insulin

insulin Glucose, dissolved in the blood (blood sugar), is one of the main sources of energy for the body. Different organs and tissues use other fuels to varying extents, but the brain uses glucose exclusively. To protect vital functions mammals have evolved a mechanism for keeping the concentration of glucose in the blood fairly constant — an example of homeostasis. This includes diverse hormonal responses that increase the blood glucose concentration. Yet, in what seems a remarkable oversight of nature, the body relies almost entirely upon just one hormone, the protein insulin, to bring about a decrease in blood glucose. Insulin facilitates the entry of glucose from the blood into the tissues of the body.

It has been known since 1899 that removal of the pancreas from dogs led to diabetes, with its characteristic persistent increase in blood glucose (hyperglycaemia) and presence of sugar in the urine (glycosuria). The fascinating saga of the eventual discovery of insulin by Banting and Best in 1921 is well known. They were able to show that injection of an extract from the pancreas of a healthy dog led consistently to a decrease in the amount of sugar in the blood and urine of diabetic dogs. They published their account, entitled ‘The Internal Secretion of the Pancreas’, in 1922. Their experiments, which were to prove life-saving, assured the insulin molecule a key place in medical history, and won a Nobel Prize for Banting and Macleod (in whose Canadian laboratory the work was done) as well as earning the grateful thanks of diabetic people in their millions around the world. It was some 30 years later that Frederick Sanger embarked on his painstaking but highly successful molecular dissection of insulin, which unravelled its precise amino acid sequence. This was a landmark achievement, representing as it did the first successful sequencing of any protein molecule, and it earned Sanger his first Nobel Prize. With subsequent establishment of its three-dimensional structure, insulin was revealed as a vital protein of classic polypeptide design. Despite 300 million years of divergent evolution, the molecular form and function of insulin has been remarkably well conserved across the entire zoological spectrum.

The dynamic glucose–insulin system on which the body's metabolism so critically depends is controlled and modulated by various factors impinging on the ‘b-cells’, which are found in the pancreas in cellular nodules, the Islets of Langerhans — named after the German pathologist who described them in 1869, long before their function was known. These ‘b-cells’ detect glucose in the blood and secrete insulin in appropriate amounts in response to the meal-induced tidal changes in blood glucose level.

Insulin is normally quite rapidly removed from the blood and survives in the circulation for only 5–15 min, thus placing a continuing demand on the b-cells for the release of more insulin in order to establish an effective feedback control of blood glucose concentration. This moment-by-moment process requires, in the b-cells, mechanisms for the manufacture, storage, and rapid release of insulin. To replenish its insulin supply, the genes of a pancreatic b-cell switch on their protein manufacturing machinery, producing a much larger single chain precursor molecule, called pro-insulin, which contains the amino acid sequence of insulin. Successive and controlled proteolysis (breakdown of this protein molecule) finally leaves the 51 amino acid sequence of insulin itself, and ensures its correct folding to create the three-dimensional shape of the molecule. Once formed in the b-cell, insulin is stored in granules as a symmetrical hexagonal array of 6 insulin molecules combined in a stable crystalline structure with 2 atoms of zinc. When released into the circulation at effective concentrations, insulin is transported as, and normally acts as, a single molecule.

To exert its effects on target cells — muscle, liver, or fat cells — the insulin molecule must first be recognized by specific insulin-receptor protein molecules in the cell membranes. Part of the insulin receptor spans the membrane, so that, when an insulin molecule binds to the external part of the receptor, a signal is transmitted across the membrane to other molecules, leading to a cascade of enzyme activity in the target cells.

Insulin resistance may occur when the blood glucose level is not well controlled, as in a type of diabetes which begins in adult life, where the pancreatic b-cells do not produce enough insulin. Not only does this lead to the appearance of the symptoms of diabetes, but the high level of glucose in the blood decreases the sensitivity of the target cell receptors for insulin and so makes the situation worse. It is possible to treat this type of diabetes by mouth with agents that boost the output of insulin from any viable b-cells that are present, or reduce the blood sugar by other means. If, on the other hand, pancreatic b-cells have all been destroyed, as in juvenile diabetes, then insulin must be injected daily as replacement therapy.

Unfortunately insulin cannot be given orally because it is a peptide and is therefore rapidly broken down by enzymes in the gut. Different preparations of insulin are available for injection, depending on the duration of action required. Insulin was originally extracted on a massive scale from the pancreas of animals (cows or pigs). It can now be obtained by genetic engineering of bacterial cells, causing them to express human insulin. It is noteworthy that insulin was the first protein to be commercially produced by such recombinant technology. Although this allows large scale production and isolation, pig pancreas remains the main source of insulin for human treatment: pig insulin differs from human insulin by only one amino acid.

Various insulin formulations may combine rapid-, medium-, or long-acting forms of crystalline insulin so that individual requirements for insulin can be matched to blood glucose levels following meals. Insulin has thus become firmly established in modern medicine as a remarkably effective therapeutic agent, but a whole life-time of constant injection is an unwelcome hazard for anyone suffering from juvenile diabetes. The design and production of a non-peptide, orally-active insulin analogue therefore remains a major goal of pharmaceutical research.

E. K. Matthews

See endocrine.See also blood sugar; hormones; metabolism; pancreas.