1. Digestive Hormones:

     The best known digestive hormones are those of the stomach and duodenum. There may be others produced in other parts of the intestine as well, but evidence is lacking. Gastrin, the hormone produced in the stomach, favors the production of gastric acid secretions. The hormone is produced in response to vagal stimulation, which also produces gastric acid and pepsin secretion. However, it is produced even after the vagus is cut, meaning that local factors must also be involved.

     The most important of these is apparently protein in the stomach. The breakdown of protein, initiated by the process set in motion by astrin or the vagus results in polypeptide formation; these further stimulate the secretion of gastrin; and fairly soon, the gastric secretion is maximal. The continued breakdown of foods through mechanical activity of the stomach assisted by the gastric secretions reduces the stomach contents to a point where they can be forced through the pylorus into the duodenum.

     Until this time, it might seem that gastrin, rather than quenching the initiating stimulus, enhanced it. When, however, it is recalled that the taking of food results in the emptying of the stomach, it is quite clear that the stimulus, taking food into the stomach, is neutralized by the response, emptying the stomach.

     It may be noted that alcohol also causes gastrin release. The widespread use of pre-dinner drinks has been interpreted to indicate that the digestive virtues of alcohol are somehow known to most people. Unfortunately for this argument, breakfast and lunch are digested by the same people who require alcoholic drinks before dinner without any discernable difficulties. It may be suspected that alcohol before dinner serves other digestive purposes.

     The acid-food-pepsin mixture entering the duodenum provokes the release of five hormones: secretin, enterogastrone, cholecystokinin, pancreozymin, and villikinin. A sixth, enterocrinin, is produced lower. These hormones act on the stomach, the pancreas and gall bladder and the next parts of the small intestine, coordinating their activities.

     Secretin brings about pancreatic secretion. The fluid produced is alkaline (neutralizing gastric juice) but quite poor in enzymes. Enzyme production is brought about by pancreozymin. Enterogastrone is produced in the same area. Acid and fat in the duodenum elicit the production of this hormone. Its effects are to reduce the motility and acid secretion of the stomach, an unlooked for effect, but a very useful one. Fat is digested rather slowly; enterogastrone appears to signal the stomach to empty slowly when fat is present, which leaves time for digestion of the fat already emptied.

     The release of enterogastrone is associated with a longer emptying time for the stomach after a meal high in fat than one which is low in fat. When it is desirable to keep the stomach full for a long time, high fat diets are usually suggested, for they may act through enterogastrone production. Such diets are useful in the treatment of duodenal ulcer as well, and it is possible that they may, intelligently used, be useful in managing the obese patient.

     Cholecystokinin, produced when fat enters the duodenum, causes the release of bile from the gall bladder; its walls contract, and its sphincter relaxes. Fat in the duodenum calls for the bile which will emulsify it in preparation for digestion.

     Pancreozymin has not yet been separated from cholecystokinin and may be the same polypeptide molecule. Like seeretin, pancreozymiri acts on the pancreas, but unlike secretin, which causes the secretion of large quantities of enzyme-poor fluid, pancreozymin stimulates the pancreas to produce its enzymes. Thus secretin and pancreozymin work together to produce a pancreatic fluid which contains the pancreatic digestive enzymes.

     The last four hormones acting on the stomach and pancreas set the stage for duodenal digestion. Villikinin and enterocrinin prepare the next portion of the small intestine to carry out its digestive activities. Villikinin, stimulating intestinal smooth muscles attached to the villi at their basis, increases the movements of the villi. Enterocrinin increases intestinal enzyme secretion. Both hormones are of uncertain structure.

     The digestive hormones are schematically summarized in Figure 348.

2. Hormones Concerned with Water and Extracellular Ions:

     The antidiuretic hormone, controlling water, and aldosterone, controlling sodium, have been mentioned in Chapter 23. The other major hormones involved in the control of ions are the parathyroid hormone, calcium and phosphorus, thyrocalcitonin, calcium and perhaps renin.

     Antidiuretic hormone is a polypeptide whose structure is precisely known, the physiological factors involved in its formation and release are also known, and its site and mode of action are fairly well known. All in all, this is probably the best understood hormone, though there are some unanswered questions.

     Antidiuretic hormone appears to be formed in the hypothalamus. Neurons originating here give rise to fibers, which form a tract terminating near the blood vessels of the posterior lobe of the pituitary. The process of formation (not release) of the hormone appears to go on much of the time, and it results in the accumulation of a great deal of antidiuretic hormone in the posterior lobe. 

     Stimulation of the hypothalamic neurons involved in antidiuretic hormone production results in the release of antidiuretic hormone to the blood. This stimulation may occur when blood osmolarity increases, but it should be remembered that other factors influence it. Emotion, exercise, and sleep are the best known. Oddly, morphine (in non-users) stimulates release of the hormone, though the reason is unknown. Tobacco, again in non-users, releases antidiuretic hormone, the effects perhaps being a result of the discomfort of smoking in a non-smoker.

     After it is released, antidiuretic hormone has one proved action, one whose status is presently uncertain. The proved action is the increase in permeability of the distal tubule as it descends through the renal medulla. As has been indicated before, this results in the formation of small volumes of hyperosmolar urine, the tubular contents coming into osmolar equilibrium with the hyperosmolar medulla. In the usual case, the cycle, activated by hyperosmolarity of the body fluids, results in water conservation. This effect is schematically shown in Figure 349.

     The second effect has to do with the fact that in very high concentrations, the anti-diuretic hormone causes blood vessels to constrict. This effect cannot normally be elicited by reasonable doses. For example, the amount of antidiuretic hormone which causes the antidiuretic effect may be as much as 1000 times less than that which causes the vascular effect, so it probably is never released.

     However, the anterior lobe of the pituitary is largely supplied by blood which has passed through the posterior lobe, the rest coming by way of blood which has passed through the hypothalamus. There is no arterial blood supply to the anterior lobe. This arrangement is called a portal system.

     Although the amount of antidiuretic hormone is small, the amount of blood going to the anterior lobe is also small. The concentration of hormone in the blood supplying the anterior lobe is probably a thousand times that supplying the rest of the body. At this concentration, the vascular effects may be expected. It has been proposed that these stimuli which cause the posterior lobe to release the antidiuretic hormone may, through altering its blood supply, influence the anterior lobe. Figure 350 summarizes this possible role of ADH.

     Aldosterone is made in the adrenal cortex. It is a steroid hormone, the physiological member of the group of mineralocorticoids. Its structure is shown in Figure 351.

     The stimuli for aldosterone secretion are multiple. Emotion, anesthesia, injury, and pain all produce general increase in adrenal cortical activity, aldosterone included. Low sodium and high potassium diets seem to increase aldosterone secretion specifically, and so do factors such as congestive failure or quiet standing, which decrease the cardiac output.

     The exact factors which control the release of aldosterone are not clearly known. The release may be multiply regulated. The most important factors are probably the level of plasma sodium and potassium. Sodium rises and potassium falls suppress aldosterone secretion; conversely sodium falls and potassium increases enhance it. The anterior pituitary, through its adrenal stimulating hormone (adrenocortotrophic hormone) probably plays a role in some conditions in which aldosterone secretion is altered, but its importance is not clear.

     Much interest has been focused on the possibility that the secretion of aldosterone is linked to the renin-angiotensin system. It seems probable quantities of renin organization are injected into the circulation. However, there are very few circumstances in which such large amounts of renin are releasesd, so one must regard this mechanism for aldosterone control as unproved at present, though it seems to exert some kind of appeal to writers of textbooks of physiology.

     The renal effects of aldosterone are also not clearly understood. It seems to cause sodium retention and potassium excretion in most circumstances through an action on the tubules. Unfortunately, neither effect is quite regular; thus aldosterone does not cause sodium retention in a normal person after a day or so.

     Despite these uncertainties, there seems to be a relationship between changes in body sodium and aldosterone secretion, which corrects the depletion and discourages the accumulation of potassium. The relationship and its possible mechanisms are schematically shown in Figure 352.

     Parathyroid hormone: The parathyroid glands are very inconspicuously attached to the thyroid, and before their importance was realized, they would sometimes be surgically removed along with a diseased thyroid. Such removal often terminated in death. Characteristically, such patients would show muscular hyperexcitability with twitching strong contractions and spasms, or tetany. The plasma calcium would fall to half its normal value, and death would follow when laryngospasm obstructed the airway.

     The hormone, a polypeptide of molecular weight 8500, appears to be secreted by the parathyroid in response to low calcium in the plasma. Conversely, high plasma calcium acts to prevent the secretion of the hormone.

     The primary target organ is bone. Elevated parathyroid hormone induced by low plasma calcium releases calcium from bone to plasma, restoring the level of plasma calcium. High plasma calcium causes deposition of bone calcium by way of the parathyroid hormone.

     The intestine and kidney are also target organs. Calcium absorption from the gut decreases when plasma calcium is high, and likewise, calcium excretion in the urine increases. Both effects, partly mediated by parathyroid hormone, correct the increased plasma calcium level. The opposite effects are seen when plasma calcium falls, but these effects are quite minor relative to the major effect on bone.

     Thyrocalcitonin: This recently discovered hormone seems to have exactly the opposite effects from parathyroid hormone. It is secreted by the thyroid. When given, it lowers plasma calcium, and in its absence, the parathyroids being absent also, plasma calcium rises.

     Physiologically, thyrocalcitonin reinforces the effects of parathyroid hormone despite its opposite effects. The reason is simple. Low plasma calcium, which stimulates parathyroid hormone secretion, inhibits the secretion of thyrocalcitonin, while high plasma calcium, which inhibits the parathyroids, stimulates the secretion of thyrocalcitonin.

     Overall, the thyrocalcitonin effects are minor compared to parathyroid hormone effects. However, it is of interest that two hormones do the same job, though in different ways. Thyrocalcitonin is a polypeptide, whose molecular weight is about half that of parathyroid hormone. The relationship of parathyroid hormone and thyrocalcitonin to bone and plasma calcium is shown in Figure 353.

     Renin: Kidney extracts contain a protein which, when released into the blood, acts as an enzyme to break down the plasma protein renin substrate. The breakdown product, a polypeptide called angiotensin, is a powerful vasoconstrictor, though ineffective in a few areas, notably the heart and brain. The renal pressure system is schematically shown in Figure 354.

     Intensive work on renin began with the demonstration that partially clamping the renal artery produced hypertension. Within a few years, the mechanism of action of renin described above was clarified, and the logical conclusion appeared to be that clamping the renal artery produced hypertension through renin release (See also Chapter 16). Unfortunately, this hypothesis was not supported in animal experiments or human observation. It had meanwhile been suggested that renin release occured when blood pressure was low, so that the kidneys would serve as an endocrine organ to keep blood pressure normal. This effect appears to be of secondary importance, for blood pressure in hemorrhaged animals recovers almost as well without the kidneys as with them, but nevertheless, not as well.

     Many physiologists now favor the idea that renin controls the rate of aldosterone secretion through angiotensin. The possibility exists, but it is disappointing that the amounts of renin needed to produce the effect have not been found in the circulating blood in circumstances that provoke aldosterone secretion.

     An alternative possibility, which lacks much of the dramatic appeal of the renin angiotensin-aldosterone hypothesis, is that angiotensin by itself can decrease the renal excretion of both water and sodium by decreasing the glomerular filtration rate. The tubular effect on sodium is in the opposite direction: tubular reabsorption of sodium decreases, but the glomerular effect predominates. The concentration of angiotensin required to produce this effect is still rather high, but it may be realistic, since the angiotensin produced may be diluted only by the renal circulation rather than the entire cardiac output. 

     In either case, blood losses, resulting in renin secretion, are followed by retention of water and scdium, which correct the volume loss. For the present, it seems safes to admit ignorance about the mechanism.

3. Hormones Affecting Intermediary Metabolism:

     These hormones are the thyroid hormone, insulin and glucagon, the hormones of the pancreas, the glucocorticoids of the adrenal cortex, and the growth hormone of the pituitary.

     In a sense, every hormone affects intermediary metabolism. Thus the hormones considered in the previous sections undoubtedly produce chemical changes in their target organs. The hormones to be discussed below do so also. The hormones taken up under this heading appear to act throughout the body, meaning nearly every organ is the target organ. At the same time, they do not mimic the autonomic nervous system (part 4); nor are they related to sex (Chapter 26).

a. Thyroid hormones:

     The thyroid hormone (thyroxine) is produced in the thyroid gland. It has a number of effects which will be described later. The most important is its Calorigenic effect: it causes increased utilization of oxygen and production of heat in most organs, only the brain, testicles, and uterus being immune to this effect. Thyroxine is also involved in normal growth and development.

     The release of thyroxine occurs when the thyroid gland is stimulated by thyrotropic hormone from the anterior lobe of the pituitary, which in turn is released when an animal is exposed to cold over a long period of time. Thus, exposure to cold eventually produces increased heat production. Other factors causing increased thyroid hormone production have not been clearly identified.

     Release of thyrotropic hormone is under hypothalamic control. It will be recalled that temperature centers exist here. Presumably, cold exposure activates thyrotropic hormone release. However, the important factor controlling the release of the thyrotropic hormone is the concentration of free thyroxine in the blood. When this rises, thyrotropic hormone release falls. The resultant fall in thyroxine level stimulates the release of thyrotropic hormone. Likewise, tissue destruction and absorption or renal excretion of thyroxine can be expected to increase thyrotropic hormone release. Unfortunately, it has not yet been established what physiological circumstances lead to such thyroxine destruction and uptake by tissues, or excretion by the kidneys.

     The structure of thyroxine is shown in Figure 355. The hormone contains four iodine atoms attached to an amino acid formed from two tyrosine molecules. Synthesis of the hormone begins with trapping of plasma iodide by the thyroid cells. This trapping is very effective: the thyroid extracts 98% of the iodine coming to it. The trapped iodide is converted into a reactive form, which combines with the tyrosine of a thyroid protein. Some of this tyrosine captures only the iodine, while some captures two iodines. The iodinated tyrosines still in the thyroglobulin molecule may combine to yield thyroxine, when two doubly iodinated tyrosines combine, or tri-iodothyronine, when a singly iodinated tyrosine combines with a doubly iodinated one.

     The iodinated protein, now called thyroglobulin, is stored in the follicles of the gland as a material called colloid. Thyroxine is not released into the blood until thyroid-stimulating hormone is secreted. When this occurs, the protein is broken down, probably by the thyroid cells themselves, and the released thyroxine enters the circulation. Here it is bound to, but not combined with, plasma proteins. The thyro-protein complex breaks up into its two components a little, at about one part in a thousand, so that only one thousandth of the plasma thyroxine is immediately available.

     Nevertheless, it is just this"free" throxine which controls the release of thyroid stimulating hormone. Total binding leads to massive release, and conversely, reducing binding , which may be expected when the plasma proteins are low, may lead to diminshed production of thyroid stimulating hormone, and therefore to reduced production of thyroxine.

     A small amount of free thyroxine is excreted by the kidneys, while the remainder is taken up by tissues. The "bound" thyroxine in the blood breaks up to replace it, so that it can be considered a reservoir of thyroxine. The fate of thyroxine in tissues is obscure. It seems to bind again, this time to tissue proteins, but how it achieves its effects in tissues is not known.

     Thyroxine, as noted above, affects most tissues, but there is usually a considerablc "lag" period before any effects are noted. The greatest effects of thyroxine are not usually seen for more than a week, so patients receiving thyroid treatment may become concerned when there are no effects in the first few days. Tri-iodo-thyronine shows effects within six hours, the greatest effect occurs within two days. This substance, which is normally produced in small quantities by the thyroid, can be used when quick responses are desired.

     The most obvious response to thyroxine is an increase in oxygen utilization. Increased rates of sugar absorption from the intestine are also seen. Cholesterol synthesis increases, and its removal is increased even more, so that the plasma cholesterol falls. This effect may be of some use in the treatment of atherosclerosis.

     There is a complex relationship to the sympathetic nervous system. Despite intensive investigation, the mechanism of the calorigenic effect is not known. It has been suggested that thyroxine acts like dinitrophenol, a drug once very popular in the treatment of the overweight. This drug made it possible to oxidize foodstuffs without producing the normal amount of high energy phosphate. Heat production was, therefore, increased, though work production was normal or even reduced. This would result in gratifying weight losses in persons who were unwilling or unable to increase their work output. Unfortunately, dinitrophenol had two undesirable side effects. Large doses increased heat production beyond the subjects' capacity to eliminate heat, and many patients died as a result of the very high body temperatures induced by taking the drug. Fowl treated with dinitrophenol often developed cataracts, as did 1% of humans taking it (See Chapter 8). After a brief popularity the drug was withdrawn from the market.

     The thyroid hormone's "dinitrophenol effect" appears to be limited. Small quantities of thyroxine have no effect at all, since they simply prevent the formation of pituitary thyrotropic hormone and therefore decreasethe thyroid's own production of hormone. Very large doses may increase oxygen utilization to twice its normal value. The following is a partial list of symptoms associated with such doses: Muscular weakness, insomnia, anxiety, chronic congestive heart failure, and muscular wasting. Examination of this list would suggest that obesity is best cured by some other means. Nevertheless, there is a thriving industry in which the overweight are treated with pills containing thyroid, among other things. 

     The relationship between the thyroid hormone and the sympathetic nervous system is a two way one. Thyroxine effects are in part blocked by removal of the sympathetic nervous system or using drugs which block it. Conversely, many effects of the sympathetic are blocked by removal of the thyroid or the use of thyroid blocking ager, but the nature of these relationships is not understood.

     The effects of the thyroid on growth and development are best observed in children. Bone growth is slowed and mental development is retarded. The administration of thyroid can reverse these effects if started early. There is no evidence that excess thyroid accelerates human growth and developme, although it does so in tadpoles, which quickly become frogs under thyroid treatment.

     The interrelationships between thyroxine, the thyroid stimulating hormone, some other hormones, and the target organs are shown in Figure 356.

     Some aspects of thyroid physiology are best understood in terms of thyroid diseases, which will be discussed in Part 6 of this chapter.

b. Insulin:

     The history of the discovery of insulin and some of the developments of this hormone which have occurred since then are as fascinating as the hormone is important. Some of this history will be described below.

     Deficiency in the pancreatic production of insulin produces a disease called diabetes mellitus. This disease, which affects 1 l/2% of the U.S. population, has been recognized since the beginnings of medicine. The name diabetes, a Latin word meaning "siphon," derived from a Greek word meaning "to run through", has been in use for almost two thousand years. It comes from the fact that the diabetic person drinks and urinates excessively. The fact that the urine contained sugar was first recorded in the 17th century, and the disease was then named diabetes mellitus, mellitus meaning honey flavored or sweet.

     It was not until nearly the end of the 19th century that the disease was associated with the pancreas. This conclusion was reached on the basis of experiments in dogs from which the pancreas had been totally removed. The first hormone had not yet been discovered, but nevertheless, the experimenters suspected their pancreatectomy had removed an internal secretion of the pancreas which regulated blood sugar. The secretion was named insulin about twenty years later, though its existence had not been proved. The name, which means island-material, was given to it because it was suspected that the hormone came from "islet cells" in the pancreas (Figure 342).

     Insulin is a small protein molecule, molecular weight 5000. Though many attempts were made to prepare a pancreatic extract which would control blood sugar, they were quite unsuccessful, for in the process of extracting the pancreas, the insulin was broken down by the trypsin, a proteolytic enzyme in the pancreas.

     In 1921, Banting, a Canadian surgeon, approached McLeod, Professor of Physiology at the University of Toronto, with the suggestion that it might be possible to extract insulin from the pancreas if its digestive parts were destroyed. Earlier work had indicated that tying the pancreatic duct lead to destruction of most of the pancreas. The islet cells, however, did not disappear and the animals did not develop diabetes.

     McLeod, who was normally a good physiologist, was reluctant to permit Banting to work on this idea in his laboratory. However, Banting was unusually persistent and McLeod finally agreed to allow him the use of his laboratory while he was on vacation in Europe, giving him ten dogs and an assistant for 8 weeks, but no salary or title. A part of a room used for routine chemistry was also made available.

     Banting began work on May 16, 1921 with Best, a medical student who had been assigned to him by McLeod as his assisant. He began his work by tying the pancreatic ducts in the ten dogs allowed to him. In some of them, the secretory part of the pancreas atrophied. Using the residual pancreas of these dogs, Banting and Best made an extract which produced a remarkable improvement in another dog dying of diabetes. The improvement was temporary, but encouraging.

     Soon afterwards, Banting and Best hit on the idea that they might be able to extract the active agent from a norm1 pancreas if they inactivated the trypsin. It will be reclled that trypsin acts in the duodenum, which is made alkaline by the enzyme poor secretion of the pancreas, stimulated by secretin. It seemed reasonable to try extract of the whole pancreas with weak acid to inactivate the trypsin. This procedure was successful, to the pleasure of all concerned, particularly McLeod, who had returned from Europe, and reported these findings to various learned bodies, including the Association of American Physicians. All who heart the report were enthusiastic, and all commended Professor McLeod and his "associates" for their achievement.

     The general enthusiasm extended so far as Sweden, where the Nobel committee awarded Banting and McLeod the Nobel Prize in Physiology and Medicine in 1922. An even greater enthusiasm developed in diabetic patients, who for the first time saw a chance to bring their disease more or less under control. The reasons for saying "more or less" will become obvious in Part 6 of this Chapter.

     Insulin is normally released by islet cells whenever blood sugar (glucose) rises above 1.1 mg / ml. The islet cells may be slightly influenced by secretin and pancreozymin, and are probably stimulated by glucogen (See below). They may be stimulated by epinephrine as well. Outside of these, there is no known endocrine or nervous control of the production of insulin. Of the factors listed above, the blood sugar plays the dominant role, the others being quite minor.

     Once released, insulin appears to increase the rate of glucose entry into and utilization by the cells of almost every organ. There are a few exceptions, including red blood cells, the tubules of the kidney, the intestinal mucosa, and most of the brain. The liver occupies a special position. The digestion of most carbohydrate results in the formation of glucose, which is carried to the liver by the hepatic portal vein and converted to glycogen, which is stored in the liver. Glycogen breaks down to form glucose, which is released gradually to the blood and thence to the tissues. However, insulin does not appear to increase the rate of utilization of glucose by the liver.

     When blood glucose falls, insulin production stops. Liver glycogen, converted to glucose, enters the circulation. The slight rise in blood sugar is enough to provoke insulin secretion, which lowers blood glucose by a double effect. The rate of entry of glucose into the cells is increased and the breakdown of liver glycogen to glucose is inhibited. This cycle continues (Figure 357). Any rise in blood sugar is countered by insulin, and whenever blood sugar falls, insulin secretion stops.

     It may be clear from this account that the overall effects of insulin is to dole out intermittently the glucose it received at meal times and to insure that the glucose so doled out will enter the cells. It should also be obvious that the system as described is imperfect: such a system as this might function well at rest, but sudden demands for glucose would not be met. In fact, of course, they are. The factors which increase the rate of glucose formation by the liver are both autonomic, through the sympathetic nervous system, and endocrine, through adrenaline and nor adrenaline, glucogen, and the glucocorticosteroids of the adrenal gland. These hormonal effects are discussed in Part 5 of this chapter.

     Insulin regulates the metabolism of fats and proteins as well as carbohydrates. Some of the effects may be indirect, since insulin makes carbohydrates available to cells, which can then go about their normal business with respect to fats and proteins, rather than using them as foodstuffs. Some of the effects are quite direct. Insulin favors the conversion of carbohydrate to fat and increases protein formation. The protein effect is a double one: amino acids gain access to the cell interior in the presence of insulin, and once within the cell they are built up to proteins by the process enhanced by insulin. How insulin makes the cell permeable to glucose and amino acidsis not known.

     The structure of insulin is well known and the hormone has recently been synthesized in mainland China and in the United States.

c. Glucogen:

     Pancreatic extracts contain a small protein, molecular weight 3500, other than insulin. This protein, called glucogen, raises blood sugar by causing the break down of glycogen. It also stimulates insulin production.

     The stimulus for glucogen release is low blood sugar, especially when the fall in blood sugar follows a fast.

     In these respects, glucogon appears to behave just oppositely to insulin. It is not known whether this symmetry extends to the action of insulin on cell permeability.

d. Glucocorticoids:

     These hormones exert an important effect on carbohydrate and protein metabolism. There appears to be other effects as well, some of which are discussed in Part 6 of this chapter.

     The most important metabolic effects are related to the formation of glucose from protein, the release of glucose from liver glycogen, and decreased utilization of glucose by tissues. Taken together, it is obvious that these effects will result in a rise in blood sugar, so that, so far as blood sugar is concerned, the glucocorticoids have the opposite effect from that of insulin.

     There are two natural glucocorticoids, both steroids. Their chemical composition is shown in Figure 358. Both steroids originate from cholesterol, which in turn is derived from acetate in the metabolic pool. The rate of synthesis of these hormones is increased by the adrenocorticotropic hormone of the anterior lobe of the pituitary. The hormones are released immediately after synthesis: they are not stored to be released by the pituitary hormone.

     Unlike aldosterone, which can be produced by the adrenal cortex whether or not adrenocorticotropic hormone is present, the glucocorticoids are completely dependendent on the adrenocorticotropic hormone. When it is absent, as after pituitary removal, their synthesis stops. The formation of the adrenocorticotropic hormone is also suppressed by the glucocortoids. Thus the very factor which initiates glucocorticoid formation is "turned off" when excessive amounts of glucocorticoids have been formed

     In the blood stream, the glucocorticoids are bound to specific protein. The bond is a weak one: about 5% is unbound. Comparison with thyroxine may be helpful here. Thyroxine is stongly bound, about 0.1% remaining free. Yet, it is the free thyroxine which controls the release of thyrotropic hormone; similarly it is the level of free glucocorticoids which controls the release of adrenocorticotropic hormone.

     The fact that the binding is weak is responsible for an odd aspect of the physiology of the glucoeorticoids: the protein which binds them can potentially bind three times as much of the glucocorticoids as is normally present. How then does the "free" 5% escape binding? The answer has to do with the weakness of the bond. The bonds may be compared to a weak cement bond which connects the steroid hormones to the protein carrier. Some hormone molecules will break away from the carrier, since the cementing bond is weak, yet much of the cementing bond is unused. When glucocorticoid production is increased by adrenocorticotropic stimulation of the adrenal cortex, the level of free glucocorticoids rises, but only 5% as fast, since there are unused bonds on the carrier molecule. When glucocorticoid production is increased three times, the carrier bonds are all in use. Now any further increase in glucocorticoid production result in the appearance of a corresponding amount as free glucocorticoid.

     This may be illustrated numerically. Suppose that the binding protein had a capacity for glucocorticoids of 300 units, and 100 was the normal level (these units are arbitrary). Five units would be free. Doubling glucocorticoids in the blood to 200 would raise the level of free glucocorticoid by 10, tripling it to 15. At this point, the binding capacity would be used up. Now, if the blood glucocorticoids were raised another hundred units, the level of free glucocorticoids would increase to 115. By increasing glucocorticoid levels one third (from 300 to 400), one would increase the free glucocorticoids almost 8 times, which would easi1y be enough to turn off the adrenocorticotropic hormone.

     The weakness of the bond also makes the transfer of the glueocorticoids to the tissues which will use them relatively easy. The principal target organ is the liver, the suppression of glucose utilization by other tissues being a minor effect. These effects can be summarized briefly.

     It will be recalled that the breakdown products of proteins and amino acids enter the metabolic pool and that carbohydrates can be synthesized from the materials of the metabolic pool. The glucocorticoids favor both these effects, and they also favor the breakdown of liver glycogen to glucose. Thus, they serve to balance the glucose-lowering effects of insulin. In a sense, these steriods are the physiological antagonists of insulin.

     It may be of some interest that many of the derangements of diabetes mellitus can be corrected by removal of the adrenal gland. The lack of insulin is countered by the removal of the source of the glucocorticoids which act against insulin. The procedure, which also involves the loss of the mineralocorticoid aldosterone, is entirely too dangerous for use in medicine, though it still has some advocates in certain circumstances. A much milder procedure is removal of the pituitary gland. The source of adrenocorticotropic hormone being gone, the glucocorticoids disappear, and the effects of insulin lack become less noticeable. Dogs subject to removal of the pancreas and the anterior lobe of the pituitary do much better than those which have lost only their pancreas.

     The doubly maimed animal is a physiological curiosity. The removal of the pituitary in man could not even be considered for the treatment of diabetes, though it is sometimes necessary for other reasons.

     Gluococorticoids are in some manner not yet known involved in the adaptation of animals to exposure to cold, injections of certain foreign materials, some types of injury, and some types of pain. They prevent many inflammatory responses, and they suppress many allergic responses. All these effects have led to the ever increasing use of both natural and synthetic glucocorticoids in medicine. They are exceedingly useful drugs when properly used, though they are potentially harmful. Single doses are ordinarily without harmful effects, but prolonged use may cause long term damage that outweighs the effects of the illness. The harmful effects include increased susceptibility to infection, a consequence of the anti-inflammatory and anti-allergic effects, muscular weakness, severe behavioral disorders, including major psychoses (which may or may not disappear when the corticosteroid is discontinued), hypercoagulability of blood, and a variety of other complications. Patients receiving glucocorticoids often show an elevation of mood which deceives them and the physician into thinking that they are doing better than they really are. For example, patients receiving glucocorticoids develop peptic ulcers fairly frequently, some of which may perforate. The patient who has been receiving glucocorticoids may not even complain of pain, although his perforation presents the same threat to life as it does in the patient not so treated.

e. Growth hormone of the pituitary:

     The anterior lobe of the pituitary produces a protein hormone, molecular weight 29,000, which is involved in the growth of bone and muscle. It is not, by any means, the only growth hormone. Thyroid hormone and the sex hormones also play important roles.

     The stimulus for the release of this hormone appears to be lowering of the blood sugar. This is detected by hypothalamic receptors, which convey a message to the anterior lobe of the pituitary, which is then stimulated to produce growth hormone. As in many other cases where hypothalamic centers cause pituitary secretion the nature of the message is not clear. It will be recalled that there are no nervous connections between the anterior lobe of the pituitary and the central nervous system, the only known functional connecting being by way of a portal circulation which carries blood from the hypothalamus and the posterior lobe to the anterior lobe. Muscular exercise also promotes the release of growth hormone, whether or not blood sugar falls. The mechanism is unknown.

     Growth hormone probably begins its effect in the metabolic pool, where breakdown products from fats are combined with nitrogen from the amino acids of food protein to form new amino acids. These amino acids gain entry to cells, an entry facilitated by growth hormone. They are then combined with each other, again with an assist from the growth hormone, to form new cellular proteins. The overall effect is to make protein from fat and amino nitrogen which would otherwise have been eliminated. These protein accumulations are observed in most cells.

     The effects of growth hormone bones are particularly impressive. The shaft of long bone is separated from its end by a cartilaginous layer. This layer is the only part of bone which grows. When the bone ends fuse to the shaft, growth stops, since the cartilaginous layer can no longer grow. Growth hormone has its major effect on just this layer. Under its influence, the bones increase in length until fusion of the bone end and shaft occurs. This fusion usually occurs at sexual maturity under the influence of the sexual hormones. For this reason, early sexual maturity seems to be associated with short stature. There is some reason to doubt this statement. Sexual maturity appears to be occuring earlier than it used to in the United States, but body height has been increasing steadily.

4. Hormones Acting Like the Autonomic Nervous System:

     The post ganglionic-fibers of the autonomic nervous system exert their effect by way of chemical mediators. Acetyl choline mediates all parasympathetic impulses and some sympathetic. Adrenaline and nor adrenaline, the catecholamines, mediate the impulse in the remainder of the sympathetic nervous system.

     Since the catecholamines can be released in quantities sufficient to enter the blood stream and act at distant sites, they may be considered true hormones. Acetyl choline is destroyed so quickly by cholinesterase in the blood that it cannot act at any distant site.

     Not only are the catecholamines produced at sympathetic nerve endings; the adrenal medulla also secretes them into the circulation. Qualitatively, the effects of the catecholamines are the same whether they originate in the adrenal medulla or at sympathetic nerve endings. In general, however, it appears that catecholamines secreted at nerve endings produce much greater effects than those produced by the adrenal medulla simply because they are closer to the affected structure and probably in much higher concentration at their effective site than can be produced by the distant gland, whose secretions are diluted in the blood.

     It was noted in Chapter 5 that the "emergency" function of the sympathetic was a convenient, but not quite exact, way to summarize its functions. The same is true of the catecholamines. Their effects are more or less what would be expected in some kinds of emergencies, but sometimes they have effects quite opposite to those expected. For example, any "emergency" system would close down the blood vessels to the skin when danger threatened, yet some people respond to emergency by dilating these and other vessels. They may consequently show disastrous falls in arterial pressure and faint, so that they become totally unprepared to deal with any emergency, unless it is the emergency of being attacked by an animal which likes to see its antagonists fight back. In the same way, animals which have lost blood can, quite literally, kill themselves by an "emergency" vasoeonstriction of the blood vessels of the intestine. If they recover, they may find themselves with an irrepairably damaged intestine, from which they will die.

     The naturally occurring catecholamines are adrenaline and nor epinephrine. They are among the simplest hormones, chemically speaking. Their structure is shown in Figure 360. lt has been shown that the amino acids phenylalanine and tyrosine can be converted to nor epinephrine rather easily in the animal; of that, nor epinephrine is converted in one step to epinephrine. The adrenals of most animals contain both epinephrine and nor epinephrine, but the proportions vary. Thus the adrenal glands of cats contain mostly nor epinephrine: in dogs and men, 80% of the nor epinephrine is converted to epinephrine.

     Both catecholarnines are destroyed rather slowly, unlike acetylcholine, which is destroyed in the blood stream almost at once. The chemistry of their destruction will not be discussed here, but it appears that any one of several routes of destruction may be followed. Some very effective agents have been developed which prevent the destruction of both of them. These must be used with caution, particularly after eating certain cheeses, which supply large quantities of phenylalanine or tyrosine. Some deaths have been reported in persons taking these agents and cheese at the same time.

     The adrenal medulla is under nervous control. It is stimulated by vasodilator fibers of the sympathetic nervous system (Sec Chapter 12). Activated as the sympathetic nervous system is, and releasing substances like those released by the sympathetic nervous system, it may be considered that the adrenal medulla supplements the activity of the sympathetic nervous system. Yet this effect is very minor. Animals (and men) without the adrenal medulla show almost exactly the same responses as those with it. This is another example of physiological redundancy: there are at least two ways of achieving the same response.

     All organs respond to the eatecholamines. Some do so by way of their smooth musclcs and glands, while some by way of their blood vessels. For example, the oxygen utilization of the heart is increased by these hormones, the pupil dilates and the ciliary muscle relaxes, the secretory activity of the stomach stops, and the liver breaks glycogen down to glucose. Some blood vessels constrict, for example, those of the kidneys and skin, while others dilate, like those of the brain and heart.

     Nor adrenaline was not recognized as an adrenal secretion for a long time. When it was discovered, the tempting hypothesis was advanced that the two hormones which have slightly different effects were released in the proportions best likely to equip the animal to meet the emergency, which brought about sympathetic discharge. Unfortunately, this hypothesis has not withstood the test of time. As noted above, it is not even clear what the "best" response is in any circumstances. Apart from this, the responses to the two hormones do not differ as much as would be necessary to think the hypothesis credible. The main difference between the hormones has to do with the conversion of liver glycogen to glucose. This response is much greater for adrenaline than nor adrenaline.

     A peculiarity in the response to the catecholamines seems likely to be of increasing medical importance. In blood vessels, both stimulate the alpha receptors (Chapter 12), and both relax beta receptors. Two examples of this have to do with the responses of the blood vessels of the intestine. Catecholamines tend to constrict these blood vessels moderately. But if they are preceded by a beta blocking agent, the same dose of catecholamine causes intense vasoconstriction. As noted above, catecholamines released in shock can damage the intestine beyond repair. Alpha blocking agents have been used in the treatment of shock in man with fair success.

     It will be recalled that in Chapter 16 it was mentioned that nor adrenaline alone was mentioned as a shock treatment. This produces vasoconstriction in the intestine, but it does raise the blood pressure, at least temporarily. Both nor adrenaline and beta blocking agents have been recommended in the management of shock, sometimes by the same people, sometimes even in the same patient. Clearly, much remains to be learned in this field.

     The exact manner in which catecholamines exert their effects is not yet known. It has been suggested that their excitatory effects result from their activation of a system which converts glycogen to glucose. Their inhibitory effects are not understood at all, and though hypotheses have been advanced, they have not worked out well. It seems quite certain, however, that thyroxine and the catecholamines are intimately related in their effects. Thus catacholamines, which ordinarily cause increased animals; thyroxine, which increases heart rate, does not do so when catecholamines depleted.

5. Hormones Controlling Other Endocrine Glands:

     To a certain extent, every hormone influences every endocrine gland. However, some hormones appear to have no function other than to effect such control.

     These hormones, secreted by the anterior lobe of the pituitary, are the adrenocortiocotropic, thyrotropic, and gonadotropic hormones. The last will be considered in the next chapter, and the first two,already mentioned in connection with the adrenal cortex a thyroid, wil be reviewed here.

     The adrenocorticotropic hormone, a polypeptide, regulates the production of glucocorticoids and, to a smaller extent, that of aldosterone by the adrcnal cortex. The response of the healthy adrenal cortex is very rapid, beginning in two minutes and lasting from 10 minutes to an hour. An atropic adrenal cortex may not respond. The importance of this fact will be stressed in Part 6 of this chapter.

     Secretion of the adrenocorticotropic hormone is under the control of the central nervous system, acting through the hypothalamus to the level of glucocorticoids in the blood. The hypothalamus increases the production rate of the hormone; glucocorticoids decrease it. In general, it appears that stimuli which are perceived by the organism as dangerous or harmful lead to adrenocorticotropic hormone secretion. Collectively, such stimuli are called "stress". Stress will be discussed further in Part 6 of this chapter. There is, however, a disturbing paradox: the highest concentration of this hormone in the blood is observed just after waking, and the concentration falls through the day, rising again beginning at 2:00 a.m. This suggests either that the relationship to stress is not as close as one would like to believe, or that work is actually pleasant. Another possibility, which does not seem to have been investigated, is that the level of the hormone is influenced by the time of eating. The value falls after breakfast, and it continues to fall after lunch and dinner. Beginning at 2:00 a.m., one enters a period of undernutrition which increases until breakfast. Adrenocorticotropic hormone through the glucocorticoids may serve to maintain blood glucose during this time.

     The only known target organ is the adrenal cortex. Some injected adrenocorticotropic hormone is found in the kidney, but it seems to exert no effect there. How the adrenocorticotropic hormone influences adrenal cortical activity is by no means clear. It increases adrenal blood flow, but this may be a consequence of increased adrenal activity rather than its cause.

     The nature and mechanism of the primary adrenocorticotropic effects have been considered under the glucocorticoids (Part 3 of this chapter). It should be reemphasized that an effect on aldosterone secretion exists, though the adrenal cortex can secrete aldosterone in the absence of the adrenocorticotropic hormone.

     The interrelationships between the secretion of adrenocorticotropic hormone and the factors which influence it are shown in Figure 361.

     Thyrotropic hormone and thyroid hormone form a self-regulating system. Thyrotropic hormone acts on the normal thyroid gland, causing it to release thyroxine, most of which is protein bound in the blood. The unbound portion regulates the pituitary production of thyrotropic hormone; high levels suppress its formation, while low levels increase it. Thus, the thyroid hormone remains at a fairly constant level all the time (See Figure 362).

6. Diseases of the Endocrine System:

     Diseases of the endocrine system, except for diabetes mellitus and perhaps thyroid diseases, are very rare. They are, however, so sensational that they excite attention out of all proportiion to their importance. It is a rare person who does not know that giants and midgets result from over- or underproduction of the pituitary growth hormone, and most people who cannot think of anything else which ails them attribute their problems to "stress," though most of them are not medical problems.

a. Disorders of the Digestive Hormones:

     Undersecretion of gastrin probably occurs in pernicious anemia, where the gastric mucosa is very poorly developed. Hydrochloric acid secretion is also impaired, and it is not certain whether the atrophy of the mucosa results from faulty release of gastrin with under stimulation of the gastric glands or is primarily a mucosal disease. See also Chapter 9.

     Enterogastrone, produced from the duodenal mueosa when fat intake is high slows down the emptying of the stomach. Its absence is often noted after eating Chinese food, which is quite low in fat. Americans, accustomed to feeling full for several hours after eating, are often surprised to find themselves hungry two hours after a Chinese dinner. This is probably due to the low fat of the food and the rapid emptying of the stomach, uninhibited by enterogastrone.

     A once rare disease, diabetes insipidus, is becoming more common with surgical assistance. In this disease, the production of antidiuretic hormone is impaired by disease or overenthusiastic removal of the posterior lobe of the pituitary. In the absence of antidiuretic hormone, large quanties of urine are formed, up to 20 ml / mm, and the patient may be forced to spend most of his time in urinating and drinking. The surgical production of diabetes insipidus often occurs when the pituitary gland is removed, as it sometimes is, to slow the growth of cancer. The development of the disease after such an operation can be prevented if particular care is taken to preserve as much of the pituitary stalk as possible. The disease can be controlled reasonably well by the use of antidiuretic hormone preparations.

     It has been suggested that alcohol may decrease the sensitivity of the osmoreceptors to hyperosmolar solutions, and that by so doing, it prevents the secretion of antidiuretic hormone. This would account for the increased urine flow in drinking alcoholic beverages, and it may, account for the characteristic dry mouth of the morning after.

     The disturbances in osmolarity and the consequent fluid shifts may also be responsible in part for hangovers, suggesting that antidiuretic hormone taken after drinking might prove a useful hangover remedy. The hormone has recently become available as a nasal spray, though it is not sold for the treatment of hangovers.

     Primary Aldosteronism is the name given to the condition in which excessive quantities of aldosterone are produced by tumors of the adrenal cortex. The disease was first described in 1956. In the next 10 years a world-wide total of 400 cases was reported: it is hardly a significant disease. Sodium is retained to an unusual extent; potassium is excreted in excess. Most patients have hypertension, though edema, which would be expected from sodium retention, is mild.

     Secondary Aldosteronism occurs when there is a physiological stimulus to aldosterone formation or a defect in aldosterone destruction. As was noted earlier, blood volume reduction (or sodium deficiency) appears to activate the aldosterone producing mechanism. This occurs in animals that have suffered blood loss. It also occurs in persons in whom the loss of plasma proteins leads to a reduction in blood volume, as in cirrhosis of the liver or nephrosis (See Chapter 13).

     In chronic congestive heart failure, the cardiac output and the blood flow to the liver are reduced. Destruction of aldosterone occurs primarily in the liver, so that when the hepatic blood flow is reduced, normal aldosterone production results in increased levels of aldosterone in the blood. The sequence of events which follows is a particularly unfortunate one: the retention of sodium prompted by aldosterne results in hyperosmolarity of the body fluids, which causes antidiuretic hormone release, retaining water. The already overloaded heart is subject to an increased load, and the cardiac output and hepatic blood flow fall further. Chlorothiazide, which enhances sodium excretion by reducing the tubular reabsorption of sodium, is very often the only treatment needed by such patients. Antialdosterone compounds, steroids or spirolactones, are also useful.

     Destruction of the adrenal cortex by tuberculosis leads to hypoaldosteronism. Sodium retention is impaired, and the volume of blood and extraeellular fluids is reduced. The condition, called Addison's disease, involves glucocorticoid deficiency as well as hypoaldosteronism. Such patients do reasonably well on substitution treatment with adrenal cortical extracts. (See also below on glucocorticoid deficiency).

     Accidental removal of the parathyroid glands during thyroid removal is very rare, now that their importance has been realized. Tumors of a parathyroid gland, resulting in hypersecretion of parathyroid hormone, mobilize bone calcium. Plasma calcium elevation is often associated with an ill-defined sense of malaise. Increased renal excretion of calcium and phosphate sometimes leads to the formation of kidney stones and these may be the first clue to the diagnosis.

     Later, so much calcium may be removed from the bones that they may become less dense than normal. This may be general, or there may be one or more "punched out" spots, called bone cysts. Bones so affected may fracture very easily, and such fractures are not infrequently the first unmistakeable sign that there is parathyroid disease. The treatment, usually very successful, is simply removal of the affected gland.

     Hypothyroidism: Deficiency in the thyroid hormone may result from a defect in the thyroid gland itself, failure of the anterior lobe of the pituitary to produce thyrotropic hormone, or a lack of dietary iodine. The appearance of the disease varies with the age at onset. Thyroid failure in the newborn or infant leads to severe developmental abnormalities. This condition, called cretinism, and it can be corrected by the administration of thyroid, provided that it is recognized in time. Delay in diagnosis results in defective development, and the greater the delay, the more serious are the consequences. Thyroid atrophy in older children and adults results in a number of changes to which the term myxedema is spplied. The myxedematous person tends to have a dull, bored expression, puffy eyelids, and thick, dry, rough skin. The voice is hoarse, almost croaking. There seems to be a generalized "slowing down" of mental and physical activity.

     Most cases of myxedema due to thyroid failure can be treated with thyroid hormone taken by mouth. If the myxedema is due to pituitary failure, it is usually associated with other endocrine changes, and its treatment is more difficult. However, such cases are rare.

     Both cretinism and myxedema may be seen when the diet is deficient in iodine. Lacking iodine, thyroxine cannot be made in sufficient quantity, and hypothyroid manefestations follow. In addition to these, the pituitary gland is stimulated to produce thyrotropic hormone because of the low level of thyroid hormone in the blood. The thyroid responds by growing, and when it is large enough to be felt or seen, it is called goiter. Usually, the formation of a goiter serves to keep thyroid function normal. Only when dietary iodine is extremely low do myxedema and cretinism develop.

     The fact that thyroid enlargement keeps thyroid function normal on low iodine intake is easily explained. Ordinarily dietary iodide entering the blood stream goes to both the thyroid and the kidneys. The kidneys excrete some of it, and the thyroid accumulates the rest. A goiter is not only larger than the normal thyroid, but also it has a greater blood flow. Proportionately, more dietary iodide goes to the goiter than to the normal gland, and less is excreted by way of the kidney.

     These facts can be used to diagnose early goiter. Radioactive iodide, I¹³¹, is handled just as the non-radioactive element. In normal persons, about 30-40% of this is taken up by the thyroid in a day, but in patients with goiter, the thyroid uptake is increased greatly. At the same time, the fraction of radioactive iodide appearing in the urine (normally 60-70%) may be reduced to one quarter of its normal value.

     Hyperthyroidism is caused by a material similar to, but not identical with, thyrotropic hormone. Its source is uncertain, though it seems probable that it is of pituitary origin. Patients with true hyperthyroidism usually have warm, moist skin. They complain of feeling warm at temperatures which others find confortable, and they tend to be nervous, apprehensive, and anxious. In many, the eyeballs protrude. Oxygen consumption at rest increases, and there is often weight loss. Some have obvious goiters. Like people with goiters due to iodine deficiency, hyperactive thyroids take up an unusually large proportion of radioactive iodide. This disease is a serious end. The increased cardiac output which goes with the generalized vasodilatition due to high body temperature may overload the heart, leading to failure.

     At one time, the treatment was surgical tbyroidectomy, a rather hazardous procedure, since these people were quite susceptible to ventricular fibrillation under anesthesia. Temporary suppression of the thyroid for long enough to make surgery possible could be brought about by the administration of large amounts of iodide. The mechanism of the iodide effect is unknown.

     Most hyperthyroid patients are now treated with antithyroid drugs. These compounds prevent the conversion of inorganic iodide to iodine. This conversion is necessary for the formation of thyroxine. Patients receiving antithyroid drugs should also be given as much thyroid as they need to maintain normal function.

     Because radioactive iodide is concentrated in the thyroid gland, it is possible to destroy most of the thyroid (and only the thyroid) by giving large amounts of radio-iodide. Many physicians hesitate to do this, particularly in younger patients, since possibility of total thyroid destruction exists. It is, however, becoming more and more the treatment of choice. Surgery is still useful in selected cases.

     Diabetes mellitus: Despite the remarkable progress made in the understanding and treatment of diabetes, it remains the fifth largest cause of death in the United States, exceeded only by heart disease, cancer, pneumonia, and motor vehicle accidents. This is partially due to the fact that only half of all diabetics are recognized. Many diabetics unrecognized in their lifetimes may remain unrecognized at death: it is quite possible that if the same proportions hold among the dead as among the living, diabetes would be the third leading cause of death.

     The disease is usually suggested by the appearance of sugar in the urine, but this may not always occur, particularly if there is reduced glomerular filtration (See Chapter 22). Rarely glucose is found in the urine when diabetes not present. This may occur in perfectly normal people who have taken glucose after a few days on a low carbohydrate diet. It may also occur when the ability of the renal tubules to reabsorb glucose is defective.

     A more reliable method for diagnosing diabetes is the determination of fasting blood sugar. A value of 1.00 mg / ml is normal. Higher values indicate the need for further testing.

     The best test is the glucose tolerance test. A blood sample is taken from the fasting subject who then drinks a solution containing 100 gm of glucose. Blood samples are taken at 1 / 2 hour, 1, 2, and 3 hours. All the samples are now analyzed for glucose. The results of a normal glucose tolerance test are compared with those of a diabetic in Figure 363.

     The rise in the curve in both cases is due to intestinal absorption by glucose. The normal, however, does not rise very much, because the rising glucose triggers pancreatic production of insulin, which prevents glucose from reaching the peripheral circulation by converting it to glycogen in the liver. The diabetic, lacking this ability, allows absorbed glucose to enter the peripheral circulation, so levels of 3 - 4 mg / ml are reached. Return to the resting level is accomplished by excretion of sugar in the urine and utilization of sugar by the brain and a few other tissues. 

     We have seen that insulin opens the cells to glucose; in its absence cells must use other foodstuffs for energy. The chief problem of the diabetic is not the fact that he has too much glucose in his blood, but rather that he cannot use what he has. He is forced to use fats at a rate which exceeds his ability to do so safely.

     Fats are broken down in diabetics and normals alike when other foods are unavailable. Small amounts can be oxidized to carbon dioxide and water, about 100 gm / day, yielding 900 Calories. Any caloric need beyond this results in the moblization of fat, which is oxidized only incompletely. Such excesses of fat do oxidize, but only to the point of forming strong acids, ketone bodies. These are produced in normal metabolism too, but in small quantities, so that they can be burned further to carbon dioxide. In addition to burning fats incompletely, the diabetic converts proteins to carbohydrate uselessly. Thus, his entire metabolic foundation is deranged.

     The most serious derangement is a consequence of his mishandling of fat. The highly acid ketone bodies react with NaHCO₃in the blood. Some are excreted in the kidney as ammonium salts and sodium bicarbonate is restored. But this process has its limits, and soon the ketone bodies are excreted with sodium, and plasma bicarbonate disappears. The diabetic is now acidotic, and in addition, his renal losses of glucose and sodium, accompanied by water, make him dehydrated; and he shortly lapses into a diabetic coma in which his blood pH may be as low as 7. 0, while his tissues, lacking fluid, are shrunken and dry.

     These events may come on quite slowly. As they progress, the body proteins, which have been uselessly broken down, also disappear. The diabetic characteristically shows a combination of polydipsia (too much drinking of water, stimulated by his dehydration), polyphagia (too much eating of food, probably due to the fact that hypothalamic centers for appetite, though surrounded by glucose, have no glucose inside their cells), pofruria (too much urine formation resulting from the osmotic load of glucose and sodium salts of ketone bodies on the tubules), and weight loss (due to the wasting of glucose, the breakdown of protein and the utilization of fat).

     Almost precisely the same changes can be seen in starvation, though of course the polyphagia is absent. However, for a little while after the termination of a long fast, the islet cells seem to "forget" how to secrete insulin, and the faster may show the signs of diabetes though he has returned to a normal diet.

     Polyphegia, polydipsia, polyuria, and weight loss are often the reasons for the diabetic's seeking medical attention. Acidosis is usually present, and the odor of one of the ketone bodies can be detected in the breath.

     The treatment of diabetes is directed toward making glucose available to the cells. Ideally, insulin should be given by mouth in a form which could be absorbed and would be resistant to digestion. It seems improbable (but not impossible) that such a form of insulin will become available soon. The injection of insulin is a rather crude substitute for the fine regulation of carbohydrate metabolism by the normal pancreas, but it is the best treatment available. There are always two dangers in the use of insulin. When too much is given, blood sugar may fall so low as to deprive the central nervou system of its energy source (brain tissue can use only carbohydrates). Insulin requirements may suddenly increase, particularly in infections, and a previously adequate dose now becomes quite inadequate.

     The oral hypoglycemics are substances which stimulate pancreatic secretion of insulin. In this sense, they are nearly ideal substitutes for insulin. Unfortunately, not all diabetics respond to them, and many have so little islet tissue left that they cannot respond. However, about a third of patients with diabetes developing late in life can be completely controlled by a judicious combination of oral hypoglycomics and a diet which does ot too much insulin.

     No matter how treated, diabetics are unusually susceptible to atherosclerosis. Apparently, this is not a result of the disorder in carbohydrate metabolism, but simply another manefestation of the same disease process which leads to islet failure. This process has not been identified, but it seems to be familial, and a family history of diabetes or atherosclerosis should alert a person to the possiblity that he may have one or the other.

     Diabetic women have some problems in pregnancy. The babies grow to be unusually large, and insulin requirements are increased. It is imperative that a diabetic woman who becomes pregnant should have competent and frequent medical advice.

     Hyperinsulinism sometimes occurs as a result of pancreatic tumors involving the islets. It may result from excessive dosage of insulin taken in the treatment of diabetes, and occasionally the responsiveness of the islets to blood sugar is increased. Whatever the cause, blood sugar tends to fall, and as it falls, cerebral metabolism is compromised. Usually, the secretion of catecholamines, glucagon, and the glucocorticoids compensate for the hypoglycemia (low blood sugar), but it is sometimes necessary to give glucose by mouth. The manifestations of hyperinsulinism are sometimes felt by young people, whose pancreases "overreact" to carbohydrates taken at mealtimes. The excess insulin not quite balanced by the catecholamine produces a hypoglycemia, which leads mild restlessness and confusion and, in many cases, an overpowering desire for glucose containing foods, such as candy.

     Hypersecretion of glucocorticoids usually results from excessive production of the adrenocorticotropic hormone. Proteins are broken down to carbohydrate leading to a hyperglycemia, which unlike the hyperglycemia of diabetes is not associated with acidosis. The muscles, skin, and subcutaneous tissues waste away. The anti-inflammatory action of the glucocorticoids predisposes these people to easy infection. For some reason, not well understood, bone calcium is removed. Mental symptoms are very common, and blood pressure is usually high. The disease is called Cushing's Syndrome.

     Addison's disease has been mentioned in connection with hypoaldosteronism. Since it usually involves the entire adrenal cortex, one can expect the manifestations of glucocorticoid defiency as well. Weakness, loss of appetite and indigestion, weight loss, and very low blood pressure are almost always seen, along with a peculiar bronze discoloration of the skin.

     Although patients with Addison's disease do reasonably well on replacement treatment with adrenal steroids, provided that their environment is stable, sudden stresses are badly tolerated by them. They lack the ability to adjust either their glucose formation or their retention of salt to the varying needs of a stressful environment. They are, in consequence, delicately poised between the results of overtreatment (Cushing's syndrome) and the results of undertreatment which may lead to what is called the Addisonian crisis. In the latter, all the manifestations of the disease are seen, but in exaggerated form. Such crises are often fatal.

     Increased production of pituitary growth hormone in children results in overgrowth of the skeleton; pituitary giants result. The converse, extremely rare, is the pituitary dwarf, a perfectly formed and well-proportioned person whose height may be less than three feet. Over production of growth hormone in the adult results in the enlargment of hands, feet, jaw and nose. The skin and subcutaneous tissues thicken and the features becorre coarse. This condition is usually associated with tumors of the anterior pituitary and is best treated by removal of these tumors. Removal will not reverse the disease but serves on to prevent its progression.

Continue to Chapter 26.