Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 84

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189

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is to be regretted, that we are still unable to measure the linity of the organs themselves. But in spite of this lack have complete evidence of the influence of acids upon what aking place in the organism. I will give you a striking mple from the field of normal metabolism. The production ven small quantities of lactic acid in the working muscles, their entrance into the blood will excite the breathing er, although in this case, on account of the small amount cids brought into play, no change in the ionic concentration he blood occurs. This excitement of the respiratory cen- is to be compared with the far stronger irritation occur- in coma. I will remind you also of the dreaded casts in urine, which suddenly appear in many cases before the reak of the coma. I believe them to be acid casts, and I k that they indicate a local decrease of alkalinity in the eys, whilst the alkalinity of the blood and of the vital n centers is yet normal.

o sum up the objections regarding the state of reaction in organism I would say that alkalinity, in the sense of physi- chemistry, and alkalinity in the common language of istry and of biology, are by no means identical. When is no change in the ionic concentration, lessened alkalin- the biological sense may be present and may be of great- nportance.

10 older objections to Stadelmann's theory are mentioned y more rarely than in former times, but even to these deration must be paid. Sometimes a comatose state was ntered in diabetic patients, who did not show any signs le acidosis. Neither the deepened breathing was present as the amount of carbonic acid in the blood diminished ; alysis of the urine failed to give oxybutyric acid. Upon observation of the clinical symptoms these comatose s have proved to be phenomena of a different order. A ic may die quite as well of uræmic coma or of epileptic and even the weakness of the heart may be accompanied jort of coma. These forms of coma have nothing in in with the dyspnoic form of coma save unconsciousness. itical eye of the clinician has little difficulty in recog- them. Objections of this kind seldom are met with at

the other hand, there have been observed symptoms of

dyspneic coma in non-diabetic diseases. I have seen myself such a dyspneic coma only once and then in a uræmic patient ; " but older authors of the eighties affirm that it was by no means exceptional in uræmia and in fever. Here also a diminution of carbonic acid in the blood and of the titrated alkali occurs similar to that in diabetes. Since the comatose state in neph- ritis and diabetes have at least two symptoms in common, must we consider that acid-poisoning is present also in uræmia ? And is fatal acid-poisoning a symptom which is not specific for diabetes? Also in infectious diseases similar changes of the alkalinity are held to have been found. Of all the objections against the doctrine of Stadelmann, I believe this one to be the most important. A full contradiction and definite refutation of this objection-I own it frankly-is as yet not possible; no detailed description of the clinical symptoms is given in the older observations which have been published, and the method of measuring the alkalinity has generally been inadequate. No attention has been paid any more to such events for 20 years, and I myself, though highly interested in the subject, have not had occasion to make researches upon this point, either clinical or experimental. But I am inclined to believe

· that a certain kind of weak acidosis could be in play here too. It is conceivable that lactic acid may have accumulated within the body of uræmic or infected patients. New inquiries on this point are needed. It should also be determined, whether acids are stored up in the tissues of such patients in the same way as in diabetic coma. Although one should be cautious in predicting the results of future investigations, I will express my opinion that neither of these lines of research will reveal the existence of a true acidosis in nephritis, fully correspond- ing to diabetic acidosis. Even should an accumulation of lactic acid be found, there will be a difference in its intensity. Although certain symptoms of acidosis as lessened alkalinity of the blood and deepened breathing may be present, other and more important symptoms may be missed, and also with the first symptoms differences are to be found. I find a sup- port for this opinion in an unpublished piece of work of Fraenkel, a pupil of Kraus. He demonstrated that in spite of a certain resemblance, the figures of alkalinity obtained either by titrimetric methods or by measuring the carbonic acid in uræmia and infectious diseases were by no means identical with those obtained in the diabetic coma.

Having thus discussed the clinical aspect of acidosis I turn towards the chemical problem.

The inquiries upon the chemical connections of the acetone bodies, performed during the last decade, have broadened our knowledge, not only regarding the special pathogenesis of diabetic acidosis, but even concerning the general problems of metabolism.

It has been well known for years that acetone and the allied acids do not originate from carbohydrates. In the old con- troversy, however, the first reliable proof as to whether pro-

* Having just returned from America I observed it for a second time in a uræmic patient, but this time on closer observation, its character struck me as being different from the dyspneic coma in diabetes.

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tein or fat was the mother-substance of the acetone bodies, was given only then, when it became evident that in a single experiment the amount of metabolized protein did not suffice for the formation of oxybutyric acid. I found in a boy suffer- ing from diabetic coma, during three days a sum total of 342 grams of acetone bodies in the urine, but during this space of time only 270 grams of albumen were decomposed, in other words a far smaller amount. From the protein large quanti- ties of sugar had been formed; it was, therefore, obvious that the protein alone could not have furnished such immense quantities of organic acids in the same time. In this example at least a great part of the acetone bodies must have been de- rived from the fat. However, this fact did not contradict a simultaneous formation from protein. Further experiments, carried out by Schwarz, Embden and Baer, proved, indeed, that acetone bodies may originate from both protein and fat.

All the researches of these authors are based upon the prin- ciple of feeding-in the presence of acidosis-a certain sub- stance and of observing its influence upon the output of ace- tone bodies. Previous experiments had given no clear results, because the unbroken molecule of protein or fat had been given. Schwarz on feeding butyric acid was the first to ex-

· amine the influence of intermediary products of fat. Later on amino-acids, the components of the protein molecule, and different fatty acids which could be assumed to be intermediary products of the katabolism of fat were administered in such experiments. Such investigations were necessarily carried out, as I said before, when acidosis of a certain degree was present, that is upon diabetic patients or dogs, or upon healthy animals and men fed exclusively on animal food. However, as spontaneous variations occur frequently in acid- osis, the results of such feeding experiments are somewhat doubtful. A discovery of Embden, therefore, was of great advantage in the study. Embden, as you know, found that the isolated dog's liver on artificial circulation produced diacetic acid, which was no doubt derived from the oxybutyric acid. The amount of acetone bodies transferred from the liver to the blood increased considerably when certain substances were added to the blood. This method of investigation, employed with great skilfulness by Embden, has proved its value by giving striking results. Both methods of inquiry, that on the liver and that on living diabetic subjects, supplement and con- trol each other exceedingly well.

We learn from them the following facts: The immediate predecessor of oxybutyric acid is butyric acid, which, by oxida- tion in ß position, is converted into its oxy-acid. Butyric acid has shown itself to be the strongest producer of acetone bodies. The reason is to be found in the fact that this conversion needs only a simple and slight chemical reaction, the addition of one atom of oxygen. The higher fatty acids, however, have to undergo far greater decomposition, a splitting off of many atoms of carbon, before they reach the stage of a chain with + C atoms. In feeding fatty acids, with from 4 to 10 atoms of C, it became manifest that capronic, caprinic and caprylic acids, all having an even number of carbon atoms yielded

oxybutyric acid, while other acids with an uneven number d carbon atoms, such as propionic and valerianic acids, did D: yield oxybutyric acid.

Inasmuch as true fatty acids with an uneven number carbon atoms occur but rarely in the animal metabolism. ! only in small quantities, the practical value of this demonstrar tion is of no importance in the metabolic changes in diabe :. For biological chemistry, however, this discovery was of great: moment. From it, in connection with other experiments, - have been enabled to conclude that the katabolism of far acids goes on by the loss of two carbon atoms from the orie- inal chain. The splitting off begins with an oxidation at t. ß carbon atom. Thus a ß oxy- and further on a B keto-fatrs acid is formed; finally the & C atom is found to be at the end of a new fatty acid in the shape of a carboxyl group. In the way from stearic acid very likely is formed palmitic acid, and from this an acid with 14, 12, 10 and 8 C atoms is derived. and then capronic and butyric acid.

In the same way as acid decomposition goes on by the los of a chain of two carbon atoms, so the building up of fat- acids by synthesis seems to be accomplished by a gradual i- position of two combined carbon atoms. The formation of fr. or rather of fatty acids from sugar, which in the animal king- dom goes on in large proportions, has been explained in the way by Nencki, Hoppe-Seyler and myself, and Heath En others have found new supports for this theory.

The relations existing between amino-acids and acetos- bodies are not so clearly known as with the fatty acids because the chemical processes are more complicated. Some of the amino-acids, leucine, tyrosine and phenylamine, seem to * katabolized to oxybutyric acid, while others, alanine, valize and glycocoll apparently are not, but appear, on the contrary. to diminish the output of acetone bodies. In studying these substances very interesting results have been obtained regard- ing the oxidative decomposition of the amino-acids which ? to this time has been completely unknown.

However, I will forego a discussion of the purely chemsa. aspect of this question. For the present it is sufficient to state the principal result of these investigations, which is a well- marked antagonism between two groups of amino-acids. Pri- tein is by no means to be considered as a unit, in so far ** acidosis is concerned, because some of its components may increase, and others decrease acidosis. So, too, in the forma- tion of sugar the two groups behave differently. It should * remarked that those amino-acids, which in the present state of our knowledge are convertible into sugar, do not yield oxy- butyric acid, while on the other hand that group of amina- acids which undergo transformation into acetone bodies das not give any sugar. Since the protein molecule contains groups of different behavior regarding acidosis, it is clear why it failed to show obvious results in those experiments, in which the whole unsplit protein molecule was given.

Ten years ago I mentioned another possible way for the formation of oxybutyric acid. I thought that it might be formed in a synthetical way. This might take place by unien

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Of two chains with two C atoms, but this way of formation - has not yet been proven. Under this conception alcohol could furnish the material for the synthesis, but not only does it not increase the amount of acetone bodies in urine, but, on the contrary, it rather seems to diminish them.

Allow me to cast a retrospective glance at a period in which therapeutists have drawn erroneous conclusions from the re- sults of these inquiries. When at the end of the last century only the fat, but not yet the protein, had been recognized as a source of acetone bodies, some physicians thought it necessary, to restrict the amount of fat taken by the diabetic, because they feared to raise the acidosis by giving fat. There are two errors in this deduction. The first is the wrong supposition, hat increased ingestion of fat means increased decomposition f fat. But any one, possessing an elementary knowledge of he metabolism of matter and energy, knows that this is not the ase. A surplus of fat given in the diet does not raise oxida- jon any more than does a higher amount of oxygen in the spired air. There is no danger that by giving more fat more it will be decomposed, and more acetone bodies set free the body. And even if this were true, a second factor as neglected, the factor of the destruction of the formed ybutyric acid. Acidosis, and I repeat it again and again, es not only, or perhaps not at all, depend upon the forma- n of acids, but also and perhaps exclusively upon their com- stion. Indeed after analyzing and taking into account the ults of all experiments carried out in this direction, I may , that the ingestion of fat in almost no case of diabetes has luced a marked increase in the output of acetone. An ex- tion is given alone by butter, on account of its richness in ceryls of butyric acid.

n opposition to the behavior of fat a higher intake of pro- may sometimes increase acidosis. But this does not hap- in a direct way, due to the formation of oxybutyric acid n protein, but in an indirect way. The demand made n the katabolizing and oxidizing powers of the organism arge quantities of protein ingested, may lessen the oxida- powers which concern the combustion of acetone bodies. h disturbances may arise also from other incidents such as bles of the digestive tracts. Since fat does not directly case acidosis, we should always try, not only to maintain weight of the diabetic patient by a sufficient supply of fat e diet, but even to increase the same.

e endeavor to avoid those food stuffs, which may form tyric acid, is in vain, since protein and fat each do so. hol and sugar-and the latter is not available by the tic patient-are the only material which do not yield ne bodies. We ought rather to look for some substance would diminish acidosis by increasing the splitting up he combustion of the acetone bodies.

merous substances are known which do this, and they cluded under the name of anti-ketonuric substances. The hydrates exert the strongest anti-ketonuric effect. From 80 grams of sugar are sufficient in a healthy man to

dissipate a strong acidosis, induced by a starvation or by ex- clusive animal food. As yet we do not know how this effect is accomplished. Naunyn's explanation that the decomposition of the acetone bodies is due to the simultaneous combustion of carbohydrates by secondary oxidation is merely a paraphrase. We are, therefore, compelled to look upon the occurrence as a fact without explaining it. A like efficiency is due to the pre- formed carbohydrates of the food, and to those which are newly formed within the body from protein or other material. Gly- cerine owes its anti-ketonuric efficiency to its being trans- formed into sugar. In healthy men the decomposition of large quantities of albumen can dissipate acidosis. Its efficiency likewise is to be referred to the partial conversion into sugar. For those very amino-acids-alanine, glycocoll and aspartic acid, which in the experiment of Embden and Baer showed an anti-ketonuric effect-are the ones from which sugar is formed. However, glycerine and albumen, which in healthy persons diminish the quantity of acetone bodies, are as good as useless in severe diabetes.

This fact, which previously appeared surprising, is now understood. The sugar, formed from glycerine and from protein, whose combustion induced the combustion of acetone bodies in healthy persons, is eliminated in severe diabetes and thus cannot be utilized for the oxidation of the acetone bodies.

Most other materials, known to be anti-ketonuric, such as gluconic acid and others, are not food stuffs and, therefore, cannot be employed permanently. Alcohol, though in bad repute as a poisonous substance, is the only food stuff, which acts beneficially on the diabetic acidosis. It has been shown by experiments of Neubauer and of Benedict that it decreases materially the amount of acetone bodies in the urine. In coma I would not only consider the ingestion of alcohol to be al- lowed, but even to be desired. Therapeutic experiments with this substance in coma require great discretion because of the effect upon the patient and judgment in the interpretation of this effect. Besides alcohol no other compound of the food is at our disposal for combating acidosis. The difficulties of the struggle against acidosis depend upon the fact that the energy of sugar, the most powerful anti-ketonuric body, is not avail- able in severe diabetes. Every improvement in the toleration for carbohydrates will be followed by a decrease in acidosis ; but the general treatment of diabetes is outside of the limits of my lecture. You may attain your purpose of increasing sugar combustion and at the same time lessening acidosis by different means: you may restrict the quantity of protein in the food, you may prescribe fasting and vegetable days, you may give an oatmeal diet for two or three days, you may pre- scribe muscular exercise, or you may combine all these meas- ures, and this will depend on the peculiarities of each indi- vidual case.

The use of bicarbonate of soda, which we continually em- ploy in the treatment of severe acidosis, does not act directly against it; neither does it diminish the formation of acetone bodies, nor does it favor their combustion. In many cases, on the contrary, the amount of acetone bodies found in the urine

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will increase, if great quantities of alkali are given. That by no means signifies a weakness of the oxidative powers, nor must it be considered as disadvantageous, or even dangerous. Rather the contrary is the case. While in general the amount of organic acids in the urine may be considered as an indicator of the degree of acidosis, this is different when alkalies are administered. Alkalies facilitate the elimination of acids by neutralizing them and thus withdraw the acids from oxida- tion ; thus the amount of acids present in the body in a certain moment is diminished, and sufficient alkali is present always to neutralize them and to prevent poisonous action upon the cells. Naunyn contends that he has never seen a sudden death by coma following the withdrawal of carbohydrates since the time when he began to give sufficient quantities of alkalies from the beginning of a strict diet. But no matter how bene- ficial is the action of alkalies, we should not forget that they act only as a palliative remedy and that we should seek for more efficacious substances with which to combat directly the acidosis.

If that substance is once found, which will enable the dia- betic to utilize carbohydrates, acidosis and its dangers will have disappeared.

I return to the problem which I touched slightly at the beginning of my lecture. I have mentioned the possibility that acidosis might have nothing to do with an increased for- mation of oxybutyric acid, but that it depended exclusively on disturbances of oxidation. One may imagine that also in normal life oxybutyric acid may be formed to the same extent as in the coma. This doctrine presupposes that each molecule of fatty acid and of amino-acid, which, according to our knowledge may be transformed into acetone bodies must really be so without exception. In other words, that this way of decomposition of fats and certain amino-acids, leading to oxybutyric acid, is not a facultative one, but that it is obliga- tory. I was able to prove that in diabetic coma such a maxi- mum of oxybutyric acid was formed. One of my patients had decomposed 90 grams of protein and almost 200 grams of fat within 24 hours. From these substances, as far as calculation is possible to-day, about 110 grams of acetone bodies could be derived. This quantity really was found to be eliminated by the urine during three subsequent days. A healthy man living on a carbohydrate free diet would consume about 120 grams of albumen and 210 grams of fat daily ; from these about 120 grams of oxybutyric acid could be formed; that means about 1} to 2 grams per kilo. Are we allowed to assume that he really forms such quantities of acids? We are allowed to do so if we can make it probable, that he is able to destroy them by combustion. Rabbits and dogs have oxidized 3 grams of this acid and even more per kilo introduced at one time into their stomachs. Since combustion is far easier when such sub- stances are formed within the body, it might be possible for a healthy man to decompose 2 grams per kilo.

I furthermore call attention to the great amount of ace- tone bodies, which may be formed by non-diabetic organs. In Embden's experiments, the isolated dog's liver, an organ of

scarcely 200 grams in weight, yielded 3, 4 and even 9 grace of diacetic acid, calculated for 24 hours. Since a part of i: certainly had been destroyed, in the course of the experimar the production was in reality much larger.

No reasons exist in my opinion to disprove the concepti: that a healthy man may form and oxidize such large quantiti- of acetone bodies. For a long time these substances have been recognized as products of intermediary metabolism. Accord ing to my doctrine they would not be facultative, but they would be the obligatory products of the decomposition of fat acids and of some amino-acids. If this doctrine is right, you se clearly that acidosis is only the consequence of disturbed orist tion. However, this conception is as yet not absolutely prorez

Embden takes the opposite standpoint. He observed thx the surviving dog's liver, which was found to produce acetote bodies, was able also to katabolize diacetic acid. In continuita his researches on the liver of a depancreatized dog, he fousi that the destruction of diacetic acid was not smaller than wi" the liver of a healthy animal. Thus finding no decreased oxidation, he considered acidosis to be caused by increase? formation of acids. However, it is not allowable to transfer the results of the experiment upon a dog to the metabolism ! man. Both behave differently. In living dogs accumulatie of acids does not occur so generally and to the same intensi? as in man, they do not lose the capacity for combustion < acetone bodies so completely as diabetic patients. There is a very marked difference between carnivorous and omnivores: animals. Men, using carbohydrates as food, destroy the or- butyric acid, formed from fat and from albumen, only by tx help of carbohydrates; they lose this capacity more or less ? they become unable to katabolize the sugar molecule. Car- nivorous animals, on the contrary, living on meat and fat, are enabled by nature to burn oxybutyric acid without the help !! ingested carbohydrates. That means a wise arrangement { nature-and thus in diabetes of dogs accumulation of acide never reaches such an extent as in men.

You might ask me why accumulation of acids is increased so suddenly in diabetic coma. One may ascribe this sudden increase, at least in some cases, to a sudden decrease or even !! a loss of the sugar combustion. Spitzer reports a case where this was obvious. Coma set in immediately after a strong physical shock combined with a psychical emotion. From that moment the elimination of sugar, up to then rather slight. rose to an abnormal height, and at the same time with it- creased loss of sugar the oxidation of acetone bodies was n- duced to a minimum. Here no time was left for adaptation. which in the general course of diabetes prevents the rapid ir- crease of acidosis. I might quote other examples where such : sudden increase of the toleration for sugar can be observed: 1 mean those very rare cases of acute diabetes, the beginning of which may sometimes be determined almost up to the hour by the sudden appearance of a terrible thirst in patients who unti. then showed not the slightest symptoms of diabetes. In such cases acidosis also arises suddenly and advances rapidly. The time being far advanced I confine myself to these few remarks

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Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 84

Author: Jacob Anthony Kimmell Publication date: 1910 Publisher: Number of Pages: 1189

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189