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CHAPTER 5

CELLULAR THERAPY


ANTECEDENTS OF INSULIN

In the general theory of HUMORS, there is no conjecture about insulin. In 1686, J.C. von BRUNNER suggested that some correlation existed between the pancreas and the metabolism of fats and carbohydrates.

Later, there was a belief that a link existed between diabetes mellitus and the pancreas, by post-mortem observations of this organ in diabetics.

Y. Minkowski and J. von Mering, in 1889, published their discoveries of a state similar to diabetes mellitus, produced artificially in dogs from which the pancreas had been removed. This discovery apparently contradicted the works of Claude Bernard and Schiff, who had closed the pancreatic ducts with paraffin. This occlusion did not produce any alterations in their health of the subjects.

It was Edouard Lépine who, in 1891, repeated the experiments of Mering and of Minkowski. He confirmed the observations and suggested the possibility of an internal secretion of the pancreas as an active agent in the metabolism of fats and carbohydrates. Then came a series of experiments tending to clarify the supposition of Lépine. Physiologist Gley obtained decisive results in causing a diabetic state by ligating the veins giving circulation to the pancreas, thus depriving the organism of the internal secretions of this gland. Laguesse and Diamare suggested, in 1893 and 1889, respectively, that this secretion could come from islets of the pancreas, described by Langerhans in 1859, which took the name of their discoverer. Cirrhosis of the pancreas, produced by the ligation of its ducts, left the islets of Langerhans intact, which satisfied their function in a normal manner. The removal of the atrophied gland led to crystal-clear diabetic states.

The research acquired a sensational character, led by M.A. Lanc, in 1907, who found out that two types of cells exist in the tissues of the islets of Langerhans, which he named Alpha and Beta. He also found that excess of work of the pancreas caused a diabetic condition corresponding to destruction of the Beta cells. Thanks to these discoveries, medicine learned that in diabetic human beings, the pancreas, and especially the islets of Langerhans, showed remarkable degenerative changes.

The specific function of internal secretion of the islets of Langerhans was defined, apparently completely, by the work of J.J.R. McLeod, and others. The existence of an internal secretion of the pancreas was clearly established by the work of Laguesse and Diamare. The problem consisted of managing to extract and to isolate it. Only this could provide conclusive proof of the presence of such secretion. Numerous attempts were executed from 1890 to 1922.

In 1890 began the constant and pathetic fight to obtain the active principle of the pancreatic internal secretion. Extracts of part or the whole pancreas, like that pancreatin from Laleuf, were used as useful medications for the relief of diabetes symptoms. For reasons that we now know perfectly, such extracts were disturbingly inefficient. We know that these medications even if they had some active principle being administered by mouth, were hydrolyzed by the digestive juices.

Various attempts were made, with little or no effect for the objective intended. It was the researchers Zuelzer, Leyden, Blumenthal, Battistini, and Vanni who tried subcutaneous administration of the preparation that they had obtained, but its strength was inadequate.

J. de Meyer, in a study published in the International Archives of Physiology, in 1907, was the first to use the term INSULIN, today universal. And Schafer, in a book on the endocrine glands published in 1916 in London, mentions the same word, insulin. That translated into Spanish it is INSULINA, which would be proper, considering that it is a hormone. Insulin happens to be equally improper, etymologically and technically with the word hormone. Both names have already become common, and we will continue using them, in order not to cause confusion.

In 1855, when the French physiologist Claude Bernard punctured the fourth ventricle, that he called diabetic, he demonstrated that the central nervous system takes part in the production of a substance that regulates carbohydrates. In 1922, Banting, Best, and Collip managed to extract from the pancreas the substance produced by the islet of Langerhans. But it was not only the pancreas and the fourth ventricle taking part in glycemia. It was later observed that a complete and complex blood-glucose regulator system exists, in all vertebrates, that is mainly formed by the suprarenal glands, the thyroid, the hypophysis, the parathyroids, the ovaries, the testicles, which have opposite actions, to the previous two. Also the carbohydrates, the liver, kidneys, lipids, the protids, and the vago-sympathetic nervous system play their role in that regulation.

In the course of this presentation we will see in detail the role of each one of these elements.

 

 

BIO-PHYSICO-CHEMICAL ASPECTS OF INSULIN

The contribution that biochemistry lends to this new system is very small. Because of the intimacy of the biological phenomena, we know very little. In the last years it seems that we cannot begin to see the wall that so jealously Guards the secrets of life.

We will divide our presentation into two parts: first about what we know of the hormone of the islet of Langerhans and its biological effects; and second about the pharmacodynamics of medications on the cells in general, during the maximal action of the hormone.

For better understanding of the action of this hormone it is necessary to remember something about its composition and properties.

INSULIN used to be called “albumose”; it is a polypeptide whose molecular weight varies from 35,700 to 46,000 (1939), according to the latest determinations. And in agreement with the first data, the number of peptide bonds in this molecule is 292, give or take 10, experimental data that is in agreement with the calculations by Bergmann, that is 288.

To the amino acids composing it, of the original seven (1939) it is necessary to add 4, two of them already determined and the other two isolated but not yet determined; the average composition is thus:

- Glutamic acid 21 %

- Arginine 3 %

- Cystine 12 %

- Histidine 8 %

- Leucine 30 %

- Lysine 2 %

- Tyrosine 12 %

- Serine 3.57 %

- Threonine 2.66 %

- Phenylalanine Isolated

- Proline Isolated

_______________________

94.23%

The N-peptide relation to N-total was determined and it was found to be of: 0.765 which is very close to the calculations, in agreement with the composition of amino acids which is: 0.749, data that Bergmann used to calculate the number of peptide bonds, which we have already mentioned. There is still doubt about the shape of this molecule, because the old concept that it was constituted by a single polypeptidic chain of 580 A of length, is modified today by the determinations of the N-amino assuming that it is a structured molecule with 18 short chains, as Chibnall suggested in 1942, although this requires a later confirmation that will be demonstrated when we have more data and more precise measurements.

Its isoelectric point is not yet definitively known because its great insolubility between pH 4.5 to 7.0 prevents it; they have a minimal and maximal range: 5.3 and 5.9, which would give so far an average of 5.6.

The electrophoretic studies have not shed much light, given the limitations of the method, since they used homogenous preparations of smaller strength in comparison with samples of the crystallized and active hormone at the maximum.

Recent determinations of sedimentation with the ultracentrifuge, and of constants of diffusion, give the molecular weight of 46,000, which we mentioned earlier and that is 30% greater than previously determined by other methods.

The fact that it is inactivated by acetylation and recovers its properties with desacetylation, leads to the thinking that its activity is due to the OH or the NH2, but this last radical is eliminated, since it is being blocked by diazotization with nitric acid, its hypoglycemic characteristics are not suppressed. But as contradictory data, we have the action of methanol that would react on amines to produce methylamines, and that if all activity is suppressed, it recovers by elimination of methylenes.

If it is a fact that reducers inactivate it, it seems that by breaking the disulfide group with formation of sulfhydryls and that oxidants reactivate it, all the preceding leads one to think that the biological activity of the hormone, so treated in vitro and soon in vivo, must lead to the breaking of the disulfide group. But the experiment of reduction in vivo finds that the hypoglycemia produced by insulin was inhibited by the cystine, not by reduction of the disulfide group with production of two sulfhydryls, but by hypersecretion of adrenaline produced by this amino acid in the organism. These suppositions are confirmed by the works of Fellows and Cunningham (1941), who, looking for a substitute for the pancreatic hormone, tried bodies such as paraamino-benzoil-1-cystine, which gave negative results in vivo.

Haddock and Thomas also indirectly arrived at this concept. They prepared plasteins (synthetic protids, obtained by contrary reaction of the hydrating enzyme that reunites or concatenates the amino acids that were previously formed) from concentrated extracts of insulin digested by pepsin in acid solution, and by papain in neutral solution, in which it is possible to suppose that the groups formed again disulfide, which produced a new protid structure similar to the original one. But these plasteins lack all activity and they even give an insoluble remainder of 3.3% of trichloracetic acid. By all the foregoing we come to the painful conclusion that we know very little, chemically speaking, about this polypeptide, and that its biological activity depends, at the moment, on the size and form of the molecule, and not of the presence of one or more disulfide groups.

The physiological action of the hormone is direct on glucids and indirect on the metabolism of protids and lipids. We are still not capable of asserting that the hormone of the pancreas works directly on the metabolism of protids and lipids; but its action is indirect through the effect of this hormone on the metabolism of glucids.

Man is an “osmotic-furnace”, that is, he lives at a fixed osmotic pressure in his internal medium. His humors: blood, interstitial plasma, and aqueous lymph, have osmotic pressure that varies from 0.25 to 0.62. Complicated physico-chemical mechanisms regulate it. This causes poikilosmotic secretions, such as sweat and especially urine, which allow the conservation of their “hematies” and in general of all their cells. Osmotic pressure can undergo certain variations for small periods of time, positive or negative. 7.2 atmospheres of osmotic blood pressure, which receives the generic name of osmo-nocivity, if it is continuous, will produce the death of cells first, and later, of the organism to which they belong.

In the plasma of human blood there are two classes of substances in solution that maintain their homo-osmotic characteristics: the main compounds heteropolar or ionizable, formerly called “inorganic or mineral”, between them, they separate sodium in its chlorinated combinations and the two phosphates, that are mono and bi-acid and bicarbonated, in smaller proportion with potassium, since this element is rather cellular, and both alkaline-earthly: Mg and Ca, in much smaller relation, but which in a marvelous balance, eliminate the toxic effects that each one of them has on diverse parts of the organism.

Of the homopolar or non-ionizable compounds, which are found mainly in dispersed (colloidal) form or in true solution, we have in decreasing order: albumin (4.50%), globulin (2.40%), fibrinogen (0.30%), lipids (0.25%) and glucose. The later is the only one of these mentioned that gives true solutions. Because of this, it has a major role in osmotic regulation and we can, by means of insulin, as it is used in Cellular Therapy, lower it to one fourth of its normal concentration. This produces a cellular imbalance that at the appropriate moment —which is the Therapeutic Moment — is restituted by hypertonic solutions, along with specific medications. Those being in true solution, also contribute to eliminate the resulting osmo-nocivity, quickly getting to act at the ailing location and penetrating inside the cells. That, in other conditions, would be very difficult or impossible to obtain, since there would not be the “cellular hunger and thirst” like that taking place with this therapeutic system.

Man is homo-ionic, because as you know, blood is the most regulated liquid in existence. A slight variation of 0.2 in the mean value of blood pH, either too much or not enough, will produce death by alkalosis or acidosis respectively. Therefore life takes place within an average pH of 7.15 in the City of Mexico. In North America and Europe, it is 7.35. If the variation of blood pH is brief, it can be resisted without producing death, as it is observed daily with Cellular Therapy, dropping a little more than one unit. Since insulin acts on the three regulating systems of blood pH — anhydrous carbonico-bicarbonates, mono and bimetallic phosphates, and the amphoteric character of protids — the direct action of insulin takes place. Because when we have a lowering of glycemia, there is an alteration of lipid metabolism, these remaining in the penultimate beta-oxidation, according to the hypothesis of Gnoop, and appearing beta-oxybutyric and beta-isobutyric acids, or acetyl-acetic acid, those that do not become acetic acid, as the final stage, previous to the formation of CO2 and water, ACIDOSING THE ORGANISM AND CONTRIBUTING THUSLY TO THE ORGANIC COMMOTION THAT FACILITATES THE PHARMACODYNAMIC ACTION OF DRUGS USED IN THIS THERAPY.

 

 

CONVENTIONAL ACTION OF INSULIN

Thousands of papers have been published to date on the physiological action of insulin. In general, all of them concern its most important action, which is to reduce the quantity of dextrose in the blood when being provided parenterally.

The examination of the physiological action of insulin in other aspects has been neglected and passed over in silence, probably because the decrease of glucose in the blood is of so much importance for diabetes mellitus, and also because of “many other physiological disturbances”. Likewise, the actions of insulin have not been experimented sufficiently when they take place in individuals who do not have any pancreatic deficiency.

For these reasons, because a classic use of insulin has already been established, it would be truly revolutionary to research that repertoire of the “many other physiological perturbations”.

It is generally believed, to date, that the field of action of insulin is exhausted, because our work has not had the necessary diffusion to get incorporated in the medical legacy. Our eminently practical research, which has been applied to this therapy, and born from the same practice, has not been properly laboratory tested, in animals or in vitro, but in patients with various diseases, and furthermore in cases of patients declared incurables.

All the references contained in the book INSULIN of Hill and Howitt, New York, 1936, exhaustive of whatever had been published until then, do not mention anything referring to the action of insulin provided intravenously. They discard the administration by mouth, because of the action exerted on it by the juices of the digestive apparatus, which signifies its destruction. The book is also limited to intramuscular application.

In the paper Clinical Diabetes Mellitus and Hyperinsulinism, of Wilder, 1941, the intravenous application of insulin is mentioned, but only in very serious cases of diabetic coma, and in very small doses. The classic work of Best and Taylor on the physiology and the physiological bases of the therapy — notwithstanding Best being, with Banting, one of the discoverers of the effective existence of insulin — makes no mention either of intravenous application or the physiological action that it could have.

All the research to date is contained within the limited framework of the conventional action of insulin. Insulin shock is nothing more than a hypoglycemic state. The authors of treatises have directed their attention only to the physiological action believed most important, being the maximum reduction of blood glucose level.

The reduction of blood glucose is accompanied by many other physiological disorders and if that blood glucose is sufficiently low, it will end up with hypoglycemic coma, convulsions, and the list of already well-known symptoms, and finally death. When small doses are applied, the blood glucose drop depends on the method of application. Subcutaneous administration produces a reduction of the blood glucose, arriving at a minimum in a course of 1 to 3 hours.

It seems that Niitsu in 1930, and Kohl in 1933 studied in laboratory animals the rapidity of decrease of blood glucose, according to the various ways insulin was administered, and found that it was greater when insulin was applied intravenously.

It is a valuable discovery that hypoglycemia continues for several hours, whereas the insulin disappears quickly from the blood. Horsters, in 1930, reported that only 10% of the insulin provided intravenously remained in the blood after thirty minutes, and that it later appeared little by little in the muscles and the liver.

In 1931, Collens and Grayzel observed that an equivalent amount of insulin produces a much greater decrease of blood glucose in diabetic patients than in non-diabetics.

Another valuable observation was that hypoglycemic symptoms even differ between experimental animals, even in those from the same species. The influence of the temperature of the blood was emphasized when finding that insulin does not produce any obvious action in frogs, animals of cold blood.

Changes in glucose of the lymphatic and cerebro-spinal fluids were observed as side effects in conventional practice.

Schazilo and Ksendowsky who, in 1928, deduced that insulin favors the regeneration of bony tissues observed the effect in tissues regarding our purpose. Independently, Aldersberg and Perutz in 1927 indicated that they had obtained a greater regeneration of skin tissues in ulcers when they directly applied an insulin solution on the ulcer.

The experiments we are presenting have been meticulous, and executed separately or with a clear criterion of specialization, without effective coordination with other events. L.G. Bustamante in 1928 reported having discovered that insulin increases the acidity of gastric secretions; this has been confirmed lately. Whereas L. Cannavo, had found in 1926, that insulin does not exert any action in the acidity of gastric secretions, but in diabetics K. P. Becker and E. Geiss in 1933, indicate that the administering of insulin to individuals whose stomachs can be considered as normal, follows an increase of acidity and chloride concentration. Bulata and Carison in 1927 published their discovery that insulin, provided to dogs, increases gastric mobility.

 

 

CHANGES IN BLOOD DUE TO INSULIN

Within this conventional action, numerous observations have been made about possible modifications occurring in the blood; almost all were oriented in a purely biochemical direction. Yamada, in 1933, reports that the normal dose of insulin diminishes the amount of lactic acid in the blood, and Kuhn, in 1924, had established the existence of a remarkable relation between the amount of lactic acid and the pH. In other words, Yamada in fact found that pH decreases as a consequence of the action of insulin. We have confirmed these last observations.

Brugsch and Horsters, also in 1926, published that an insulin injection in rabbits submitted to a fasting regime produced a sensible loss of blood pH, but this effect was not observed in rabbits that had ingested food.

The investigators should have investigated this modification of pH to clarify further the action of insulin, since in classic modern physiology the constancy of pH is an axiom and there are no known agents capable of modifying it. It is precisely this modification of pH, notable by its degree that lays the foundation of the effectiveness of Cellular Therapy.

Other investigations tended to look for the effect of insulin on the concentration of hemoglobin in blood. Tada and Nakazawa in 1930, extend their hypothesis that insulin causes a temporary increase followed by a decrease in the osmotic pressure of serum colloids. Stockinger and Kober in 1931 also indicated as a characteristic action of insulin an absolute increase in blood lymphocytes and a particular neutrophilic leukocytosis due to regeneration of the cells.

Other particularities were noticed. It is fitting to mention as an antecedent, that in 1931, E. Zunz indicated as an effect of insulin administered intravenously, the moderate increase of the glutathione content of blood, and a decrease of oxalic acid.

Dudley, Laidlaw, Trevan, and Brock noticed in 1923 the drop of temperature in subjects submitted to insulin, now totally confirmed; later it was clarified that the lowering of temperature presents peculiar characteristics according to the patient.

What the reader must appreciate is that in all this extremely vast experimentation, the intravenous use of insulin is almost incidental and, always came after 1926, year in which we were the first to try it that way.

We must also remark that all this research is a repertoire of hundreds of works executed separately and without a concrete purpose, without any established clinical framework. The majority are experiments in vitro or on laboratory animals.

Also, none of them has been able to reach conclusions that generated the creation of a new therapeutic technique. It is fitting to establish such a difference because our presentation is deliberately clinical, to immediately draw benefits from the fundamental observations that we have made in the first years of our effort. For us to deepen into a concrete investigation, perhaps, after the lustrums and the decades, we would have discovered nothing else but that insulin produces certain variations in the arterial pressure or stimulates the secretion of the sudoriferous glands or something more inconsequential.

From 1926 on, some remarkable discoveries have taken place, about the relations of the conventional action of insulin with the stimulation or inhibition of the other endocrine glands. All the literature on this subject is extremely vast and its simple superficial examination would require a lifetime; but, as far as our goals are concerned, it is sufficient to know the general nature of those relations, in order not to dissipate ourselves in knowledge of what, in the long run, has no clinical application and would hardly have widened the narrow horizon of physiology.

It is worthy to note that, while all these researches tend to present themselves as a medical criterion, no longer empirical but experimental, the human organism is an indissoluble unit. Medicine practically tends to disperse itself in specialties, but of course it is understood that this is antiphysiologic and furthermore antitherapeutic.


INSULIN IN DIABETES

The role of insulin in the treatment of diabetes mellitus is that of a substitute that compensates deficiencies of the pancreatic islets, a perfect example of symptomatic substitutive therapy.

Adequate administration according to the level of the deficiency and the activity of the mechanisms opposed to the action of insulin is combined with a suitable diet.

It is very interesting to indicate that in all cases of diabetes, benign as well as serious, insulin requirements also depend on other factors aside from the function of the islets of Langerhans. The first one is the proportion of dextrose taken from the food ingested by the patient; likewise, the value of the whole metabolism.

Insulin sensitivity is an ensemble of effects of the endocrine antagonisms to this hormone, which are conditioned by the pituitary, thyroid, adrenal, and other internal secretion glands, which influence the degree of irritability of the central and vegetative nervous system. The treatment of diabetes mellitus addresses individuals who have the highest degree of insensibility to insulin. This condition has been called insulin resistance, and the individuals showing it are called insulin-resistant. Treatise authors like Wilder consider as inexplicable, until now, the circumstances establishing such condition. Perhaps this lack of explanation is due to the fact that insulin was applied like a classic medicine for the treatment of diabetes mellitus, that is to say, it has been given to individuals suffering from a deficiency of the islets of Langerhans. Our practice has been derived; in contrast, from the observation of effects produced by insulin in subjects that are not diabetic or those who enjoy normality in the functions of their pancreas. These observations have allowed us to find a plausible explanation of insulin resistance, which we will talk about later.

The treatment of diabetes mellitus has evolved with the retardation of its effect when combining it with procaine, zinc, and other substances.

As this class of insulin lacks application in our Cellular Therapy, we will not discuss it, limiting ourselves to show that, in general the good success of the treatment depends upon the stability of its application and the wise combination of a dietetic regime, which has to be established according to the conditions of each patient.

The only thing remaining for us to express is that the pathogenic cause of diabetes mellitus is still obscure, nevertheless a 60% syphilitic origin has been reported, and the rest from other disorders. Independently of hereditary factors, accidents, and incidents during the life of the person who becomes diabetic, the pancreatic deficiency revealing it must be considered as a symptom of radical alterations, for example, malaria, which can lead to the atrophy or the faulty operation of the pancreas. With Cellular Therapy we have found some cases showing the possibility of a cure of diabetes mellitus, certainly by the modification of the metabolism that can be obtained, and by the functional normalization not only of the endocrine system that is classically related to the pancreas, but, in general of the nervous system.

The primary fact that we emphasize in the administration of insulin, established as our norm, is doing it intramuscularly. Until a few years ago, it was thought that it could and should be provided intravenously in cases of emergency.

There is a truly striking preconceived notion about insulin being a dangerous medication, to which one must only resort under extraordinary circumstances, exposing one to lethal consequences.

As we will see later, the action of insulin is perfectly adjustable and does not present any such dangers, if the process, different in each individual, is followed with attention and care. The possible contraindications are quite clear, also, against such preconceived idea. The facts that we will expose suggest an immense field of application for insulin, on which we have founded Cellular Therapy.

Our therapy owes almost nothing to the clinical observation of diabetic patients treated with insulin. But it comes from our original experimentation in which the essential discovery was the role played by insulin in the human organism, when injected directly into the blood stream.

 

ACTION OF INSULIN ON NON-GLUCID COMPONENTS OF PROTOPLASM

In all the experiments conducted until now, it is demonstrated that the injection of insulin is followed by a remarkable decrease in the amino acids of the blood. Accidents following the wrong administration of insulin in patients with uremia have caused a definitive decrease of nitrogenized bodies in the blood.

The hypothesis of Claude Bernard when thinking that the hepatic glycogen formed in the liver came from protids has been absolutely confirmed. Diabetic dogs submitted to a protein diet respond clearly by eliminating a greater amount of glucose. With the suppression of these proteins the excretion of glucose is smaller. The quantity of dextrose eliminated during long periods of time by diabetic dogs, fed exclusively with albuminoids, to the point of exhausting almost all fats from their organism, does not explain the quantity eliminated, any more than only thinking that protein substances are producing that dextrose.

During the passage of blood through the liver, there is a decrease of concentration of nitrogen amino acids much greater than during the passage through the rest of the body. The liver continuously metabolizes the absorbed amino acids, because it maintains indefinitely its capacity to constantly take them out of the circulation. This catabolic process brings the formation of urea, ketones, and glucose.

It has already been demonstrated that protids are also producing glucose. The amino acids carrying out this function are called glycogenetic and they are: glycine, alanine, serine, cystine, aspartic acid, proline, tyrosine, glutamic acid, and oxyglutamic acid.

Glycogenetic amino acids are those that have in their chain (open or fat) an even number of carbon atoms and therefore when they desaminate themselves (loss of NH2), and consecutively decarboxylase themselves (loss of CO2), they are transformed into fatty acids with a chain of odd carbon atoms; they would become like that because of methylglyoxal, pyruvic acid, acetic aldehyde, diacetic acid, acetic acid, even glycogen. These last immediate generating elements of glucose could be the true fundamental bodies with which the organism would constitute LIPIDS, protids and GLUCIDS. This shows us that the glycogenic amino acids division is not absolute, and then, according to the conditions of the organism and according to the chemical structure of the amino acid, any amino acid can be transformed into LIPID and GLUCID. The molecules of the disintegration of glucose are those that form the bridge between the metabolism of fats and carbohydrates.

Experimental and clinical observations actually demonstrate the narrow relationship between more disintegrated elements of fat catabolism, hydrocarbons, and proteins.

The basic character of amino acids obeys to the amine group NH2, and its acid character to its carboxyl group COOH. For this reason it has a great importance in acido-basic balance of the organism, because they form salts in two ways:

The amine group, basically, is combined with an acid to form a chlorhydrate, sulfate, etc. from protein.

The carboxyl group, acid, is combined with a base and constitutes a proteinase, according to the base with which it is combined. In one case and in another, they act as buffer whether it is the acidity or the alkalinity of the medium.

 

TRANSFORMATION OF ONE NUTRIENT INTO ANOTHER

Phloridzinic and pancreatic diabetes prove, in evident form, that in those circumstances certain amino acids are transformed into glucose. The same happens in a normal organism, and there are classic experiences demonstrating that this transformation seems to happen continuously.

This has been verified by studies of respiratory exchange, as well as by the exclusive feeding of protein to dogs previously phloridzinated and that had very little hepatic glycogen. By the ingestion of proteins and suspension of phloridzin administration, glycogen increases in the form indicated, much more than the glycogen of the control animals that received a diet rich in fat.

The transformation possibility of fats into carbohydrates must be considered under two aspects: the transformation of glycerin and that of fatty acids. As far as glycerin is concerned, there are experiments demonstrating that transformation in diabetic animals, and it is very possible that it happens normally in the organisms, but as far as the transformation of fatty acids into carbohydrates, there are at the moment no convincing experiments.

TC174.GIF (13782 bytes)

There is however much evidence that carbohydrates can be transformed into fats, storing their excess in that form. It is enough to make fluctuations of fat in animal fed almost exclusively with carbohydrates and proteins, to reach the conclusion that one part of the same fat must come from ingested carbohydrates. The same happens with respect to proteins. Although it cannot be affirmed that these can directly be transformed into fats once the nitrogen is lost. Some think that therefore, only certain amino acids are susceptible to producing fats.

As far as the possibility of formation of amino acids in the organism, and then proteins, at the expense of non-nitrogenated substances and of nitrogen of protein origin, this has already been partially considered.

It is evident, according to experiments conducted to study the essential amino acids, that the organism can synthesize most of them. It is necessary to admit, then, in these cases, that a non-nitrogen remainder originating in carbohydrates or in fats combines itself with the ammoniac of proteinaceous origin to form those amino acids.

 

PROTIDS

Definition: — Contain ammonium, natural acids, and are produced by

hydrolysis.

Distribution: — Are 90 % essential.

Hydrolysis: — Poli — Mono.

Structure: — R — CH — NH — CH — COOH

NH2OH

Esterochemical compounds. — Dicepiperazines; without

advantages.

Molecular Weight: 17,500 MW, average 500 amino acids.

Physical properties: — Ampholytes:

Zwitterion is demonstrated by:

Neutralizing heat ) Slowness of reaction

Effect on Buffers ) of the NH in comparison

Comparison of K dissociation )

Dissociation of COOH NOOH ) Iso-electric Point

Dissociation total minimum )

Solubility minimum )

Viscosity: in acid goes to the cathode

Migration: in alkali it goes to the anode

Soluble: in water.

Crystallizables:

Insoluble: in organic solvents.

Molecular Weight: 17,500 to 6,680,000 by osmotic

and ultra centrifugal pressure ) 75.000

) REV

) g.400,000

Minimum molecular Weight: 17,000

Hemoglobin for Fe 16,000 (4 Fe)

real 68,000

Ovoalbumin 1.2% tripdaria 17,000

real 34,000 (2 trip)

Colloidal state:

Precipitation: by salts is reversible.

Coagulation : by value is irreversible.

by alcohol becomes denaturalized.

See Graphic.

 

ENZYMES AND YEASTS

Generalities:

Definition: Organic and specific catalysts, colloid produced by living

organisms but whose activity is independent of the same

life.

Substratum: The substances on which they act.

History:

Blanche ferments roots colored in blue

the tincture of Guaiacum......................................... 1810

Robiquet emulsion .................................................. 1830-1832

Siebig & Wohler Emulsion and others .................... 1837

Seuchz Ptyalin (saliva) ........................................... 1831

Payen and Perzos malt ........................................... 1833

Shuann Pepsin ........................................................ 1836

Berzelius Classification ........................................... 1837

Enzymatic Liebig Theory without live organisms ..... 1870

Pasteur’s Anti-theory ............................................... 1871

Buchner ................................................................... 1897

Catalysts:

1. — They accelerate

2. — They do not intervene

3. — They do not modify the balance

4. — They transform many times their weight.

Molecular magnitude: Proteins Colloids forced.

Physical conditions of enzymatic action:

Reaction:

Temperature: They have optimal

Time x Enzyme K

Relation enzyme substrate

Average of watery action with exceptions.

Inhibition and destruction:

They are stable at low temperatures; at 100°C (212°F), almost all are

destroyed. Some resist 100°C in solution.

In powder they support until 150°C . When purer more thermolabile.

The pH influences a lot.

H OH destroys them.

Heavy metals inactivate them.

I, KMnO destroy them;

HCN, H, S and F inhibit reversibly.

Anti-enzymes: Organic substances present in organs and tissues that

inhibit the action.

Example: Antipyrine in normal serum.

Zymogens: Pre-enzymes. — Substance characteristic: Enzyme,

Example: Pepsinogen + HCl = Pepsin.

Activators: Inorganic salts: NaCl, HCl, etc.

Co-enzymes: proteic group.

Quinine related: — Activators organic col. thermolabile.

Pancreas Intestine

Trypsinogen Enterokinase

(Zymogen) (Kinase)

Trypsin

Enzymatic value or Enzymatic activity measurement:

Enzyme unit carrying out the finished transformation in the time unit.

Isoenzymes: directly.

Obtaining: Endoenzymes: milling, pressure, autolysis.

Solvents: Saline solutions or glycerin.

Purification: Dialysis or prec. frac: alcohol, acetone, etc.

Absorbent: Al (OH); Kaolin: Ca ( )

Absorption and elution.

Concentrations of 250 to 3,000 times are obtained.

Crystallization:

Constitution: a) Enzymatic protein Proteic Group Enzyme

(Oxidize-reducing)

b) Enzymes purely proteid

Proteic Groups: Lactoflavins

Co-enzymes

Adenopyrophosphoric acid

Heme and Hemin

Copper.

Distribution: In all the cells, digestive juices, secretions and in some

excretions (urine):

Endoenzymes or endocellulars.

Isoenzymes or isocellulars.

The easily soluble are LIO-ENZYMES.

The hardly soluble ones are DESMO-ENZYMES.

Nomenclature: The name of the substratum ending in “ASE”.

Classic names have always been conserved outside of all

rules like Trypsin (Protease), Emulsin (Glucosidase or

Carbohydrase).

Specificity: Catalytic Enzyme, specific Catalyst.

Carbohydrase (Glucidase): Glucosidase.

Peptidase: CO –NH –, Dehydrogenases: Dehydrogenate.

(See graph)

 

ACTION OF INSULIN ON PROTIDS

In a communication published before 1938, in the Revista Médica Militar, there was already mention of the effect of insulin on protids, observed in many non-diabetic patients. Cynically it is demonstrated that in spite of the lack of glucids, the ingestion of protids, slowly brought the blood sugar up to normal.

Formulas

This observation in humans has been corroborated completely by foreign researchers; we will now relate what has been done in other countries in this respect.

To date, all the observations on animals agree, there is no discrepancy. Okada and Hayashi removed the pancreas of dogs and immediately they observed the INCREASE OF AMINO ACIDS IN THE BLOOD. Within 15 days, more or less, it returned again to normal in some animals, but also in others, not only did it not end up being normalized, but also rather it dropped definitively below normal.

In dogs with increased blood glucose, these demonstrations are more evident, subcutaneously injecting pancreas extract into these animals immediately after the ablation, the phenomena of decrease of amino acids no longer appeared.

This demonstrates that the internal secretion of the pancreas takes part in the normalization of the blood amino acids, in some form. Nevertheless, in diabetic patients with acidosis, few modifications have been observed. In a few, the gravity of their state has changed; in others the amino acids have clearly decreased; and in the less serious, there have been some favorable changes. But invariably, in all, it has more or less lowered their aminoacidemia.

Bickel, Collazo, and Wiechmann verified that insulin clearly diminishes the concentration of amino acids of the blood, as well as eliminates nitrogen amine of the urine in diabetics.

It is considered that an insulin injection in normal dogs clearly reduces by about 3% the amino acids of the liver and muscles. The same occurs in the dog without pancreas; the amino acid content of the liver, muscles, and blood is higher and is clearly decreased by the action of insulin. Comparing amino acids of the blood, venous and arterial, in several locations and after the injection of insulin, it has been observed that this hormone inhibits proteolysis, and even favors the synthesis of peptides and protids.

The diminution of aminoacidemia after the insulin injection, in normal animals, is due to the increase of adrenaline, by the excitation that this injection produces, according to Davis and Winkle. In agreement with these results, it is accepted that the hypoaminoacidemia produced by insulin is due to an increase of adrenaline secretion.

In most patients with high blood pressure and with hyperaminoacidemia, the decrease of aminoacidemia under the action of insulin is common. This puts in evidence, the participation of the pancreas and insulin; we do not know whether it is direct or indirect. But the facts observed until today, make us think that its participation in the metabolism of amino acids is direct.

Animal experiments as well as the observed clinical facts set out to determine that the insulin injection is always followed by a sharp decrease of aminoacidemia of the blood; it is also generally observed that with the decrease of blood amino acids, there is a decrease of hypertension.

According to these results, from the therapeutic point of view, insulin lowers aminoacidemia, blood sugar, and arterial pressure, this reduction being almost always parallel.

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