By Dr Ananya Mandal, MD
Diabetes mellitus has been known to physicians since ancient times. Early Indian literature in the 6th century BCE and in ancient Egyptian papyrus references to this condition of high blood sugar has been found.
Greek physician Areteus of the Imperial Roman province of Cappadocia, in now Turkey, first described the classic case of diabetes mellitus. It was Persian physician known to the West as Avicenna who noted that diabetics were two distinct groups of individuals - thin, younger, or more obese, older persons.
Role of the pancreas
It was in 1869 Paul Langerhans, a medical student in Berlin found clumps of cells in the pancreas. These were later called ''Islets of Langerhans''. Edouard Laguesse later suggested that they might produce secretions that play a regulatory role in digestion. The term ''insulin'' origins from ''Insel'', the German word for islet or small island.
In 1889, German physiologist Oscar Minkowski and his colleague Professor Von Mering at the University of Strassburg investigated the role of the pancreas and to further investigate the role of the pancreas they performed a pancreatectomy on a dog. They found that the dog passed copious amounts of urine. The urine was found to be loaded with sugar and the dog was diabetic.
The researchers found that the pancreas delivers digestive enzymes by a duct into the gastrointestinal tract and also contains clumps of cells known as Islets of Langerhans. Their function is to produce insulin and deliver it directly into the blood stream.
The next step in the discovery of insulin was by Dr Frederick Allen, an American physician in the early part of the 20th century. Allen performed a 90% pancreatectomy in which case the dog became diabetic but did not die immediately and was a much more realistic model of insulin dependent diabetes in the human. He also noted that if the dog was given a low calorie diet, it had a significantly prolonged life.
Pancreatic extract in treatment of diabetes
Based on earlier experiments Dr Georg Zeulzer, a Berlin researcher, even got as far as registering a patent in the United States for a pancreatic extract said to be suitable for the treatment of diabetes. The extract was found to be too toxic for clinical use as it also contained the digestive enzymes.
Discovery of insulin
In 1921, the Canadian scientists Fredrick G. Banting, Charles H. Best, J.J.R. Macleod and James B. Collip discovered insulin. They found insulin to be a small protein which lowers blood sugar. They extracted insulin from the islets of animal pancreases. The researchers gave the patent rights to the University of Toronto so that diabetics worldwide could utilize the benefits of insulin.
In 1923 Banting and Macleod were awarded the Nobel Prize. Banting was a bit unhappy about dividing the prize with Macleod and announced that he would share his with Best. Macleod shared his with Collip.
First Diabetics on Insulin
In January 1922, bovine insulin was ﬁrst given to humans by injection. It was still so impure that as a result of the ﬁrst insulin injection Leonard Thompson had a 7.5 cm callus or lesion at the injection site on his left buttock. James Collip, continued their work to purify the insulin extract to make it safer and more effective.
Elizabeth Hughes, one of the ﬁrst diabetics to be treated with insulin also developed insulin related hypoglycaemia. She also suffered pain and swelling at the injection site, especially when large quantities of insulin were injected.
Animal to human insulin
After initial success in 1936, protamine, a low-weight protein, was used to develop a slow-release insulin. Protamine and zinc enabled slow-acting insulin. Protamine zinc insulin (PZI) was an insulin whose effect lasted for 24–36 hours.
In 1950, isophane NPH (neutral protamine Hagedorn) insulin was made. This was also bound to protamine. It has a maximal effect of 24 h and can be mixed with any proportion of fast-acting regular insulin.
In 1951, the amorphous ‘lente’ insulins (IZS) – semilente, lente and ultralente – were developed. The proportion of zinc in the preparation changed the duration, onset and peak action. In 1956, the ﬁrst antidiabetic oral drugs or pills (Sulfonamides such as tolbutamide, carbutamide and biguanide derivatives such as metformin, phenformin) – came to the market.
In 1974, chromatographic puriﬁcation techniques were developed to manufacture highly puriﬁed animal insulin (less than 1 pmol/l of protein impurities). Between 1963 and 1966 German researchers Meienhofer et al first synthesized human insulin chemically in laboratories. In 1975, fully synthetic insulin was synthesized in the laboratories of Ciba-Geigy in Basel.
In 1978, scientists from the biotechnology corporation Genentech in San Francisco, Calif., succeeded in using a genetically modified plasmid of E. coli bacteria to synthesize insulin. This was called the Recombinant DNA technology that is still being used today.
Reviewed by April Cashin-Garbutt, BA Hons (Cantab)