Part 3

The rôle of the liver.--The next stages of metabolism occur in the liver, to which the blood passes immediately after leaving the intestine. Here is a veritable chemical laboratory wherein innumerable transformations are worked. Some of them are now understood, and here, as later elsewhere, at every step of change, a catalyst is present to facilitate each separate chemical alteration. Many catalysts are very specific, accomplishing one definite task; others are more generally active. They have been likened to keys, which, fitting into certain locks, permit the locks to be turned. Without these catalysts or accelerators, transformations would occur so slowly that active life, such as ours, would be impossible.

In the liver much of the sugar is removed from the blood and organized into a starch-like substance called glycogen. Thus stored, it is available later, when the blood may be poor in sugar. One of the main functions of the liver is to maintain a nearly constant concentration of sugar in the blood, which it does by subtracting sugar whenever, as after meals, the blood stream is flooded, and adding sugar at those times between meals, and at night, when the sugar level in the blood is low.

In the liver, the amino-acid fragments of proteins are partly destroyed, ammonia is split off from them and changes into a waste product, urea, which is later excreted by the kidneys. Also sugar is made from many of the fragments of protein, and this sugar is either stored away as glycogen with the sugar originating from carbohydrate, or added to the blood. Nearly 60 per cent, by dry weight, of the protein eaten is thus changed to sugar, and as a final result of the normal processes of digestion, and action of the liver, we find that all of the carbohydrate, approximately 58 per cent of the protein, and it is supposed, 10 per cent of the fat of the food, eventually finds its way into sugar.

If we desire to know how much sugar a certain food will add to the metabolism, that is, the sugar value of the food, we must know both the weight of the food and how much of this weight is carbohydrate, how much is protein, and how much is fat. The sugar value will be the sum obtained by adding the weight of the carbohydrate, 58 per cent of the weight of the protein, and 10 per cent of the weight of the fat. For instance, a slice of bread weighing 2 ounces or 60 gm., spread with one-third of an ounce or 10 gm. of butter would be 32 gm. of carbohydrate, 6 gm. of protein and 11 gm. of fat. The sugar value of this mixture would be 32 plus 3.5 plus 1.1 or 36.6 gm. A glass of whole milk, 6 ounces or 180 gm. of milk, would contain 9 gm. of carbohydrate, 5 gm. of protein and 7 gm. of fat, and its sugar value would be 9 plus 3 plus 0.7, or nearly 13 gm.

After passing the liver, the blood enters the heart which then pumps it throughout the system of tubes called arteries into all the crevices of the body. Every tissue is thus bathed constantly with circulating fluids which contain sugar and the other elements of nutrition in forms suitable for utilization.

The liberation of energy in the tissues.--In the blood itself, no important chemical transformation occurs. The food fragments are picked out of the blood by the tissues and in the living protoplasms of each tissue, those important changes occur which constitute the most essential processes of life. These are, first, the building up of new protoplasmic matter, namely, growth and tissue repair, and, second, the liberation of energy by further decomposition and final burning or oxidation. Again each step of transformation requires the aid of some energizer or catalyst. The presence of many of these catalysts is only surmised. Some of them, however, have been captured and their mysteries are exposed. Among these is thyroxin, which Kendall showed to be the chief product of the thyroid gland. Thyroxin sets the pace of life. The rate of oxygen utilization is governed largely by it, so that when the thyroid gland is destroyed or not functioning, as in some forms of goiter, energy transformation proceeds at a slower tempo.

Insulin a catalyst.--We come now to diabetes, a condition which results from the lack or deficiency of a catalyst called insulin. The function of insulin, it seems, is to prepare sugar for utilization.

Diabetes a lack of insulin.--In diabetes, sugar escapes utilization in whole or in part. As it circulates normally in the blood, it is locked up, so to speak, and is unavailable either for storage as glycogen, or for oxidation or other transformation. Its energy is sealed, and before it becomes available a lock must be turned. The key to this lock is insulin, and in the absence of this key the normal means by which sugar is removed from the blood are unavailing, and in consequence, the level of sugar in the blood rises, and sugar appears in the urine.

Symptoms of diabetes.--The symptoms of diabetes are due for the greater part to the accumulation in the blood and excretion in the urine of unused sugar. On leaving the body, sugar carries water with it. A diabetic patient may pass many quarts of urine daily. This is a phenomenon like the drying of meats or fish by salting them. Water is subtracted in such amounts that the body dries; even the skin becomes dry, and the tongue may cleave to the roof of the mouth. Furthermore, much otherwise available food energy is lost with sugar in the urine. As much as a pound of sugar may be passed in a day. Consequently, the tissues starve in the midst of plenty. The appetite, therefore, is sharpened, but the more the patient eats, the greater becomes the wastage of food energy, and the more severe the symptoms.

Acid poisoning.--This is not all or, by any means, the worst. It so happens that fat, which under suitable circumstances, is readily metabolized, fails to oxidize smoothly when less than a certain minimum of sugar is being used. The fats, it is said, burn in the fire of carbohydrates. If a perfectly normal person is deprived of carbohydrate and fed only fat and a little protein, certain products of incompleted combustion of fat will accumulate in the body. These substances are acetone, aceto-acetic acid, and the hydroxybutyric acid. Acetone is not very poisonous, nor is hydroxybutyric acid, but aceto-acetic acid behaves somewhat after the manner of the anesthetics like chloroform. If a person has diabetes of some severity, acetone bodies may arise even when carbohydrate is fed because only burning sugar prevents their formation, and in severe diabetes the carbohydrates fail to burn.

Diabetic coma.--In diabetes, therefore, such amounts of aceto-acetic acid may be formed that the patient is actually anesthetized and falls into unconsciousness. This is diabetic coma, which in the past has been the chief cause of death in the diabetes of children and young persons. The proper use of insulin should prevent these deaths from coma.

THE STORY OF INSULIN

Minkowski’s discovery.--The story of insulin began a generation ago with the discovery of German investigators, Minkowski and von Mehring. This was in 1889, and until then the relation of the pancreas to diabetes was scarcely suspected, and no one had an idea where to look for the means to check the disease. The pancreas is an organ about the size of one’s hand which pours digestive juices into the intestine.

Removal of pancreas causes diabetes.--Minkowski was studying digestion and it happened in the course of certain investigations, that it became necessary to operate on a dog and remove this organ. A few days later it was noticed that flies were attracted in great numbers by the urine of this dog. The urine was examined, and the reason for the flies and the relation of the pancreas to diabetes was at once apparent. The urine contained sugar. Another animal was operated on, the pancreas removed and diabetes followed. Cats, swine, and frogs were then experimented with. In every case, complete removal of the pancreas resulted in severe diabetes, while partial removal caused a more chronic and milder diabetes.

The islands of Langerhans.--Previously, in 1869, Paul Langerhans, described peculiar clumps or islands of cells which differ in appearance from the bulk of the tissue in the pancreas. In 1890, Scobolew and Schulze showed that if the ducts leading from the pancreas were tied off, the islands withstood the destruction that was wrought in the rest of the organ by backing up of the pancreatic secretions. Animals treated in this manner did not develop diabetes, and it was concluded, therefore, that it was the islands that manufactured the anti-diabetic material of the pancreas. The name “insulin” was suggested for this material in 1916 by an Englishman, Shafer.

Previous attempts to obtain insulin.--In the meantime, efforts were being made by numerous scientists to extract from the pancreas the anti-diabetic principle. Some of these attempts nearly succeeded. Many of them failed because it was not known then that insulin is rendered inactive when it is given by mouth and subjected to the disintegrating action of the juices in the digestive tract. Innumerable attempts were made to control diabetes by feeding either fresh pancreas, or pills and pellets manufactured from the pancreas. Thus far, all such efforts have been in vain, and yet various drug companies continue to sell pancreatic pills as diabetic remedies. The results obtained by grafting pieces of pancreas into dogs previously made diabetic by the removal of the pancreas have been more successful. The experimental diabetes of animals so treated can be controlled, but such procedures offer nothing to mankind, because grafts made from a lower animal to man invariably atrophy, that is, shrink up and disappear.

Banting’s idea.--Thus the subject stood when, in the autumn of 1920, Frederick Banting, recently home from the war, began his work. The idea came, he writes, while reading an article dealing with the relation of the islands of Langerhans to diabetes. In his own words, it was this: “From the passage in this article, which gives a resumé of degenerative changes in the acini (cells connected with the ducts or passageway system) of the pancreas following ligation of the ducts, the idea presented itself that since the acinous, but not the islet tissue, degenerates after this operation, advantage might be taken of this fact to prepare an active extract of islet tissue. The subsidiary hypothesis was that trypsinogen (one of the digestive ferments prepared by the acinous cells) or its derivatives was antagonistic to the internal secretion of the gland. The failures of other investigators in this much worked field were thus accounted for.” In other words, the failure of his predecessors, Banting thought, was due to the probability that the digestive juices of the pancreas destroyed insulin before it could be extracted from the islands, and his plan was to circumvent this difficulty by first destroying the part of the pancreas concerned in making these juices.

The first insulin.--Banting took his idea to Professor Macleod of the University of Toronto. He received encouragement and facilities for work, and in the laboratory of Professor Macleod, with the skilled assistance of Mr. C. H. Best, he put the idea to the test, and it worked. Dogs made diabetic by removing their pancreas were treated with material obtained from degenerated pancreas, and could be kept alive. The sugar in their blood decreased each time this material was injected beneath the skin and the sugar in their urines diminished. This was the first insulin. The next step was taken soon after. Banting and Best knew from the work of their predecessors that the pancreas of animals in the womb, that is, of embryos or fetuses, show island tissue some time in their development before the tissue responsible for the digestive juices is fully formed. It occurred to them, therefore, that they could circumvent the destructive action of the juices by making insulin from embryo calves. This was tried, and it succeeded. Enough insulin was obtained to try on a patient. Later developments permitted the preparation of insulin from adult animals. Swine and beef pancreas from the slaughter house became the source of insulin. At first these preparations contained some protein which made it poisonous, and unsuitable for use in patients. Another chemist in the University of Toronto, Professor J. B. Collip, overcame this difficulty, and, with the co-operation of a group of able physicians in the university, Doctors Graham, Campbell and Fletcher, the new insulin was used on a large group of patients, and its value thus became definitely established.

Insulin now available for everyone.--Insulin can now be obtained in every drug store and fortunately, thanks to wise provisions for maintaining control of its manufacture arranged for by the University of Toronto, it is everywhere of uniform strength. This matter of constant strength is of the greatest importance. As will appear later, danger attends its indiscriminate use, and the dose must be made to match the amount of sugar derivable from the diet. Unless the strength of various lots of insulin is constant, accurate treatment would be impossible. This was recognized early by the workers in Toronto and, to protect the public, it was decided that insulin must be patented so that its manufacture could be restricted to those firms who would permit the control of their products by an insulin committee in Toronto. The firm of Eli Lilly and Company of Indianapolis put their plant at the disposal of the insulin committee and assisted in developing methods of large scale production. Subsequently, other firms have been licensed, by the insulin committee, to make insulin.

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The patenting of discoveries by physicians is usually frowned on by physicians. It is opposed to the ethical code of the profession. The patenting of insulin, however, does not violate this ethical code because the patent, while secured in the name of Doctor Banting and his associates, was given outright by them to the University of Toronto to be used, not for any commercial advantage, but as a means to guarantee that this splendid discovery would not be exploited by others to its discredit.

Insulin described.--Today, insulin, as sold, is a clear, watery solution. A small vial contains 50, 100 or 200 units, as indicated on the label. The strength of the unit is standard. A unit of insulin will have a certain definite lowering effect on the sugar in the blood of a normal animal. The rabbit is chosen as the test animal. In the patient with diabetes, a unit of insulin will increase tolerance, that is, it will add to the amount of sugar that can be utilized, from 0.5 gram to 4 grams, depending on the character of the diet and the presence or absence of complications. The average patient uses between 10 and 30 units a day. The cost has been reduced to below one cent a unit, so that insulin is now brought within the reach of everyone. Indeed, the cost is negligible when we consider that patients who, without insulin, were helpless invalids, dependent on relatives or charity, are now as fit and strong as their neighbors, and able to work again.

THE CAUSE OF DIABETES

Disease of the pancreas a cause of diabetes.--The pancreas, whose removal Minkowski showed caused diabetes, is located in the abdomen near the stomach and pours its digestive juices through a channel or duct into the intestine. The organ has a second function, as has been told above, namely, to make insulin. This second product, which is elaborated by the islands of Langerhans, goes into the blood. The Langerhans islands are properly regarded as a distinct and separate organ. They are, however, so intimately associated and intermingled with the rest of the pancreas that any disease or injury of the pancreas may affect them seriously, reduce their insulin-making capacity and thus cause diabetes. Actually a large part of the pancreas may be destroyed before diabetes results. In dogs, little more than one-tenth of the gland remaining intact is sufficient to prevent the excretion of sugar. Men are more susceptible to diabetes than dogs, but even in men the pancreas may be seriously affected by inflammation or cancer before its insulin capacity is reduced to the point where actual insulin shortage is manifest.

The body is so constructed that every organ has a factor of safety. A very large amount of the liver, for instance, can be diseased before any failure in its function is detectable. The same is true of the kidneys and of the heart, and the factor of safety in the case of the pancreas explains why we do not all have diabetes. Very few people have a normal pancreas, because inflammations in organs near the pancreas are fairly common; for instance, inflammation of the gallbladder, and very frequently the pancreas is involved in such inflammation. However, the number of persons with known gallbladder disease who develop diabetes, is not appreciably greater than that of persons without any evidence of such inflammations.

Hardening of arteries a cause of diabetes.--The pancreas may be injured, as is true of all of the organs of the body, by disturbance of its blood supply, especially through hardening of the walls of the arterial tubes which bring it its blood, and narrowing of their lumens or passageways. Older persons with hardened arteries may develop diabetes in this manner. On the other hand, many persons have extreme arterial disease and consequent destruction of pancreatic islands without diabetes.

Infections a cause of diabetes.--The delicate tissues of the pancreas, just as in the case of other organs, may be poisoned in the course of a general disease, such as scarlet fever, mumps, or influenza and, in consequence, diabetes may result from such diseases. There is, however, nothing specific in this. A certain number of cases of diabetes can be traced to a preceding acute intoxication of this character, but it is by no means true that any one of the known infections is always followed by diabetes.

Functional overstrain the chief cause of diabetes.--Functional overstrain is a recognized cause of disease, especially of the heart, but also of other organs. The heart may be irreparably injured by excessive exertion. Functional overstrain of the pancreatic islands resulting from long continued overeating is a cause of much diabetes. Persons who persistently overeat are usually markedly overweight. Some thin people are also equally prone to overeat, and yet, for some thus far unknown reason, remain thin.