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The Nobel Prize in Physiology and Medicine in 1923 for the discovery of insulin in 1921 was awarded to Frederick G. Banting and John J.R. MacLeod. This choice was highly debated: Banting decided to share his part of the prize with his younger co-worker Charles H. Best, and MacLeod, too, decided to share his part with biochemist James B. Collip. Although previous investigators such as Nicolas C. Paulesco, had obtained some positive results isolating "the internal secretion" of the pancreas, only the group in Toronto succeeded in proving consistently the efficacy of their insulin extracts. Banting had the idea of isolating insulin after reading an article in a medical journal. He received support for his proposed research at the University of Toronto, under the direction of John J.R. MacLeod and was assisted by Charles H. Best, a medical student. Banting's and Best's initial experiments were not definitive, but their apparently favorable results encouraged greater efforts that, with the important contribution of biochemist James B. Collip who has hardly ever been associated with this event, culminated in the discovery of insulin.

Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being studied in type 1 diabetes prevention with promising results.

The discovery of the insulin which took place at Toronto, Canada in 1921-22 is one of the most important medical discoveries of the modern age. For this miracle, Prof. John James Macleod and Frederic Grant Banting were Jointly awarded the Nobel Prize in 1923 for Physiology or Medicine. Frederick Sanger a British biochemist discovered the structure of insulin in 1958 and was awarded Nobel prize for chemistry. Diabetes mellitus is called Madhumeha in ancient Indian Ayurvedic medicine. Egyptians and Greeks knew about it. Greek physician Aretaeus of Capadocia first suggested the term "Diabetes" and described it. Though insulin was discovered about 80 years ago research interest in it still continues unabated. This paper also gives case details of the first patient on whom Insulin was first tried and chronology of research on pancreas and Insulin.

This paper shows that the linkage between basic science and clinical research has characterized the field of sulfur amino acid metabolism since 1810, when Wollaston isolated cystine from a human bladder stone. The nature and consequences of this relationship are discussed.

Rudolf Karl Freudenberg was Physician Superintendent at Netherne Hospital, Couldsdon, Surrey from 1951 to 1973. In his work as superintendent and government adviser he made important contributions to mental hospital reform and to the establishment of community psychiatric services in Britain. Earlier, in Vienna and following emigration to Britain, he was one of the pioneers of insulin coma treatment with a series of publications on this topic. The paper gives an account of published papers of both phases, and it highlights the background to Freudenberg's shift in professional interest from physical to social intervention. It argues that the change of emphasis reflects important general trends, i.e. profound change due to new forms of physical treatment on the one hand and similarly convincing evidence of the impact of social factors on clinical course and outcome on the other hand.

This paper is an autobiographical study of the author's early work on the chemical cross-linking of proteins as well as on oligomer and peptide synthesis from 1949 in Heidelberg until the synthesis of insulin in 1963 in Aachen.

After the two Canadian researchers, Banting and Best, had succeeded in extracting the pancreatic hormone, insulin, from bovine pancreatic tissue in 1921, August and Marie Krogh brought insulin to Denmark on 12 December 1922. With H.C. Hagedorn, who at the time was senior registrar in the III Department of Kobenhavns Kommunehospital (Copenhagen Municipal Hospital), August Krogh immediately began experiments to produce insulin, and already on 21 December, they succeeded in isolating a small amount of insulin from a bovine pancreas. August Kongsted, owner of Lovens Kemiske Fabrik (Leo Chemical Factory), paid the expenses for the experiments and afterwards helped to start the production of >>Insulin Leo<<. At the start, there was not enough insulin to treat all the diabetics in Denmark, and since Hagedorn was employed in the III Department of Kobenhavns Kommunehospital, this department was the first that had insulin at its disposal. Krogh made it clear that it would probably take several months, maybe even a year, before insulin would be available for all the diabetics in the country. The II Department of Kobenhavn Kommunehospital could not accept this, and as early as May 1923, this department began to treat diabetics with Diasulin Medicinalco, a pancreatic hormone preparation manufactured by H. L. Gad Andresen at Det Danske Medicinal- og Kemikalie-Kompagni (Danish Medicine and Chemical Company). Later Det Danske Medicinal- og Kemikalie-Kompagni began to sell Diasulin under the name Isulin Medicinalco.

Henry Dale, a Nobel laureate and statesman of science, helped to organize the meetings in 1923 and 1925 to set up international standards for insulin and other biologicals. He made the National Institute for Medical Research one of the two world centres for standards. Some milestones in the work of the London centre are described: (i) the first standards; (ii) vitamins and hormones; (iii) WHO standards for many antibiotics; (iv) the provision of an international working standard for ACTH; (v) the old and new methods of ampouling; (vi) the impact of research and immunoassay on the need for standards; and (vii) the special ECBS sessions for endocrinology and haematology. Dale tells how he had to preserve the first batch of insulin for use as the standard instead of for treatment.

Dr Peter Jones gave the 1997 R.D. Lawrence Lecture to the Medical and Scientific Section of the British Diabetic Association. This prestigious award, made to an outstanding young researcher, is named in honour of the man who, with H.G. Wells, founded the British Diabetic Association, and was given to Dr Jones in acknowledgment of his work in the field of islet cell physiology and pathophysiology. In this article, Dr Jones recalls his lecture and describes the principles of intracellular signalling in insulin secretion and the need for beta-cells to live together.

Since the discovery and isolation of insulin in 1921, many advances in diabetes research and management have been made. Funda Suleyman charts the successes over the years.

This year, 1998, marks the 75th anniversary of the general availability of insulin in the United Kingdom. To mark the occasion, Diabetic Medicine publishes this account of the early days of insulin therapy in one of Britain's district general hospitals, Hereford General Hospital. The authors describe the first tentative use of insulin and draw some interesting parallels with the issues which still concern the introduction of novel therapies in endocrinology today.

Since its inception in 1898 the American Journal of Physiology has been a leader in diabetes research and has published many key articles on the subject. The Journal first published studies of phlorhizin-induced diabetes in 1898, and after many other contributions went on to publish the first reports of Banting, Best, Macleod, and Collip in 1922 concerning the isolation and purification of insulin (5-8, 13). This review highlights some of these key contributions of the Journal.

Recent research on the role of classical conditioning in homeostatic regulation (Dworkin, 1993; Siegel, Krank & Hinson, 1987) has underscored the potential importance of the work of earlier Eastern-European work on physiological conditioning. The present article is a translation and discussion of a paper on blood glucose conditioning, first published in 1954 by the Russian physiologist M.I. Mityushov. Mityushov was able to demonstrate conditioned hypoglycemia in humans and dogs after using an injection procedure as the CS and intravenous glucose as the UCS. The translation is preceded by a general introduction and followed by a reanalysis and discussion of Mityushov's results.

It is suggested that some 16 million Americans have diabetes, although about only one-half of them are diagnosed. Type I or IDDM diabetics must take insulin in some form to maintain their life. A larger number of Americans have Type II or NIDDM, and many can be treated with a combination of diet and exercise. Many of the Type II diabetics will need to take oral medications at some point in their life and a somewhat smaller number may find that they must use insulin injections if they are to maintain good control of their diabetes. This article describes the historical events leading up to the present therapeutic options for both Type I and Type II diabetics. Also included is a list of drugs that are in the research phase at the present time as well as a list of internet sites where the practitioner and patient alike can keep up to date on new developments in the treatment of diabetes.

When a medical problem is studied intensively by several investigators in the world, a solution may sometimes be found simultaneously in different countries. Seventy-five years after the discovery of insulin, the chronology of this event can be reconsidered objectively and the role of each of the protagonists evaluated. The stubbornness of Banting and Best, the technical abilities of Collip and the active support of Macleod were determinant in the use of insulin for the treatment of diabetic patients. Moreover, in the long line of experimentalists and physicians, Lancereaux and Paulesco also deserve special mention.

The most celebrated medical discovery of this century is comprised of two distinct stages: (1) that of fundamental research, i.e. the experimental demonstration of the presence in the pancreas of an antidiabetic hormone done by Paulescu and published on 31 August 1921 in the Archives Internationales de Physiologie; and (2) the clinical application of the discovery of insulin in the treatment of diabetes in man, the stage completed in 1922 by the Canadian group comprised of Collip, Macleod, Banting and Best.

The world observes the 75th anniversary of the landmark discovery of insulin this year, a medical miracle that bears a large "made-in-Canada" stamp. CMAJ played a part in this story by publishing preliminary results of the first clinical trial on a human in March 1922. November is Diabetes Month, and to mark World Diabetes Day on Nov. 14 CMAJ once again heralds the accomplishment of the four discoverers of insulin.