INSULIN. Insulin belongs to the group of substances known as hormones and is secreted into the blood by cells which are situ ated in or near the pancreas. In the mammalia, in which the pan creas is well defined, the insulin secreting cells lie in scattered groups, called the isles of Langerhans, distributed among the rela tively much larger groups, or acini, of pancreatic cells. In certain fishes in which the pancreas does not occur as a definite gland, but is spread out diffusely in the mesentery, e.g., in Lophius and Myoxocephalus, the islet cells form compact encapsulated glands called the principal islets which are often of considerable size and contain no pancreatic (acinar) cells.
Evidence that insulin is present in the pancreas of mammals was originally furnished in 1889 by Mehring and Minkowski. They found that complete extirpation of the gland in dogs imme diately caused severe diabetes, and it was not long before the hypothesis was formulated that this must be due to the with drawal from the body of a hormone having the function of regu lating the metabolism of the carbohydrates. The name insulin was suggested (by Sir E. Sharpey Schafer) for this hormone in the belief that it comes from the islets, and many attempts were made to extract it from the pancreas, but with little success. In 1921, however, Banting and Best, working under the direction of J. J. R. Macleod, found that extracts of partially degenerated pancreas contained the hormone. This method was based on the supposition that the powerful digestive ferments of the intact pan creas destroy the insulin during the process of extraction and on the knowledge that the cells which secrete these ferments undergo degeneration more rapidly than those of the islets after the pan creatic ducts have been tied (Schultz and Ssobolew). This obser vation demonstrated that insulin does exist in the pancreas, and the next step was to devise a method for extracting it in more puri fied form and in quantity from normal pancreas. Alcohol was found to be a suitable extractive, in that it dissolved the insulin and at the same time inhibited the action of the digestive fer ments, and Collip succeeded, in 1922, in sufficiently purifying the alcoholic extracts, by a process of fractional precipitation, so that they could be injected subcutaneously in man without causing local irritation. Very potent extracts were also prepared from the principal islets of fishes. Further purification of the extracts was effected by precipitating the insulin, either by adjustment of the reaction (isoelectric precipitation) or by means of picric acid fol lowed by treatment with alcoholic hydrochloric acid (insulin hydrochloride) . Extracts capable of lowering the blood sugar have also been prepared from other organs than the pancreas, or principal islets, but it is doubtful if their action is really due to insulin. Certain guanidin salts also depress the blood sugar.
The function of insulin is to control those chemical processes of the body which are concerned in the preparation of the food stuffs for oxidation in the tissues. The material which is immedi ately oxidized to produce this energy is carbohydrate, a supply of which is always present, as glycogen, in the muscles where it is formed out of the sugar of the blood. This sugar comes from the liver and is derived either from sugar absorbed from the intestine and temporarily stored in this organ as glycogen, or when diges tion is not going on, from glycogen which has been manufactured out of protein and fats (gluconeogenesis). Insulin controls the rate of supply of sugar from the liver in proportion to the utiliza tion of glycogen by the muscles.
When insulin is absent from the blood, as after pancreatectomy or when the islets are destroyed by disease (diabetes), sugar pro duction occurs in the liver more rapidly than glycogen formation so that glycogen disappears from this organ, the blood sugar be comes very high (hyperglycaemia) and sugar appears in the urine (glycosuria). At a later stage substances known as the ketone bodies also appear in the blood and urine (ketonuria), being de rived from the incomplete oxidation, chiefly of fatty acid but partly also of certain of the amino acids. Death ultimately occurs, either because of starvation caused by the excessive using up of the available foodstuffs of the body, or because of toxic effects for which the ketone bodies are believed to be largely responsible (diabetic coma). Insulin promptly removes all of these symptoms when injected subcutaneously or intravenously, but is inactive when given by mouth, because it is destroyed by the digestive fer ments (pepsin) of the stomach. The effect passes off in a few hours, so that the injections must be repeated twice daily. When this is done the symptoms of diabetes remain absent apparently indefinitely, at least two dogs that were depancreatized for over four years were still living in Dec. 1927 and in excellent condi tion as a result of insulin treatment. In diabetes in man, although the islets are more or less diseased they are never completely destroyed, so that when treatment with insulin is continued for some time the damaged islets may possibly become regenerated.
One of the most significant effects of insulin when given to dia betic animals is that it immediately causes glycogen to be again deposited in the liver and a change occurs in the respiratory metabolism. In a normal animal fed on carbohydrates the ratio between the oxygen absorbed and the carbon dioxide expired, the so-called respiratory quotient, is near to unity, whereas in complete diabetes it never rises above 0.7. When insulin is given the dia betic, the quotient behaves as in the normal animal. Insulin therefore has three fundamental effects in diabetes, it restrains the excessive gluconeogenesis, it stimulates glycogen formation and it raises the respiratory quotient. When insulin is injected into normal animals the blood sugar, which usually stands at about o. Io5 %o, rapidly diminishes and when it reaches a level at between 0•04o and 0.050% curious symptoms supervene. In most labora tory animals these hypoglycaemic symptoms consist at first of nervous hyperexcitability leading to convulsions, and later of coma and fall of temperature. That the symptoms are related to the disappearance of free glucose from the blood is indicated by the fact that they are promptly removed by restoring glucose to the blood, either by giving sugar by mouth or by injecting solutions of glucose subcutaneously or intravenously. Glucose is conspicu ously more efficient as an antidote than any other sugar, even than mannose and laevulose which are so closely related to it chemically. The substitution of one hydrogen atom in the glucose molecule by some other radicle such as a methyl group, robs it entirely of its antidoting powers. The mechanism by which excess of insulin causes hypoglycaemia in the normal animal is not clearly understood.
Since insulin can now be prepared in crystalline form (J. J Abel and Geyling) and a readily dried, solid, compound can be formed with hydrochloric acid—insulin hydrochloride—it may be weighed out for medicinal use, but it is more convenient to use it in liquid form which keeps well in acid reaction. The strength in actual insulin of the liquid is determined by a biological method which depends on the lowering of blood sugar in a normal rabbit. The strength is gauged in units, one unit of insulin being originally defined as that amount which on subcutaneous injection will lower the percentage of blood sugar to the convulsive level, for a period of 5 hours in a fasting rabbit of 2 kg. weight. This original unit was subsequently reduced to one-third. The assay is now carried out by a comparative method in which the hypo glycaemic effect of the solution to be tested is compared with that of a solution containing an accurately weighed amount of insulin hydrochloride. In order to ensure uniformity in the strength of insulin manufactured in different countries the Health Committee of the League of Nations has set aside a sufficient quantity of dried insulin hydrochloride of which 1 mg. contains 8 units. Test ing laboratories maintain their own standards, but they can have them checked against the international standard from time to time. By such international uniformity in strength of insulin the diabetic patient is insured against variable dosage and the risk of hypoglycaemic symptoms. (J. J. R. MACL.) BIBLIOGRAPHY.-F. Dickins and others, "The Purification and Bibliography.-F. Dickins and others, "The Purification and Properties of Insulin," Biochem. Journ. (1927), xxi. 56o; N. R. Blatherwick and others, "Studies on Insulin," Journ. Biol. Chem. (1927), lxxii., 57 (bibl.) ; E. Aubertin, L'insuline (bibl.) (Paris, 1926) ; League of Nations Health Organization, The Biological Standardization of Insulin (bibl.) (Geneva, 1926) ; J. J. R. Macleod, and W. R. Campbell, Insulin (bibl.) (Baltimore, 1925) ; E. Frank, M. Nothmann and A. Wagner, "Heber synthetisch-dargestellte Korper mit insulin artiger Wirkung auf den normalen u. diabetischen Organismus," Klin.
Woch. (1926), V., 2,100.