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A fast development in therapy with insulin was observed after its discovery. Besides the widely used human regular insulin preparations, nowadays ultrashort and long-acting insulin analogues are also available for the patients. At present, the results of large clinical trials enable an evidence based diabetes care. It is well documented, that near-normoglycemia should be achieved by intensive conservative insulin treatment or pump therapy in type 1 diabetic patients. The beneficial effects of the good metabolic control could also be observed years later concerning late specific complications of diabetes. Similarly, as good as possible metabolic control should be aimed with antidiabetic treatment including insulin, if necessary, in type 2 diabetic patients. It is documented that the risk of cardiovascular complications is not increased in type 2 diabetic patients treated with insulin. Hypoglycemia and weight gain are the most important side effects of the insulin treatment. Recently, evidence based recommendations for treatment with ultrashort (insulin lispro, insulin aspart) and long-acting insulin analogues (glargine) can also be determined.

The discovery of insulin remains the greatest and one of the most controversial events in the history of endocrinology. Hypotheses about the possible existence of an internal secretion of the pancreas date from the early 1890s and were steadily modified with the development of the concept of an endocrine system. In the spring of 1922, after many false starts and dead ends, a team of researchers at the University of Toronto provided conclusive evidence of the existence of the internal secretion of insulin. The discovery process was fraught with personal and scientific rivalries more striking than fiction. The early use of insulin on starved, dying diabetic children awed everyone involved in the process. With the discovery of insulin, endocrinology moved into the mainstream of medical science., ((c) 2005 S. Karger AG, Basel.)

This article concerns the events in Toronto during June 1921 that led to the discovery of insulin and the controversy that followed. It draws attention to the hitherto unnoticed participation of E. C. Noble in the early lab work on dog 386 between 17 June and 26 June 1921. None of the accounts of the discovery of insulin written by the principal discoverers, Frederick Banting, Charles Best, J. B. Collip, and J. J. R. Macleod, acknowledge Noble's participation in the lab. The fact of his participation has several implications worth noting, as they refine the history of the discovery of insulin-not the least of which is the demonstration of his credentials as a reliable witness to the lab environment in which the first successes were achieved. He remains the only participant in the discovery whose account of the insulin project has not been published; this article includes Noble's anniversary account of 1971.

In 1936, Kimmelstiel and Wilson described the nodular glomerulosclerosis in patients with diabetes mellitus on insulin treatment. The nodular glomerulosclerosis is referred to as diabetic nephropathy. Fifteen years earlier insulin was discovered. This discovery at the University of Toronto (Canada) in 1921-22 by Banting, Macleod, Best and Collip was one of the most dramatic events in the history of the treatment of the disease. The impact of insulin was so sensational because of the incredible effect it had on diabetic patients. Those who first watched starved, sometimes comatose, diabetics receive insulin and return to life witnessed one of the genuine miracles of modern medicine. The discovery has became the "elixir of life" for millions of human beings around the world. Insulin had not emerged out of a vacuum but was the culmination of years of work by dozens of scientists in many countries. The Canadian scientists were the first to succeed in isolating insulin. Their work, however, was accurately constructed to confirm the ideas of earlier researchers, such as Murray, Paulesco, Allen, Minkowski, Derwitt, Zuelzer. These men, in addition to Banting, Macleod, Best and Collip, knew they were making medical history but paradoxically, with their "elixir of life" they allowed some complications of diabetes to emerge. Diabetic nephropathy was one of them. The struggle of the "Toronto quartet" for credit was inspired by man's desire to have a place in history, to have a sort of immortality open to him, an aspiration that is certainly legitimate. But perhaps the Canadian group misjudged both their situation and posterity's point of view. They probably failed to consider the unintentional effect of insulin treatment: diabetic nephropathy as a consequence of adding years to a diabetic's life.

Following on from the first article in this series (Vol 12(18): 1091-5), which described the history of diabetes, this article, the second of three literature reviews, explores the early production and development of insulin, from its initial production in a university laboratory to becoming a major pharmaceutical product. Also discussed are the various forms of insulin developed over the last 80 years and their means of delivery to the patient. The future is considered and the development of insulin analogues (substances that mimic the effect of human insulin) is described. The article also looks at the introduction of DAFNE (dose adjustment for normal eating) - an intensive programme of education aimed at teaching individuals the necessary skills to adjust their own insulin injection dosage to reflect their individual eating patterns.

This article, the first of a three-part series, gives a historical account of events for diabetes, dating from antiquity and its first recording in the Ebers Papyrus--an Egyptian document circa 1500 BC. This article describes initial thoughts that diabetes was linked to an alimentary complaint, and concludes with the discovery of it being a chronic systemic disease. It highlights the discoveries and also includes details of the failed attempts to locate the cause and identify a solution to the ancient mysterious disease which became known to all as diabetes mellitus. Early remedies and treatments are included. The article tells how for many centuries individuals suffered from the debilitating complaint with very little offered in terms of treatment or relief. Eventually the pancreas was identified as the causative organ and, some time later, animal experimentation resulted in the abstraction of the substance insulin. The article concludes with Frederick Banting and John Macleod being awarded the Nobel Prize in 1923 for their revolutionary discovery of insulin.

There are no established conventions for portraying scientific women. At the Royal Society, the first image of a female scientist was Henry Moore's drawing of Dorothy Hodgkin's hands, cruelly twisted by agonising arthritis. In her famous oil portrait, Maggi Hambling also focuses on Hodgkin's hands, thus symbolising the Nobel-prize winner's dedication to research and the importance of manual dexterity. Although Hambling's picture features a model of insulin, it is very different from photographs celebrating the discovery of DNA.

The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan. Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed. 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada. The preparations were raw extracts of bovine or porcine pancreas. These did not prevail widely in Japan because of the low incidence of DM before World Wan II. After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production. Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001). Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared. Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively. These were also adopted for JP7 (1961). Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965. Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy. Insulin from animal origin has been supplied for almost 60 years since its discovery. Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates. Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method. Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year. Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes. Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol. These anti-DM drugs were recently studied and developed in Japan. 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002. DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2). Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life. Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy. DM patients with complications should have a therapy devised to match their circumstances. 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000. The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970. The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations. The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy. The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded. The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM. The effect of drug therapy on all of the death resulting from DM is not detected. Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan. This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it. These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM. It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.

Clark Noble was one of the first members of the University of Toronto insulin team and came within a coin toss of replacing Charles Best as Frederick Banting's assistant during the summer of 1921. Noble performed important early studies helping to characterize insulin's action, and he co-authored many of the original papers describing insulin. Because mass production of insulin from livestock pancreata had proved elusive throughout 1922, J.J.R. Macleod hired Noble during the summer of 1923 to help him test and develop a new method for producing commercial quantities of insulin that Macleod believed would revolutionize insulin production. However, commercial production of insulin from fish proved impractical and was dropped by 1924, as methods to produce large quantities of mammalian insulin had improved very rapidly. Noble later played a small but critical role in the most important Canadian contribution to cancer chemotherapy research: the discovery of vinca alkaloids by his brother Robert Laing Noble. Although one might expect that a physician involved in 2 of Canada's most important medical discoveries during the 20th century must be famous, such was not Clark Noble's fate. He died without so much as an obituary in CMAJ.

During the first two decades of the 20th century, several investigators prepared extracts of pancreas that were often successful in lowering blood sugar and reducing glycosuria in test animals. However, they were unable to remove impurities, and toxic reactions prevented its use in humans with diabetes. In the spring of 1921, Frederick G. Banting, a young Ontario orthopedic surgeon, was given laboratory space by J.J.R. Macleod, the head of physiology at the University of Toronto, to investigate the function of the pancreatic islets. A student assistant, Charles Best, and an allotment of dogs were provided to test Banting's hypothesis that ligation of the pancreatic ducts before extraction of the pancreas, destroys the enzyme-secreting parts, whereas the islets of Langerhans, which were believed to produce an internal secretion regulating sugar metabolism, remained intact. He believed that earlier failures were attributable to the destructive action of trypsin. The name "insuline" had been introduced in 1909 for this hypothetic substance. Their experiments produced an extract of pancreas that reduced the hyperglycemia and glycosuria in dogs made diabetic by the removal of their pancreases. They next developed a procedure for extraction from the entire pancreas without the need for duct ligation. This extract, now made from whole beef pancreas, was successful for treating humans with diabetes. Facilitating their success was a development in clinical chemistry that allowed blood sugar to be frequently and accurately determined in small volumes of blood. Success with purification was largely the work of J.B. Collip. Yield and standardization were improved by cooperation with Eli Lilly and Company. When the Nobel Prize was awarded to Banting and Macleod for the discovery of insulin, it aggravated the contentious relationship that had developed between them during the course of the investigation. Banting was outraged that Macleod and not Best had been selected, and he briefly threatened to refuse the award. He immediately announced that he was giving one-half of his share of the prize money to Best and publicly acknowledged Best's contribution to the discovery of insulin. Macleod followed suit and gave one-half of his money award to Collip. Years later, the official history of the Nobel Committee admitted that Best should have been awarded a share of the prize.

Over the past 30 years, a considerable body of evidence has revealed that a prior bout of exercise can increase the ability of insulin to stimulate glucose transport and glycogen synthesis in skeletal muscle. Apart from its clinical implications, this work has led to a considerable effort to determine at a molecular level how exercise causes this effect and, in particular, whether it does so by enhancing specific events in the insulin-signaling cascade. The objective of this review is to discuss from a historical perspective how our current thinking in this area has evolved and the people responsible for it. Areas to be discussed include the effect or lack of effect of prior exercise on the insulin-signaling pathway, effects of exercise on the regulation by insulin of the GLUT-4 glucose transporter in muscle, and the emerging role of AMP-activated protein kinase as a mediator of exercise-induced signaling events. In addition, we will discuss briefly some of the avenues that research in this area is likely to follow.

George Hoyot Whipple (1878-1976) was awarded the Nobel Prize in Physiology and Medicine in 1934, along with Minot and Murphy for their studies in pernicious anemia. Whipple's name has been given to the bacterial disease which he describes in 1907 that we know today as Whipple's disease or intestinal lipodystrophy. He gave the name of thalasemia to the Mediterranean anemia of Cooley, and made diverse contributions to hematology and general pathology. He worked with William Welch in the Department of Pathology at Johns Hopkins Hospital and later became director of the University of Rochester. He died in 1976 at the age of 98.

The standardization of insulin is generally considered by historians to have been a process conducted by physiologists under the direction of Henry Dale. This article shows that it actually involved many actors and began with the earliest administration to patients in Canada and the United States. During this first phase, the drug company Eli Lilly also contributed actively to the standardization, under the scientific direction of George Clowes. This is not to undermine the role of Dale, whose political leadership was paramount for the international phase of the standardization. His scientific contribution, however, was a continuation of previous work led by physiologists, clinicians, and pharmacists. The production and packaging of insulin in standardized units thus appears to be the result of the impressive working of a transdisciplinary and transnational network. It also highlights how new modes of drug regulation were elaborated by state bodies in the early 1920s and paved the way for more extensive reforms.

Fish insulin research had a very short heyday. Throughout most of 1922, production of insulin from livestock was difficult, erratic, and expensive. Although fish insulin was easy to extract and seemed to be a brilliant and logical solution to the shortage of insulin, collection of fish islets was a logistical nightmare. By the end of 1922, a scientist at the pharmaceutical company Eli Lilly in Indianapolis, IN, USA had developed a way to concentrate and purify insulin by isoelectric precipitation. As a result of this breakthrough, the scales began to tip heavily in favour of livestock insulin. Nevertheless, research on commercial production of fish insulin continued for another 18 months but was finally abandoned.

An important observation of the experiments of George Collier is that animals normally prefer to maintain their body weight by eating a large number of small meals each day. However, as the effort to obtain access to food increases, the animals adapt by changing to a schedule of eating a small number of large meals each day. A strong implication of this is that there is a hidden cost to eating large meals, and this is the basis of the eating paradox that states that although food is a necessary commodity, the act of ingesting it poses certain metabolic problems for animals. Experiments on cephalic insulin secretion, conditioned insulin secretion and meal feeding are discussed to make the point that the economy demonstrated by rats in Collier's paradigm is dictated in part by predictions of the eating paradox., (Copyright 2002 Elsevier Science Ltd.)

This paper examines the material relations of risk within a dispute about the hazards of manufacturing human insulin using gene technology, and the rôle played by the referent 'real risk' in the technical performance of risk in that dispute. It draws on recent work in science and technology studies that extends actor-network theory to examine the performance of reality in scientific practice. The multiplicity of risks in the dispute, and the links made and unmade between them, are examined. I argue that in the dispute, risks were contingently linked and separated around a referent 'real risk' that emerged within the recombinant DNA debate of the late 1970s. I contrast my account of risk with realist and relativist accounts, each of which values risk as an abstract entity. In my account, risk's value is contingent upon sets of material relations that link hazards and procedures for their minimization. Risk's realness emerges as some risks are linked and others separated, working a multiple/singular relation in an ontological politics of risk.