The author, an insulin dependent diabetic since 1979 who was originally prescribed animal insulin was switched from animal to human insulin in 1985 and suffered from hypoglycemia unawareness for 9 years. Personal tragedy motivated him to research the management of IDDM by reviewing 18 clinical papers published worldwide based upon over 1,300 references dating from 1890 - 1993.

The History of Insulin

Insulin received its name before it was discovered. In 1889 in Germany Oskar Minkowski and Joseph von Mering observed that total pancreatectomy in experimental animals led to the development of severe diabetes mellitus, and began the speculation that a mysterious substance produced by the pancreas is responsible for metabolic control.

Supporting evidence for the hypothesis gradually mounted and by around 1910 it was widely hypothesised that an internal secretion of the pancreas controls carbohydrate metabolism. In 1920 Fredrick Grant Banting, a physician and surgeon from London Ontario became interested in carbohydrate metabolism and in May 1921 began research using dogs into diabetes based on a hypothesis that internal secretion from the pancreas was somehow being nullified in pancreatic extracts by the action of externally secreted digestive ferments. Banting, assisted by a research student Best, began research in May 1921 by injecting depancreatized dogs with intravenous injections of saline extracts of chilled atrophied pancreas. A pattern of hypoglycemic effects were noted. In late 1921 Banting and Best had accumulated evidence which showed that their extract often reduced the blood glucose in diabetic dogs.

On 11 January 1922 clinicians at Toronto General Hospital injected a 14 year old severely diabetic boy with 15ml of pancreatic extract made by Banting and Best. The first clinical test was a failure however on January 23 1922 a new series of injections began on the boy who responded immediately. His glycosuria almost disappeared and his ketonuria did disappear. His blood glucose dropped to normal. This was the demonstration of the isolation of the internal secretion of the pancreas that the world had awaited for 30 years for. JB Collip, a biochemist, had produced the extract supported by JJR Macleod, professor of physiology at Toronto University. On 3rd May 1922 Macleod delivered a complete summary of the Toronto work to a meeting of the Association of American Physicians in Washington and 18 months later in 1923 Macleod and Banting were awarded the Nobel Prize in physiology and medicine for which haad become one of the fastest recognitions of a medical discovery. By the end of 1923 insulin was being used commercially and safely to treat people with diabetes in most Western countries with two major producers emerging, one in the USA and one in Denmark. In the UK on 24 July 1925 at Guy's Hospital, London, the first UK patient to be treated with insulin was a 6 year old young girl. New generations of insulin prepared from animals were introduced in the 1930's, the 1940's and the 1950's. In the 1970's another generation of animal insulins was introduced aimed at eliminating proinsulin and other immunogenic peptides. These monocomponent insulins took the purification of animal insulin almost as far as it could go. By the late 1950's chemists understood the exact structure of the insulin molecule in the context of the knowledge of DNA and the process of life. With the advent of molecular biology this led to genetic engineering techniques leading to the biosynthesis of real human insulin. (2)

Human Insulin

The first symposium on human insulin as a treatment for diabetic patients was in March-April 1981, just 8 months after the first injections of human beings insulin of recombinant DNA origin into humans and only 6 months after the first conference on the subject. Papers presented at the symposium provided the scientific basis for the performance of large scale clinical studies of recombinant human insulin. The results were presented in June 1882 at a conference of the American Diabetes Association in San Francisco. At the same time another conference was held on human insulin produced semisynthetically by the enzymatic conversion of pork insulin.

The availability of human insulin stimulated an explosion of research in insulin biochemistry and action, insulin physiology and pharmacology. Human insulin was the first product of biotechnology to enter the clinical arena and served as the stalking horse for the explosion of biotechnology worldwide.

Recombinant human insulin played a role in making the regulatory process easier for all recumbinant DNA products. The US Food and Drug Administration (FDA) took up the challenge and performed the regulatory task with due diligence and speed. One company submitted an application to the FDA in spring 1982 and was granted approvaal in October 1982.

Human insulin offers the advantages of favourable immunogenecity in comparison to animal insulins and today local insulin allergy and injection site lipotrophy are virtually unheard of in the USA. Insulin purification and human insulin introduction have ensured this. Likewise immunological insulin resistance has been virtually eliminated. Advances in recombinant DNA technology has permitted the development of other insulin related molecules. (1)

Drug Development, Mixtures, Analogues and Modeling

New directions in drug development, mixtures, analogues and modeling have resulted in intensified regimes in the treatment of diabetes. Evidence suggests that the lowering of blood glucose levels will forestall the development of chronic complications of diabetes. The importance of glycemic control in preventing the progression of retinopathy, nephropathy and neuropathy in patients with IDDM is well known. Those who choose to self-monitor their blood glucose are in a constant state of vigilance with respect to their well-beingin general and the possibility of hypoglycemia. The peak effects of neutral regular human insulin, 0.2 U/kg subcutaneously, do not occur until 3-4 hours after injection and are present for as long as 8 hours. The administration of regular insulin would seem to be an ideal method for mimicking normal insulin secretion. Patients with basal-bolus programmes have higher than normal serum insulin concentrations throughout ther day and night probably as a result of the long acting nature of the premeal bolus infusions of neutral regular insulin. Deficiences of conventional insulins led to the development of improved insulins or insulin analogues and the first analogue of human insulin was beef insulin.

The development of insulin mixtures, especially 70% NPH and 30% regular insulin has provided patients with a convenient method for taking two insulins and has obviated errors inherent in the multiple-step proceedure of self mixing thus enhancing quality of life for many, but not all, patients. (3)