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Isolation and Structure
Frederick G. Banting, Charles H. Best, and J. J. R. Macleod were the first to obtain, from extracts of pancreas (1921–22), a preparation of insulin that could serve to replace a deficiency of the hormone in the human body. The complete amino acid sequence of the insulin molecule was described in the early 1950s; insulin was the first protein to be sequenced entirely. This pioneering work was confirmed from 1963 to 1966, when several groups reported laboratory synthesis of biologically active insulin. The three-dimensional structure of the crystalline hormone was published in 1969.
Insulin has been shown to be a protein consisting of two polypeptide chains (see peptide), one of 21 amino acid residues and the other of 30, joined by two disulfide bridges (see cysteine). The two chains are synthesized in the β cells as part of one continuous polypeptide chain called proinsulin; a 32-amino acid sequence (the connecting peptide) is subsequently split out of the proinsulin molecule by an enzyme resembling trypsin to yield active insulin.
Insulin in Diabetes Treatment
See M. Bliss, The Discovery of Insulin (1982).
Produced and secreted by the beta cells of the islets (insulae) of Langerhans of the pancreas, the hormone which regulates the use and storage of foodstuffs, especially the carbohydrates. Chemically insulin is a small, simple protein. Insulins from various species differ in the composition; these differences account for the fact that diabetics treated with animal insulins develop antibodies which may sometimes interfere with the action of the hormone. The structure has been verified by synthesis of insulin from pure amino acids in the laboratory. See Carbohydrate metabolism, Immunology, Pancreas
Insulin, being a polypeptide, can also be broken down by many proteolytic enzymes to its constituent amino acids. Because of these breakdown systems, the turnover of insulin in the body is rapid; its “half-life” has been estimated to be 10–30 min. The liver alone is capable of destroying about 50% of the insulin passing through it on its way from the pancreas to the bodily tissues.
The role played by insulin in the body is most clearly approached by considering the abnormalities resulting from removing insulin from an organism by surgical excision of the pancreas or by the chemical destruction of the insulin-producing cells: A state of severe diabetes is produced. Normally the blood glucose level is about 100 mg/100 ml. A carbohydrate meal raises the blood sugar to about 150 mg and the premeal value is reached again within 1.5 h. The normal organism manages to dispose of food by storage and oxidation within this period because insulin is present. When food (carbohydrate and protein) reaches the upper intestine, a substance is liberated which in turn stimulates the beta cells to secrete extra insulin. Insulin acts on most tissues to speed the uptake of glucose. In the cells the glucose is burned for energy, stored as glycogen, or transformed to and stored as fat. The human pancreas probably produces 1–2 mg of the hormone per day. This is sufficient to regulate the metabolism of more than 250 g of carbohydrate, 70 g of protein, and 75 g of fat, the usual composition of an ordinary 2000-calorie diet.
In diabetes the rate of glucose uptake is slowed, the level of circulating blood sugar rises, and sugar spills over into the excreted urine. Calories are wasted, more water is excreted, and there is muscular weakness and weight loss; hence urinary frequency, hunger, thirst, and fatigue. Whenever glucose metabolism is defective, stored fat is broken down to fatty acids because of the actions of adrenaline and the pituitary growth hormone. Insulin is able to reverse all these phenomena by favoring storage and swift intake of glucose into the tissues, by decreasing the breakdown of stored fat, and by promoting protein synthesis.
When insulin is secreted or given in excess, it may lower the blood sugar level much below its normal value, causing hypoglycemia. Hypoglycemia is dangerous because the metabolism in the brain cells depends primarily upon an adequate supply of glucose.
The precise molecular mechanisms of insulin action are still not known. The initial step is the binding of the hormone to a specific receptor on the cell membrane. This event somehow activates a set of transport molecules, so that glucose, potassium, and amino acids enter cells more freely. At the same time, fat breakdown is slowed and glycogen storage increased. All these actions depend upon the integrity of the outer cell membrane. See Cell permeability
Not all the cells of the body require or respond to insulin. The insulin-responsive tissues are the liver, skeletal muscle, the heart, and the adipose tissue. Sensitivity to insulin is affected by many conditions. Obesity, antibodies to the hormone or its receptor, oversecretion of growth hormone or adrenal steroids, ketosis, and unknown genetic factors all cause insulin resistance. Muscular exercise, correction of obesity, and a deficiency of pituitary or adrenal hormones are associated with an increased sensitivity to the hormone.
a protein hormone formed by the beta cells of the islets of Langerhans in the pancreas. It was first isolated by the Canadian scientists F. Banting and C. Best (1921–22). The structural unit of insulin is a monomer with a molecular weight of about 6,000. Under varying conditions, the molecular weight may be 12,000 or 36,000 because the insulin molecule combines different numbers of monomers, depending on the experimental conditions. Every monomer contains 51 amino acids arranged in two peptide chains, A and B, linked by two disulfide bridges (—S—S—). The presence of these bridges is needed for the hormonal activity of insulin to be manifested. If they are destroyed, insulin becomes inactive. Insulin differs from one animal species to another solely in the position of certain amino acids in the chain. The structure of the insulin monomer, that is, the sequence in which the amino acid residues are arranged, was elucidated by the British biochemist F. Sanger (1945–56). This led to the chemical synthesis of insulin.
Insulin lowers blood sugar levels, delaying the breakdown of glycogen and the synthesis of glucose in the liver. At the same time it increases the permeability of the cell membranes to glucose, assisting its passage into the tissues. It also increases the utilization of glucose in reactions of the pentose phosphate cycle and accelerates the glycogen synthesis in the muscles. The presence of insulin is responsible for the dominance of the synthesis of proteins and fatty acids over their decomposition and promotes the conversion of carbohydrates to fatty acids and the formation of fats.
An insulin insufficiency causes a metabolic disorder—diabetes mellitus. Insulin preparations obtained from the pancreas of slaughtered cattle and other animals are used in the treatment of diabetes. Insulin activity is determined biologically (from the ability to lower blood sugar levels in rabbits). A quantity of 0.04082 mg of pure crystalline insulin is taken as a unit of activity (international unit, IU). Insulin is injected subcutaneously or intramuscularly (it is destroyed by gastric juice when taken orally). Free insulin is quickly inactivated by the enzyme insulinase. Various insulin preparations have more prolonged action than insulin, for example, a suspension of amorphous zinc insulin, a solution of protamine zinc insulin, and a suspension of protamine insulin. Low doses of insulin (also in the form of injections) are used for general exhaustion, weight loss, and some other disorders. In psychiatric practice, insulin is injected to induce hypoglycemia.
G. A. SOLOV’EVA