Synthetic insulin
repeatedly raised blood glucose damages blood vessels, resulting in impaired microvascular supply of oxygen to cells. This manifests in the long-term complications of diabetes, including blindness, kidney failure, heart attack, stroke and lower limb gangrene, necessitating amputation (7). While type 2 and other forms of diabetes may be treated by a range of medications, including tablets and injections, type 1 diabetes must be managed through administration of insulin, in place of that which would otherwise be secreted by the pancreas. The frequency of administration is dependent on the type and dose of insulin used, and on its specific blood concentration profile. The aim of insulin therapy is to try and reproduce normal (physiological) insulin secretion. Achieving this requires an understanding about the effects of dietary intake, physical activity, stress and illness on blood glucose concentrations. With this knowledge, and with reasonably accurate blood glucose measurements, it is possible to anticipate insulin requirements (8). Turning knowledge into effective treatment requires pharmaceutical insulin preparations with reliable pharmacokinetic (how the concentration of a drug and its metabolites changes over time after administration) and pharmacodynamic (how the body is affected by the drug) properties. It had been shown, by the beginning of the 20 th century, that it was possible to lower blood glucose levels in animals using extracts of pancreas. It was, however, impossible to perform tests in humans as the extracts could not be sufficiently purified. In 1921, a recently qualified Canadian doctor, Frederick Banting, hypothesized that one could destroy the enzyme-secreting parts of the pancreas through ligation of the pancreatic ducts, leaving only the islets of Langerhans intact. These islets, he correctly believed, would continue to secrete the substance, theorized by others as ‘ insuline , ’ while inactivation by digestive enzymes would be reduced. Banting took his idea to JohnMacleod, professor of physiology at the University of Toronto, who gave him laboratory space and the services of an assistant, medical student Charles Best. Together, Banting and Best tested the hypothesis, successfully reducing hyperglycaemia in dogs that had been rendered diabetic by removal of the pancreas. Purification of the pancreatic extract was subsequently achieved with the help of Professor James Collip and the first administration to a human occurred on 11 th January 1922: the treatment could now be safely administered. With the cooperation of Eli Lilly and company, the process was improved, increasing yield and implementing standardization that enabled companies across the globe to start production. For their work in isolating insulin, Frederick Banting and John Macleod were awarded the 1923 Nobel Prize for Physiology or Medicine. There was controversy between them as to who should have received it; Banting decided to share his portion of the prize money with Best, while Macleod shared his with Collip (9). Thirty years elapsed after purification of insulin before its molecular structure was elucidated by Frederick Sanger. Sanger was awarded the Nobel Prize for Chemistry in 1958 for this feat (and again in 1980 for determining base sequences of nucleic acids). The insulin molecule consists of two peptide chains, A and B, connected by two disulfide bonds, with a further disulfide bond within the A chain (see figure on first page) (4). These two peptide chains are, in fact, synthesized in ribosomes as a single peptide chain precursor, also known in medicine as a prohormone. After initial synthesis and formation of the disulfide bonds, part of the prohormone, known as C-peptide, is enzymatically removed. C-peptide and mature insulin are therefore produced in equimolar proportions (10). Natural insulin molecules in solution form dimers and hexamers (11).
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