search for an effective oral anti-diabetic drug has been going on from ancient times and still continues. Guanidines were tried in the first quarter of this century but were soon abandoned due to their toxicity. Biguanides, their successors are being used in certain diabetics. During the second world war, Janbon and his coworkers experimented with a sulphonamide during a typhus epidemic in war-torn France. They noticed that some patients who were given this drug developed coma and convulsions and died. Loubatieres, who was studying the efficacy of new compounds in diabetes, demonstrated the blood glucose lowering properties of sulphonamides. He showed that the drug stimulated pancreas to secrete insulin. He concluded that the deaths of typhus patients observed by Janbon were due to a marked drop in blood glucose. This line of investigations was taken up by many researchers from France and Germany after the Second World War. They showed that many drugs similar to the sulphonamides reduced blood sugar level by stimulating the pancreas to produce insulin. Since 1955, several drugs of THIs group have been studied and introduced in the treatment of diabetes. Although these oral anti-diabetic drugs and their successors have some important limitations, they have simplified the treatment in a vast number of diabetics.
Different national and international associations of lay diabetics, doctors and diabetes educators are making significant contributions in the field of diabetes. The rational treatment of diabetes would not have been possible without advances in other sciences like chemistry, physics, physiology etc. The diabetic owes his well-being and indeed his life to the efforts of scientists all over the world. It is therefore the duty of every diabetic to support research in diabetes so that the life of a diabetic becomes more comfortable and a complete cure of this disease becomes possible one day.