by Isaac Asimov
INSULIN AND DIABETES
The best-known hormone is insulin, the first protein whose structure was fully worked out (see chapter 12). Its discovery was the culmination of a long chain of events.
Diabetes is the name of a whole group of diseases, all characterized by unusual thirst and, in consequence, an unusual output of urine. It is the most common of the inborn errors of metabolism. There are 1,500,000 diabetics in the United States, 80 percent of whom are over forty-five. It is one of the few diseases to which the female is more subject than the male: women diabetics outnumber men four to three.
The name comes from a Greek word meaning “syphon” (apparently the coiner pictured water syphoning endlessly through the body). The most serious form of the disease is diabetes mellitus. Mellitus comes from the Greek word for “honey” and refers to the fact that, in advanced stages of certain cases of the disease, the urine has a sweet taste. (This may have been determined directly by some heroic physician, but the first indication was rather indirect: diabetic urine tended to gather flies.) In 1815, the French chemist Michel Eugene Chevreul was able to show that the sweetness is due to the presence of the simple sugar glucose. This waste of glucose plainly indicates that the body is not utilizing its food efficiently. In fact, the diabetic patient, despite an increase in appetite, may steadily lose weight as the disease advances. Up to a generation ago there was no helpful treatment for the disease.
In the nineteenth century, the German physiologists Joseph von Mering and Oscar Minkowski found that removal of the pancreas gland from a dog produced a condition just like human diabetes. After Bayliss and Starling discovered the hormone secretin, it began to appear that a hormone of the pancreas might be involved in diabetes. But the only known secretion from the pancreas was the digestive juice. Where did the hormone come from? A significant clue turned up. When the duct of the pancreas was tied off, so that it could not pour out its digestive secretions, the major part of the gland shriveled, but the groups of cells known as the islets of Langerhans (after the German physician Paul Langerhans, who had discovered them in 1869) remained intact.
In 1916, a Scottish physician, Albert Sharpey-Schafer, suggested, therefore, that the islets must be producing the antidiabetes hormone. He named the assumed hormone insulin, from the Latin word for “island.”
Attempts to extract the hormone from the pancreas at first failed miserably. As we now know, insulin is a protein, and the protein-splitting enzymes of the pancreas destroyed it even while the chemists were trying to isolate it. In 1921, the Canadian physician Frederick Grant Banting and the physiologist Charles Herbert Best (working in the laboratories of John James Rickard MacLeod at the University of Toronto) tried a new approach. First they tied off the duct of the pancreas. The enzyme-producing portion of the gland shriveled, the production of protein-splitting enzymes stopped, and the scientists were then able to extract the intact hormone from the islets. It proved indeed effective in countering diabetes, and it is estimated that in the next fifty years it saved the lives of some 20 million to 30 million diabetics. Banting called the hormone isletin, but the older and more Latinized form proposed by Sharpey-Schafer won out. Insulin it became and still is.
In 1923, Banting and, for some reason, MacLeod (whose chief service to the discovery of insulin was to allow the use of his laboratory over the summer while he was on vacation) received the Nobel Prize in physiology and medicine.
The effect of insulin within the body shows most clearly in connection with the level of glucose concentration in the blood. Ordinarily the body stores most of its glucose in the liver, in the form of a kind of starch called glycogen (discovered in 1856 by the French physiologist Claude Bernard), keeping only a small quantity of glucose in the bloodstream to serve the immediate energy needs of the cells. If the glucose concentration in the blood rises too high, the pancreas is stimulated to increase its production of insulin, which pours into the bloodstream and brings about a lowering of the glucose level. On the other hand, when the glucose level falls too low, the lowered concentration inhibits the production of insulin by the pancreas, so that the sugar level rises. Thus a balance is achieved. The production of insulin lowers the level of glucose, which lowers the production of insulin, which raises the level of glucose, which raises the production of insulin, which lowers the level of glucose—and so on. This is an example of what is called feedback. The thermostat that controls the heating of a house works in the same fashion. Feedback is probably the customary device by which the body maintains a constant internal environment. Another example involves the hormone produced by the parathyroid glands, four small bodies embedded in the thyroid gland. The hormone parathormone was finally purified in 1960 by the American biochemists Lyman Creighton Craig and Howard Rasmussen after five years of work.
The molecule of parathormone is somewhat larger than that of insulin, being made up of eighty-three amino acids and possessing a molecular weight of 9,500. The action of the hormone is to increase calcium absorption in the intestine and decrease calcium loss through the kidneys. Whenever calcium concentration in the blood falls slightly below normal, secretion of the hormone is stimulated. With more calcium coming in and less going out, the blood level soon rises; this rise inhibits the secretion of the hormone. This interplay between calcium concentration in the blood and parathyroid hormone flow keeps the calcium level close to the needed level at all times. (And a good thing, too, for even a small departure of the calcium concentration from the proper level can lead to death. Thus, removal of the parathyroids is fatal. At one time, doctors, in their anxiety to snip away sections of thyroid to relieve goiter, thought nothing of tossing away the much smaller and less prominent parathyroids. The death of the patient taught them better.)
At some times, the action of feedback is refined by the existence of two hormones working in opposite directions. In 1961, for instance, D. Harold Copp, at the University of British Columbia, demonstrated the presence of a thyroid hormone he called calcitonin, which acted to depress the level of calcium in the blood by encouraging the deposition of its ions in bone. With parathormone pulling in one direction and calcitonin in the other, the feedback produced by calcium levels in the blood can be all the more delicately controlled. (The calcitonin molecule is made up of a single polypeptide chain that is thirty-two amino acids long.)
Then, too, in the case of blood-sugar concentration, where insulin is involved, a second hormone, also secreted by the islets of Langerhans, cooperates. The islets are made up of two distinct kinds of cells, alpha and beta. The beta cells produce insulin, while the alpha cells produce glucagon. The existence of glucagon was first suspected in 1923, and it was crystallized in 1955. Its molecule is made up of a single chain of twenty-nine acids, and, by 1958, its structure had been completely worked out.
Glucagon opposes the effect of insulin, so the two hormonal forces push in opposite directions, and the balance shifts very slightly this way and that under the stimulus of the glucose concentration in blood. Secretions from the pituitary gland (which I shall discuss shortly) also have a countereffect on insulin activity. For the discovery of this effect, the Argentinian physiologist Bernardo Alberto Houssay shared in the 1947 Nobel Prize for medicine and physiology.
Now the trouble in diabetes is that the islets have lost the ability to turn out enough insulin. The glucose concentration in the blood therefore drifts upward. When the level rises to about 50 percent higher than normal, it crosses the renal threshold: that is, glucose spills over into the urine. In a way, this loss of glucose into the urine is the lesser of two evils, for if the glucose concentration were allowed to build up any higher, the resulting rise in viscosity of the blood would cause undue heartstrain. (The heart is designed to pump blood, not molasses.)
The classic way of checking for the presence of diabetes is to test the urine for sugar. For instance, a few drops of urine can be heated with Benedict’s solution (named for the American chemist Francis Gano Benedict). The solution conta
ins copper sulfate, which gives it a deep blue color. If glucose is not present in the urine, the solution remains blue. If glucose is present, the copper sulfate is converted to cuprous oxide. Cuprous oxide is a brick-red, insoluble substance. A reddish precipitate at the bottom of the test tube therefore is an unmistakable sign of sugar in the urine, which usually means diabetes.
Nowadays an even simpler method is available. Small paper strips about two inches long are impregnated with two enzymes, glucose dehydrogenase and peroxidase, plus an organic substance called orthotolidine. The yellowish strip is dipped into a sample of the patient’s urine and then exposed to the air. If glucose is present, it combines with oxygen from the air with the catalytic help of the glucose dehydrogenase. In the process, hydrogen peroxide is formed.
The peroxidase in the paper then causes the hydrogen peroxide to combine with the orthotolidine to form a deep blue compound. In short, if the yellowish paper is dipped into urine and turns blue, diabetes can be strongly suspected.
Once glucose begins to appear in the urine, diabetes mellitus is fairly far along in its course. It is better to catch the disease earlier by checking the glucose level in the blood before it crosses the renal threshold. The glucose tolerance test, now in general use, measures the rate of fall of the glucose level in the blood after it has been raised by feeding a person glucose. Normally, the pancreas responds with a flood of insulin. In a healthy person the sugar level will drop to normal within two hours. If the level stays high for three hours or more, it shows a sluggish insulin response, and the person is likely to be in the early stages of diabetes.
It is possible that insulin has something to do with controlling appetite.
To begin with, we are all born with what some physiologists call an appestat, which regulates appetite as a thermostat regulates a furnace. If one’s appestat is set too high, one finds oneself continually taking in more calories than one expends, unless one exerts a strenuous self-control which sooner or later wears the individual out.
In the early 1940s, a physiologist, Stephen Walter Ranson, showed that animals grew obese after destruction of a portion of the hypothalamus (located in the lower part of the brain). This seems to fix the location of the appestat. What controls its operation? Hunger pangs spring to mind. An empty stomach contracts in waves, and the entry of food ends the contractions. Perhaps it is these contractions that signal to the appestat. Not so: surgical removal of the stomach has never interfered with appetite control.
The Harvard physiologist Jean Mayer has advanced a more subtle suggestion. He believes that the appestat responds to the level of glucose in the blood. After food has been digested, the glucose level in the blood slowly drops. When it falls below a certain level, the appestat is turned on. If, in response to the consequent urgings of the appetite, one eats, the glucose level in one’s blood momentarily rises, and the appestat is turned off.
THE STEROID HORMONES
The hormones I have discussed so far are all either proteins (as insulin, glucagon, secretin, parathormone) or modified amino acids (as thyroxine, triiodothyronine, adrenalin). We come now to an altogether different group—the steroid hormones.
The story of these begins in 1927, when two German physiologists, Bernhard Zondek and Selmar Aschheirn, discovered that extracts of the urine of pregnant women, when injected into female mice or rats, aroused them to sexual heat. (This discovery led to the first early test for pregnancy.) It was clear at once that Zondek and Aschheim had found a hormone—specifically, a sex hormone.
Within two years pure samples of the hormone were isolated by Adolf Butenandt in Germany and by Edward Adelbert Doisy at St. Louis University. It was named estrone, from estrus, the term for sexual heat in females. Its structure was quickly found to be that of a steroid, with the four-ring structure of cholesterol. For his part in the discovery of sex hormones, Butenandt was awarded the Nobel Prize for chemistry in 1939. He, like Domagk and Kuhn, was forced to reject it and could only accept the honor in 1949 after the destruction of the Nazi tyranny.
Estrone is now one of a group of known female sex hormones, called estrogens (“giving rise to estrus”). In 1931, Butenandt isolated the first male sex hormone, or androgen (“giving rise to maleness”). He called it androsterone.
It is the production of sex hormones that governs the changes that take place during adolescence: the development of facial hair in the male and of enlarged breasts in the female, for instance. The complex menstrual cycle in females depends on the interplay of several estrogens.
The female sex hormones are produced, in large part, in the ovaries; the male sex hormones, in the testes.
The sex hormones are not the only steroid hormones. The first nonsexual chemical messenger of the steroid type was discovered in the adrenals. These, as a matter of fact, are double glands, consisting of an inner gland called the adrenal medulla (the Latin word for “marrow”) and an outer gland called the adrenal cortex (the Latin word for “bark”). It is the medulla that produces adrenalin. In 1929, investigators found that extracts from the cortex could keep animals alive after their adrenal glands had been removed—a 100 percent fatal operation. Naturally, a search immediately began for cortical hormones.
The search had a practical medical reason behind it. The well-known affliction called Addison’s disease (first described by the English physician Thomas Addison in 1855) had symptoms like those resulting from the removal of the adrenals. Clearly, the disease must be caused by a failure in hormone production by the adrenal cortex. Perhaps injections of cortical hormones might deal with Addison’s disease as insulin dealt with diabetes.
Two men were outstanding in this search: Tadeus Reichstein (who was later to synthesize vitamin C) and Edward Kendall (who had first discovered the thyroid hormone nearly twenty years before). By the late 1930s, the researchers had isolated more than two dozen different compounds from the adrenal cortex. At least four showed hormonal activity. Kendall named the substances Compound A, Compound B, Compound E, Compound F, and so on. All the cortical hormones proved to be steroids.
Now the adrenals are very tiny glands, and it would take the glands of countless numbers of animals to provide enough cortical extracts for general use. Apparently, the only reasonable solution was to try to synthesize the hormones.
A false rumor drove cortical-hormone research forward under full steam during the Second World War. It was reported that the Germans were buying up adrenal glands in Argentine slaughterhouses to manufacture cortical hormones that improved the efficiency of their airplane pilots in high-altitude flight. There was nothing to it, but the rumor had the effect of stimulating the United States Government to place a high priority on research into methods for the synthesis of the cortical hormones; the priority was even higher than that given to the synthesis of penicillin or the antimalarials.
Compound A was synthesized by Kendall in 1944; and by the following year, Merck & Co. had begun to produce it in substantial amounts. It proved of little value for Addison’s disease, to the disappointment of all. After prodigious labor, the Merck biochemist Lewis H. Sarrett then synthesized, by a process involving thirty-seven steps, Compound E, which was later to become known as cortisone.
The synthesis of Compound E created little immediate stir in medical circles. The war was over; the rumor of cortical magic worked on German pilots had proved untrue; and Compound A had fizzled. Then, in an entirely unexpected quarter, Compound E suddenly came to life.
For twenty years, the Mayo Clinic physician Philip Showalter Hench had been studying rheumatoid arthritis, a painful, sometimes paralytic disease. Hench suspected that the body possessed natural mechanisms for countering this disease, because the arthritis was often relieved during pregnancy or during attacks of jaundice. He could not think of any biochemical factor that jaundice and pregnancy held in common. He tried injections of bile pigments (involved in jaundice) and sex hormones (involved in pregnancy) but neither helped his arthritic patients.
Howeve
r, various bits of evidence pointed toward cortical hormones as a possible answer; and, in 1949, with cortisone available in reasonable quantity, Hench tried that. It worked! It did not cure the disease, any more than insulin cures diabetes, but it seemed to relieve the symptoms, and to an arthritic that alone is manna from heaven. What was more, cortisone later proved to be helpful as a treatment for Addison’s disease, where Compound A had failed.
For their work on the cortical hormones, Kendall, Hench, and Reichstein shared the Nobel Prize in medicine and physiology in 1950.
Unfortunately, the influences of the cortical hormones on the body’s workings are so multiplex that there are always side effects, sometimes serious. Physicians are reluctant to use cortical-hormone therapy unless the need is clear and urgent. Synthetic substances related to cortical hormones (some with a fluorine atom inserted in the molecule) are being used in an attempt to avoid the worst of the side effects, but nothing approaching a reasonable ideal has yet been found. One of the most active of the cortical hormones discovered so far is aldosterone, isolated in 1953 by Reichstein and his co-workers.
THE PITUITARY AND THE PINEAL GLANDS
What controls all the varied and powerful hormones? All of them (including a number I have not mentioned), can exert more or less drastic effects in the body. Yet they are tuned together so harmoniously that they keep the body functioning smoothly without a break in the rhythm. Seemingly, there must be a conductor somewhere that directs their cooperation.
