SGA, D. Perez Garcia y Bellón and D. Perez Garcia, Jr.
Medical Hypotheses20(2):199-210, 1986. [26 references]
Published on IPTQ by permission of Donato Perez Garcia MD.
In insulin potentiation therapy the hormone insulin is used as an adjunct in the medical management of the chronic degenerative diseases, including malignant neoplasia. In this, the recognized physiological action of insulin - that of increasing cell membrane permeability is taken advantage of to potentiate the pharmacological actions of medications administered concurrently in the therapy. This potentiation occurs because of the heretofore unrecognized applicability of this membrane permeabilizing effect of insulin to a much wider range of tissues than is classicly accepted, and further the observed effect of this permeabilizing phenomenon as it relates to drug molecules, most importantly the antineoplastic agents. The historical context of insulin potentiation therapy is described, and scientific corroboration for its novel hypotheses is given. Insulin potentiation therapy represents a potentially revolutionary concept in the medical management of diseases and is, in the authors' opinion, deserving of intensive scientific investigation through in vitro and in vivo experimentation and properly conducted human clinical trials in a university teaching hospital setting.
Insulin potentiation therapy embodies a potentially revolutionary concept in the medical management of chronic degenerative disease. It has been hailed by those familiar with its precepts as the summum bonum of allopathic medicine. In its applications over some fifty years, this therapy has produced a consistently higher level of clinical success as compared to conventional allopathic medical practice, and it has been found to be efficacious ' in the management of a wide range of chronic degenerative diseases, including malignant neoplasia. An innovative use of the hormone insulin is thekey to the workings of this therapy.
Many of the body's hormones have been identified and isolated. A number of these hormones are used therapeutically in current medical practice as replacement therapy in some of the endocrinopathies like hypothyroidism, Addison's disease, and diabetes mellitus. In a variety of clinical situations, certain hormones are also used as drugs. The adrenal cortical and medullary hormones are examples of this, with cortisone perhaps being the clearest example. Cortisone is often used in higher than physiological doses in the management of many non-adrenal related diseases. It is cortisone Is anti-inflammatory activity which supplies its drug effect, and this is applied with advantage in the medical management of numerous different diseases, all of which share in common the pathological process of inflammation.
In insulin potentiation therapy, insulin is similarly used as a drug. Apart from its role as specific replacement therapy in diabetes mellitus - as for cortisone and Addison's disease - insulin has been found to be of immense value as an adjunct in the treatment of a wide variety of non-diabetic disease states. In its use here, the drug-like properties of this hormone relate to its physiological action of increasing cell membrane permeability.
It is on account of this drug-like effect of the hormone that insulin potentiation therapy works as it does. Insulin seems to produce this membrane permeabilizing effect in a wider range of tissues than is commonly thought, and this to a wide variety of substances apart from simply glucose and certain other biochemical moieties. A fundamental proposition about insulin's role in this therapy is that insulin potentiates the pharmacological actions of drugs. The proposition is that it increases the cell membrane permeability to and thus increases the effective intracellular concentration of drugs that are administered concurrently with insulin according to the actual protocol of the therapy.
Insulin potentiation therapy was developed in Mexico during the 1930's by one Donato Perez Garcia, Sr., M.D. It was practiced by this pioneering physician at his Mexico City clinic for many years until his death in 1971. The continuing practice of it to the present has been undertaken by Dr. Perez' son, Donato Perez Garcia y Bellón, M.D., who had joined in working with his father at their clinic in 1955.
The development of the concept of insulin potentiation therapy originated from a personal experience Dr. Perez, Sr. had using the hormone insulin on himself. He used it to treat a chronic gastrointestinal condition from which he had suffered for several years - and which had resisted all forms of treatment available to him at that time.
In 1926, insulin was a new and exciting medical discovery. Dr. Perez read of it and became particularly interested in the somewhat obscure indication for its use in the management of selected cases of non-diabetic malnutrition. Seizing on the possibilities for his own problem here, Dr. Perez proceeded to undertake the treatment of his condition by administering small doses of the hormone to himself by intravenous injection directly before each of his meals. After several weeks of this self treatment with insulin, he became completely relieved of all his bothersome gastrointestinal symptoms, and in addition his body weight increased appreciably to a more normal level. Subsequently, he discontinued his use of the insulin, and remained in this improved state of health.
From this experience, Dr. Perez concluded that insulin had in some way created an improved absorption and assimilation of the food he had eaten. Reflecting on his experience, and putting this together with his own considerations about the physiology of this interesting new hormone, Dr. Perez decided that the improvement in his condition had been the result of several factors. First, he felt that insulin had caused a generalized enhancement of the transmembrane transport of nutrients, both across the cells of the gastrointestinal mucosa as well as into the cells and tissues of his body. Furthermore, he thought that insulin had created a significant and wide-spread alteration in the biochemical dynamics within all the cells themselves the sum of this and the membrane permeabilizing effect being to profoundly alter the biochemical terrain of his entire organism in a therapeutically positive way.
Concentrating on the membrane permeabilizing effect here, Dr. Perez looked to the possible clinical applications of this. He hoped that it might be possible to create a similar kind of enhanced assimilation of other substances - such as drugs - were these to be given concurrently with insulin.
There was a particular direction to his train of thought here which had to do with his professional dissatisfaction and frustration in treating patients with syphilis. The difficulty faced by physicians in treating this disease at that time revolved around the toxic dose-related side effects of the anti-syphilitic drugs, which then were mercury and arsenic salts. Doses of these high enough to kill the spirochetes within the CNS tissue of luetic patients were often at one and the same time toxic to the general constitutions of these patients. Dr. Perez reasoned that if there could be a better assimilation or a potentiation due to the insulin, it might be possible to use lower doses of the medications.
To test this hypothesis, he first experimented with dogs, trying to increase the intra-CNS concentrations of parenterally administered mercury and arsenic salts. In his experiment, which was published in the June, 1938, edition of Revista Medica Militar El] in Mexico, Dr. Perez took two groups of dogs and injected them with mercury and arsenic salts in a hypertonic glucose solution. In the first group, the giving of the mercury and arsenic salts was done during a period of hypoglycemia following an intravenous injection of insulin. In the second group, the salts were injected without any antecedent preparation of the test animals. After sacrificing the animals and examining their brains and spinal cords, Dr. Perez found that, for the first group, the concentrations of the mercury and arsenic salts in the CNS tissue approximated the concentration of these salts in the blood. In the second; the concentration of these salts in the CNS tissue was quite significantly lower.
From this experiment, Dr. Perez concluded that insulin had somehow permitted the blood-brain barrier to be breached. He saw that insulin had caused a certain opening of the cell membranes of this tissue - brain and this to substances other than Simply glucose. Commenting on this, Dr. Perez said, "It is quite possible that a particular advidity of the cells for glucose sets i n a t tha t very same ti me, s o tha t i f any subs ta nce i s added to the glucose which is injected into the blood, such a substance can penetrate more readily than when the hormonal disequilibrium created by the insulin does not exist."
The first clinical applications of the insulin potentiation therapy were remarkably successful. They involved cases of syphilis - some being very advanced cases of tertiary neurosyphilis. Encouraged by these, Dr. Perez proceeded to apply the principles of his therapy to more and more different diseases - relying on the insulin to potentiate those conventional allopathic medications customarily used to treat these other different diseases. With this practice Dr. Perez continued to experience similar remarkably successful results in cases of arthritis, asthma, colitis, etc. In 1947 he developed his first successful protocol for treating a case of cancer with the therapy.
The whole story of what has transpired with the history and development of Dr. Perez and his insulin potentiation therapy would read like a retelling of the history of other medical innovators of antiquity such as Semmelwise and Pasteur. Suffice it to say that Dr. Perez, like Semmelwise and Pasteur before him, was ahead of the science of his time.
For what he was able to explain of the mechanisms of his therapy, Dr. Perez felt that insulin on the one hand potentiated drugs by flushing them into cells, possibly by somehow being adsorbed onto glucose molecules. He also felt on the other hand that the insulin produced a detox-ification of the patient's body through a generalized and intense physiological activation within the host due to the transitory hypoglycemia occasioned during the treatments. This latter was one of many empirically derived notions to which Dr. Perez held rather tenaciously. Even though he did not have anything like a full and complete explanation of the mechanisms of this detoxification, he nonetheless insisted that it was an integral part of the therapy's workings, and that it was a therapeutically positive one.
It was because Dr. Perez could provide no sound scientific basis for his conjecturing here that the therapy found little acceptance. It was not that Dr. Perez did not try to communicate his ideas to his colleagues. On the contrary, he wrote voluminously. His failure to communicate was perhaps due not so much to any neglect on his part in trying to establish a sound scientific basis for his therapy as it was to the absence during these formative years of the therapy - of a medical technology sophisticated enough to be able to provide the necessary science.
The fact that Dr. Perez continued to work in his own way, satisfied with his results and unconcerned about the absence of an explicative science for it, simply caused him to become isolated from the mainstream of his contemporary medical fraternity. He was regarded as a quack because of his empirical approach to medicine, and his son after him suffered a similar fate.
In spite of this rejection and isolation, because of his clinical results, Dr. Perez Sr. himself remained convinced of the validity of his therapy. In one of his personal journals he summarized his thoughts on the therapy as he stated, "By applying the hormone insulin in this way, making the radical and intense changes of all the physico-chemical constants of the blood and, simultaneously, permeabilizing all the cells of the organism, I have succeeded in making very rapid and radical cures in cases of gonorrhea, general infections, etc, and also in neoplastic diseases."
It is clear from the foregoing historical synopsis that all the clinical experience with this insulin potentiation therapy has, to date, been based on empiricism - in contradistinction to science - and that all of its results are thus purely anecdotal. The strictest sense of the word science is intended here because, as history has shown repeatedly, only an exact science is able to bring about meaningful communication and progress in medicine.
In this exact context, the very interesting thing about insulin potentiation therapy now is that there exists a good deal of scientific documentation in our current medical literature to corroborate some of the important hypotheses upon which this insulin potentiation therapy is based.
The therapy is applied in the treatment of a diversity of diseases with the assumption that there are functional insulin receptors on the cell membranes of all the tissues involved in the pathological processes being treated. Bar and Roth in their article, "Insulin Receptor Status in Disease States of Man" appearing in the April, 1977, Archives of Internal Medicine state "There are insulin receptors on the classical target cells of insulin [liver, adipose tissue, skeletal muscl el as wel 1 as on numerous ot ' her cel 1 types such as placenta, fibroblasts, blood cells and brain." (21
As to the question of the functional nature of the insulin receptors on these other tissues, the authors go on in their discussion to ascribe a characteristically primitive role to this receptor in the cellular physiology of mammalian tissues. In summarizing this, they state that,, "The properties of all insulin receptors are remarkably similar, irrespective of cell type."
The established presence of insulin receptors on brain tissue corroborates the findings of Dr. Perez' original animal experiment, demonstrating an action of insulin in the brains of dogs. This action, as we remember from the discussion above, appears to have resulted in an increased cell membrane permeability to mercury and arsenic salts. This fact raises the questions of how generalized this effect of potentiation might be in this and other tissues, and whether it might not operate for other more complex molecules such as drugs.
There is a great deal of empirical evidence accumulated with the Drs. Perez' applications of insulin potentiation therapy to indicate that something like such an insulin-permeabilizing and drug potentiating effect does indeed operate in many of the body's tissues. Beyond this simply empirical evidence, it has been scientifically established that the cells making up chronic inflammatory tissue [white blood cells and fibroblasts [211 have insulin receptors on their cell membranes; and as well, certain cell lines of breast, (3,41 melanoma [41 and colon [4,5,61 cancers have similarly been found to possess insulin receptors.
Reiterating the primitive nature of this seeming ubiquitous entity in these disease tissues all having common properties irrespective of cell type and remembering the effect observed with insulin on mercury and arsenic transport into the brain tissue of dogs, the possibility of there being a role for insulin as an adjunct in the pharmacotherapy of disease becomes increasingly interesting i f not actual ly compel 1 i ng. I nsul i n may wel I act as a ki nd of gatekeeper affecting the transmembrane transport of many different kinds of drug molecules into these cells.
There is some excellent scientific evidence to support this concept of insulin as being such a gatekeeper in at least one kind of malignant neoplastic tissue. In an article appearing in the European Journal of Cancer and Clinical Oncology, Vol. 17, 1981, Alabaster et al. of the Cancer Research Laboratory, George Washington University, Washington, D.C. have published experimental results showing that insulin increases the cytotoxic effect of methotrexate in MCF-7 human breast cancer cel 1 s in vitro by a factor of up to ten thousand. [71
The authors argue that the increased cytotoxic effect observed was due to some activation and modification of biochemical pathways induced by insulin in the cancer cells. Research has shown that insulin does in fact increase the rate of cancer cell growth, [8,9,10] as well as DNA and RNA synthesis in certain cell lines. 1111 These effects appear to be mediated through insulin's activation of the enzyme guanylate cyclase, resulting in increased levels of the second messenger cyclic guanosine monophosphate (cGMP). [12,131 These biochemical alterations would indeed serve to potentiate the cytotoxic effect of methotrexate, as it - like so many of the cancer chemotherapy agents - acts as a mitotic poison and depends for its effectiveness on a high rate of nucleic acid synthesis and cell division.
Beyond these metabolic effects of insulin here, what is further considered to be operative is that at least some of the ten thousand fold increase in the cytotoxic effect of methotrexate is due to an increased intracellular concentration of the drug due to insulin's physiological action in altering cell membrane permeability. It is thought that this effect exists on account of the insulin receptors on the cancer cell membranes, and that these facilitate the transmembrane transport of the chemotherapeutic drug into the intracellular compartment of these breast cancer cells.
Because of considerations raised by the actual experimental evidence from this in vitro study, the authors go on in this same article to state that, "For insulin to usefully enhance methotrexate cytotoxicity in vivo, there should be a greater effect on tumor cells than on normal cells." In point of fact, Holdaway and Freisen have shown in their article "Hormone Binding by Human Mammary Carcinoma," [Cancer Research, July 19771 that "most [90%] of the tumors demonstrated significant binding of insulin as did 80% of non-malignant tissues. Autoradiographic studies indicated that insulin bound predominantly to tumor cells rather than to at and fibrous tissue within tumors'. L3J [emphasis added]
With what we know of metabolism in tumors from the classical work of Warberg, it would stand to good reason that there should be such a high concentration of insulin receptors on cancer cell membranes. Depending as they do on the anaerobic degradation of glucose for their voracious energy needs, cancer cells would certainly require insulin receptors on their cell membranesto allow for the intracellular transport of glucose and they would require these to a greater extent than normal tissues, as Holdaway and Freisen have so elegantly demonstrated.
Underscoring the significance of the point being made here for the fundamental importance of insulin in cancer cell metabolism is the fact that numerous cancers (breast (14,15.1. lung [15,161, cervix (17,181, kidney [191, fibrosarcoma [201, and Hodgkin's lymphoma ] have been shown to actually produce and secrete their own insulin and/or substances immunologically crossreactive with insulin.
From this interesting observation, one could conjecture that possibly the genetic coding for insulin's manufacture is commonly unblocked and expressible in cancer cells as a normal part of their abnormal cytochemistry. This together with their insulin receptors would supply them with the guaranteed mechanics - and autonomous, on account of their endogenous physiology as herein described - for the intracellular transport of the glucose necessary for their nourishment, survival and growth. Were these same mechanics also available to serve to increase in them the cytotoxic effects of anticancer drugs as suggested by the work of Alabaster, et al, [71, so much the better for the possibility of insulin potentiation therapy being a valid formulation.
Serendipitous would be the appropriate commentary on this "deus ex machina" phenomenon involving insulin and its receptors on cancer cell membranes - if in fact all these things are true. That very natural physiological mechanism through which nourishment and sustenance is brought into the deadly cancer cells would allow us, with our reasoned use of the hormone insulin, to more effectively poison just these same with our deadly anticancer drugs.
There exists little experimental evidence in the peer reviewed medical literature to support the applications of insulin potentiation therapy in the management of other chronic degenerative diseases - apart from cancer. However, from the evidence offered for insulin potentiation therapy with cancer, we affirm that this lack is simply an inric-ation and a direction for further study in these areas.
To recapitulate and amplify the interplay of insulin with cancer chemotherapy as it is currently perceived in this therapeutic protocol, first insulin permeabilizes cancer cell membranes to anticancer drugs. This allows for a higher and thus more effective intracellular concentration of these lethal agents. This can be accomplished using a lower total dose of medication thus reducing the many dose-related side effects of these. Complementing this, there are more insulin receptors on the membranes of cancer cells than on normal cells, and so insulin's potentiating effect predominates in the cancer cells, causing a relative sparing of the normal tissues from the impact of the anticancer drugs. Finally, insulin further potentiates the cytotoxicity of the mitotic poisons used in cancer chemotherapy by activating CGMP production, resulting in increased rates of cancer cell growth and DNA and RNA synthesis.
Overall, both the short and long-term clinical results using insulin in this adjunctive or potentiating role in cancer chemotherapy have been very good, - and better when compared to conventional practice without insulin. As with any therapeutic practice, there have been failures with it, and the far advanced cases predominate in these. Insulin potentiation therapy is not a miracle; it is simply medicine - and it may just prove to be very good medicine.
From its empirical beginnings some 50 years ago, insulin potentiation therapy can be seen from the present discussion to have evolved into a cogent and scientifically plausible system of interrelated hypotheses. We reaffirm that a great deal of scientific study is yet needed to clarify its propositions in the years to come. These studies must consist of comprehensive in vitro and in vivo experimentation, culminating with properly conducted and well controlled double blind crossover studies. It is our expectation, once these studies have been completed, that insulin potentiation therapy may well come to assume a place amongst the great scientific discoveries in the history of modern medicine.
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