S280 Science Matters
"Insulin: Discovery and Development"


Diabetes mellitus, if untreated, is a life-threatening diesease, resulting from the body's inability to utilize glucose effectively. Prior to the discovery of insulin in Ontario in 1922, there was no effective therapy for the disease.

Prior to 1922, it was thought that diabetes was attributable to a malfunction of the pancreas and in particular of the Islets of Langerhans, which appeared normally to produce an internal secretion that had anti-diabetic properties.

Prior to the work of Banting and Best, extracts of healthy pancreas were found to have uncertain and inconsistent effects on diabetic animals and humans.

Banting was inspired to work on diabetes because of his initial (erroneous) supposition that in the extraction process, the digestive enzymes in the external secretion of the pancreas would destroy the anti-diabetic hormone from the Islets. This concern prompted his use of 'degenerate' pancreas, where the pancreatic duct had previously been ligated.

Banting and Best's experiments to identify the proposed hormone insulin were faulty in conception and execustion. In particular, a potent anti-diabetic extract could be obtained from fresh pancreas (containing external secretion) and experiments were often conducted without the effective controls that other workers, notably MacLeod, suggested.

Collip was responsible for a major improvement in the extraction technique, using fresh pancreas, which resulted in a safe and effectiv eextract that consistently relieved diabetic symptoms in humans. At this point, insulin can be said to have been 'discovered', bringing to fruition a line of investigation initiated by Banting and Best's early experiments.

Administration of insulin to diabetics produced a 'miraculous' transformation, offering an opportunity for a near-normal life to those who otherwise were certain to die prematurely.

The discovery of insulin did not arise from carefully designed and controlled experiments and the strict application of scientific methodology; chance observations, erroneous assumptions, exaggerated conclusions and luck all played a part. An atmosphere of increasing bitterness and rivalry soured the relationships between the Toronto co-workers.

Banting and Macleod shared the 1923 Nobel prize for Physiology or Medicine. Banting shared his part of the prize with Best and was resentful of Madleod's recognition. Macleod shared his with Collip, whose key role in the extraction of insulin should probably have been recognized by the Nobel Committee.

Enhanced medical understanding and changes in social attitudes led to a gradual improvement in prospects for diabetics after the Second World War.

Two types of diabetes mellitus exist - insulin dependent (IDDM or type 1 diabetes) and non-insulin dependent (NIDDM or type 2 diabetes).

People with type 1 diabetes cannot survive without insulin treatment. Type 1 diabetes is a disease that arises predominantly in the young and the severe symptoms (glycosuria, thirst, weight loss) are now thought to be the culmination of diet- and/or environment-triggered, auto-immune destruction of insulin-producing Islet cells. A constituent of cow's milk (bovine serum albumin, BSA) may be implicated in tprovoking an immunological reaction.

Tyep 2 diabetes is the more common form of diabetes and usually affects older, more obese individuals. Such patients may benefit from insulin therapy, but they do not require it for survival. The disease involves a combination of impaired insulin secretion and reduced sensitivity of the tissues to insulin. Early nutrition, perhpas before birth, may be a critical factor in the development of type 2 diabetes.

Complications usually arise in both type 1 and type 2 diabetes, and are of varying severity. Malfunctions of the eyes, the kidneys, circulation and nerves can all occur, reducting life expectancy.

Glucagon acts antagonistically to insulin, i.e. it elevates blood glucose levels and promotes glycogen breakdown. Insulin and glucagon are only two of several hormones that contribute to blood glucose control and they do so in a complex way, which is difficult to simulate in the treatment of diabetics.

Current medical consensus favours maintaining blood glucose levels close to normal values, iei tight control is advocated, even though this may increase the likelihood of hypoglycaemia.

Continuous subcutaneous insulin infustion (SCII) achieves tight control by post-meal boosts supplementing basal infusion. Fully implatable pumps are in the research and development phase, through considerable problems of pump technology and of biocompatibility remain.

Most glucose sensors utilize the enzyme glucose oxidase, for example those now used in routine self-monitoring. A long-term goal is to include such a sensor within a closed-loop system of insulin delivery, relying on negative feedback to regulate insulin infusion. A large, complex artificial pancreas is already available but is usable at present only for hospitalized patients.

Of the range of insulins now available for therapy, human insulin is the most widely used, usually manufactured by recombinant DNA technology. There is evidence of reduced hypoglycaemic awareness in some patients who have been newly prescribed human insulin, but there is controversy about its frequency and cause. Unexplained deaths among diabetic patients cannot be ascribed with any certainty to the use of human insulin.

Pancreatic transplantation approaches being a 'cure' for diabetes. The technique can sometimes prevent patients developing severe complications. Surgical risks, as well as rejection and fruther auto-immune destruction, are inherent disadvantages of 'whole pancreas' transplantations that, for most patients, outweigh potential benefits. Islet transplantation offers the best hope for insulin-independence, and carries fewer associated risks.

Recent advances in technology (for example, pen injection and finger-pricking devices) have further aided effective ;self-help' in patients, iei achieving tighter control with greater patient reponsibility. Hand-held computers are likely to be increasingly used in supporting patients in the management of their diabetes.

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