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F THE glandular organs of the body, two distinct types

may be recognized; those whose secretion leaves the gland through a duct which in many cases enters some portion of the alimentary canal, and those whose secretion is passed directly from the cells of the gland into the blood which bathes the cells and is carried to various parts of the body in the blood stream to function.

Information as to the nature and activity of the secretions of the first type, those collected from the cells of the gland and poured from the ducts into the location where they are to function, is obviously easier to obtain and hence our knowledge of these glands and their secretions is more complete. Important glandular structure of this type are the salivary glands, whose secretion enters the mouth; the gastric glands, the source of the pepsin and hydrochloric acid of the stomach; and other glands which function in the digestive processes. With many of these secretions, it is possible by inserting a canula directly into the duct to collect the juice as secreted, uncontaminated by the food or other substances present in the

'An address delivered before the Sigma Xi Society and the Junior Research Club of the University of Michigan, January 9, 1925.

ANNALS OF CLINICAL MEDICINE, VOL. III, No. 10

alimentary canal, and thus to study the pure secretion.

Our knowledge of the secretions of the other type of glands, the so called ductless or endocrine glands, whose secretion enters the blood stream directly, is much more fragmentary and confused. Several factors contribute to the difficulty of obtaining exact knowledge of the secretions of these glands. Their small size in most cases makes collection of material for study laborious. laborious. Thus the parathyroids,

death. The

glands located in the neck, adjacent to the thyroids, in man are estimated to vary in weight from 40 to 400 mgm. an amount of tissue which seems insignificant. Yet complete removal of these glands in animals produces profound metabolic changes, violent muscular contractions or tetany, and ultimately death. difficulty in isolating and identifying the products poured into the blood from such small organs can readily be appreciated. A second factor which complicates studies of this sort is the dilution of the secretion occasioned by admixture with the blood. If one considers that it is estimated that at circulation cycle of the blood occurs in approximately twenty seconds and that the volume of blood in the adult human of average size may be about 5 liters, it can be seen that the amounts of any given product of a gland present

in a definite sample of blood at any time must be exceedingly small. In addition we know that the substances entering the blood stream are subject to rapid chemical changes, oxidation or reduction, and the like, and that the tissues rapidly remove blood constituents and utilize them for their own purposes. Despite these difficulties, our knowledge of the endocrine glands, both as to the chemical nature and function of their secretions, has advanced rapidly, particularly in the last decade. The discovery of thyroxin, a substance closely related to, if not actually, the active principle of the thyroid gland, and of insulin, the subject of our present discussion, occurred within this period, while during the same decade the studies of Allen and Doisy on the ovarian hormone, and of Collip, reported during the last Christmas meetings at Washington, on the parathyroid hormone make it probable that the isolation of the active principle of these important glands is not far distant.

Before discussing the particular organ which interests us this evening, the pancreas and its active principle, insulin, it will be profitable to consider in a general way the methods by which information concerning the function of these ductless glands may be obtained. These methods will be further illustrated later in the discussion of insulin. These methods of study may be roughly classified under two groups, experimental and clinical. The most successful type of experimental procedure has been extirpation of the gland in question. In order to ascertain the function of an organ, remove it and observe the results on the organism. The recent advances in surg

ical technique have rendered possible more perfect experimental methods to avoid secondary effects of the operation, not due to the absence of the particular gland under study. This procedure results in a condition of extreme hypofunction of the gland, that is, total absence of function and may be compared with the clinical picture in disease in which the function of an organ is diminished or entirely lacking. A second type of experimental procedure is the administration of the organ itself or of extracts of the organ. This method has not to date proved highly successful except in the case of the thyroid. The reasons are not far to seek. Normally the secretions of the ductless glands are not exposed to the action of the digestive enzymes in the alimentary canal and these powerful agents in many instances destroy their effectiveness. As we shall consider later, this destruction of the active substance in the alimentary canal was largely responsible for failure to isolate insulin earlier and still prevents successful administration of insulin therapeutically except parenterally. Again the tissue as obtained for administration or the preparation of extracts is dead tissue and the possibility and importance of postmortem changes has not been fully appreciated until recently. Lastly, the possibility of seasonal, sexual, or even species variation must be taken into consideration. In the case of the thyroid preparations, at least, we know that the activity varies somewhat with the season of the year, the sex of the animal, and probably the nutritive condition of the animal. Until the source, material, conditions of preservation, and

mode of administration of glandular products are properly controlled and checked, uniform results from feeding experiments can not be anticipated.

These same variable factors have also militated against the successful preparation of the active principle of the glands in pure form. Thus Kendall states that during the winter months of January, February, and March, the iodine content of hog thyroid may be so low as to make the isolation of thyroxin impracticable, while during the summer months the content of thyroxin increases from 400 to 500 per cent. The large amount of other substances present in the glands also serves to complicate the isolation of the active principle. Kendall, by working with 6550 pounds (approximately 3000 kgm.) of fresh thyroid tissue was able to isolate 33 grams of the purified thyroxin. Only in the case of the thyroid (thyroxin) and the adrenals (epinephrin) has the active principle been isolated in pure form and its chemical composition determined to date.

The clinical methods of studying the functions of the endocrine glands have also furnished valuable data and supplement the data obtained experimentally. In the case of many of the endocrine glands, we recognize clearly diseased conditions of the gland producing either hyper-, overfunctioning of the tissue, or hypo-, under functioning. These may be best illustrated in the case of the thyroid by exophthalmic goitre or hyperthyroidism, and cretinism and myxedema, examples of hypothyroidism.

In order to understand the relation of the pancreas and its secretion to normal function, it is necessary to

consider briefly the relationships which obtain in the utilization and storage of carbohydrate in the body. Carbohydrate is distinctly a food for combustion to furnish energy and heat to the organism. For this reason, a mechanism for its storage as well as its combustion is necessary in order that a supply of easily available energyyielding material may be present during the fasting periods between meals. Normally the blood carries approximately 100 mgm. of glucose, the form of carbohydrate available for combustion, per 100 cc. of blood. After a meal containing carbohydrate glucose in amounts above those required for immediate use enters the blood and gives rise to a temporary increase in blood sugar above the normal, a condition known as hyperglycemia. The carbohydrate regulating mechanism is called into play by this tendency to hyperglycemia and the liver and muscles remove the excess of sugar and store it in their cells, not as the simple sugar, glucose, active chemically, of low molecular weight and readily diffusible, but as the polysaccharide, glycogen, inert, colloidal, not readily diffusible and of high molecular molecular weight. Glycogen thus is the immobile storage form for glucose, similar in its function in the animal world to starch in the plant world. If this and other mechanisms avail, the blood sugar tends to return to normal within a few hours after the ingestion of carbohydrate food. Later, when carbohydrate is no longer available from the alimentary canal directly and the demands for energy purposes tend to use up the glucose of the circulating blood and tissues, the occurrence of hypoglycemia or