the goal of this article is to awaken the silent millions with undiagnosed diabetes to combat the Diabetes Epidemic beginning with you—and I do mean you!
In very recent times, the reality of the Diabetes Epidemic has been highlighted by all of the news media. Over 40 million in the U. S. alone and hundreds of millions worldwide already have diabetes and do not know it! Fasting high blood sugar is diabetes. Prediabetes is a term in which the fasting blood sugar is above the “normal” and less than the high fasting sugar of diabetes. Diabetes has a beginning early in life. Genetic studies have not as yet been established and are tools of the future yet to be unveiled. The Center for Disease Control (CDC) reported the following in October of 2006:
• Two million U. S. youths have prediabetes.
• Condition can be reversed.
• Left unchecked may lead to diabetes and heart disease.
• Kids are not the only ones with prediabetes. Many grownups have it, too.
The sugar in your body is carried in your blood. It is essential for life. Without it, you are no more! Your sugar can be accurately measured in your blood. A small sample is taken from you before your breakfast. This measurement is now called your fasting blood sugar. Whenever or whatever food you eat, your fasting blood sugar will immediately respond. This is exactly what must happen. All your food is changed by wonderful events within you to become sugar. This now becomes the source of energy and life of every cell of your body. This amazing event does not just happen by
itself. It needs a very special hormone that is essential for your cells to utilize the sugar. This hormone is insulin. The terms “blood sugar” and “blood glucose” are the same as applied in this article. The oral glucose (sugar) tolerance is simply having the person to be tested—after a fasting blood sugar specimen has been obtained —receive a given amount of sugar in a liquid. Thereafter, at scheduled time intervals, blood specimens for sugar determinations are obtained. Oral glucose tolerance has been an established procedure for the diagnosis of early diabetes since 1921. The oral glucose tolerance with insulin assays has been a routine procedure at St. Joseph Hospital since This test has provided the earliest diagnosis of prediabetes 1972 and diabetes even when the blood sugars were normal. *diabetic retinopathy symptoms*
The table of contents lists the chapters that highlight the history and current application of oral glucose tolerance with insulin assays in clinical medicine. The 14,384 oral glucose tolerances with insulin assays are separated according to age. There are nine groups, beginning with 3-13 years of age to the 81-90+ years of age.
This resource of the oral glucose tolerance with insulin assay is unequaled in world medical literature. The earliest diagnosis of prediabetes is hyper insulin, type 2 diabetes identified by insulin assay with normal glucose tolerance. When coupled with specific therapy, the Diabetes Epidemic will be arrested and then reversed. This is the goal of this article. If you are concerned about your future, you can find your age group in Part Two. Each group has been further divided into normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus glucose tolerance (DMGT). Each of you, upon testing by an oral glucose tolerance, would be in one of these categories.
Following the Chicago Tribune report of my presentation, “The Glucose Tolerance Examination: An Obsolete Procedure,” read at the Symposium on Radioimmunoassay in Diagnostic Medicine, Annual Convention, American Medical Association, Chicago, Illinois, June 25, 1974, Newsweek dispatched a reporter to Chicago to interview me.
The reporter was a skilled young lady with a science background. Her report highlighted the early identification of type 2 diabetes by the oral glucose tolerance with increased insulin. Whenever increased insulins of type 2 diabetes were associated with normal blood sugars, “occult” or “prediabetes” was identified. The report, “New Test for Diabetes,”
Newsweek, July 29, 1974, page 70, is now historic. It further noted that dietary control in early cases can prevent the progression of the disease.
The Evolution of the Diabetes Epidemic
1 AMERICAN DIABETES ASSOCIATION AND DEPARTMENT OF HEALTH AND HUMAN SERVICES SCREENING RECOMMENDATIONS
IN 2002, UNDER the direction of Secretary Tommy Thompson and Francine Kaufman, MD, then President, American Diabetes Association, a panel of the Department of Health and Human Services and the American Diabetes Association (ADA) unveiled recommendations for physicians to begin screening for prediabetes and diabetes by fasting blood glucose or oral glucose tolerance tests, particularly in overweight people 45 and older. Prediabetes, also known as impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), was cited as a serious condition treatable by early diagnosis.
In 2002, the normal fasting blood glucose (FBG) was less than 110 mg/dl. The panel recommended that fasting blood glucose of 110-125 mg/dl be designated impaired and require an oral glucose tolerance test. Fasting blood glucose >126 mg/dl were judged diabetes, provisional. This is an extremely high blood sugar, yet in most instances is free of symptoms. The panel emphasized that most people with prediabetes develop full-blown type 2 diabetes (hyperglycemic phase) within 10 years, with the risk of heart disease is increased by 50%. The American Diabetes Association Clinical Practice Recommendations in January 2006 and 2007, Diabetes Care Suppl 1, further defined screening for prediabetes and diabetes:
- Individuals under 45 years of age and overweight, plus if they have any other risk factors for diabetes should be tested.
- Consistent with the screening recommendations for adults, children and youths at increased risk for the presence or
development of type 2 diabetes should be tested. In 2004 and thereafter to the current time, the “normal” FBG has been designated less than 100 mg/dl. FBGs of 100-125 mg/dl were designated “impaired” and would require an oral glucose tolerance test. FBGs of >126 mg/dl were designated “diabetes provisional” and required concurrence on another day. *diabetic retinopathy symptoms*
The ADA Standards for fasting blood glucose mg/dl:
1997-2003 FBG 2004-2007
110 Normal 100
110-125 Impaired >100-125
126 Diabetes (Provisional) >126
To what extent physicians have responded to the panel recommendations for screening is not known. What normal fasting blood glucose values the physicians have been utilizing is also unknown. There are two questions you must implicitly ask your doctor:
- Is my fasting blood sugar normal?
- If normal, will I ever develop diabetes?
2 FASTING BLOOD SUGAR: WHAT IS NORMAL?
THE QUESTION of what is normal fasting blood sugar has been asked over and over again. The answer depends upon the experiences of the observers and their time in history:
Blood sugar measurements in 1925 were performed on a Folin-Wu filtrate. This was the state of the art of clinical laboratory medicine for many years. This technique contained trace amounts of other substances. For historical interest, I refer you to the following classic text: Clinical Diagnosis by Laboratory Methods: A Working Manual of Clinical Pathology by James Campbell Todd, MD, Professor of Clinical Pathology, School of Medicine, University of Colorado, 5th ed. (W. B. Saunders Company, 1925) p. 369.
From 1950 on, more precise and specific analytic methods for glucose determinations have been employed. The term “blood” glucose and “plasma” glucose specimens in this presentation are synonymous. The glucose determinations for the 14,384 oral glucose tolerances were from the blood plasma.
Table 1. Fasting Blood Glucose less than 110 milligrams per deciliter in 14,384 Oral Glucose Tolerance Tests Designated Normal (NGT), Impaired (IGT), and Diabetes Mellitus Glucose Tolerance (DMGT).
Dear reader, what is your fasting blood sugar? Please see Table 1. The 14,384 oral glucose tolerances are designated normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus glucose tolerance (DMGT). The fasting blood glucoses of less than 110 mg/dl to less than 60 mg/dl have been correlated with each category. You may take poetic license and place yourself into one of the three oral glucose tolerance categories based on your fasting blood sugar. You will fit into one of them. In the absence of high risk for diabetes and in accordance with ADA criteria (2007), those with normal fasting blood glucose, i.e., less than 100 mg/dl, would not be considered prediabetes or diabetes candidates. They would, therefore, not be subject to an oral glucose tolerance 75-g load and would thereby remain undiagnosed and potentially untreated. *diabetic retinopathy symptoms*
The oral glucose tolerance (100-g glucose load) with insulin assays were performed at St. Joseph Hospital, Chicago, Illinois. The procedure was part of the Department’s research and development program, and became a routine procedure in 1972. The persons tested were patients of the medical staff. They were submitted to identify or rule out prediabetes or diabetes. In Table 1, 40 percent of the diabetes mellitus glucose tolerances (DMGT) had fasting blood sugars less than 110 mg/dl, and 20 percent or 402 persons of the 2,011 had fasting blood sugars less than 100 mg/dl. If your fasting blood sugar is less than 100 mg/dl (“normal” 2006-2007), you could possibly still be like one of the 402 diabetics and not know it.
The New England Journal of Medicine, October 6, 2005, featured a very timely article entitled “Normal Fasting Blood Glucose Levels” by A. Tiroch et al. in the Israeli Diabetes Research Group, N Engl J Med 353:1459-62. The background for their research was the question of whether fasting blood glucose levels within the recently defined range of less than 100 mg/dl could independently predict type 2 diabetes in young adults. Their data was obtained from blood measurements, physical examinations, and medical and lifestyle information from men in the Israel Defense Force who were 26-45 years of age. A total of 208 incident cases of type 2 diabetes occurred during the follow up (1992-2004 among the 13,163 subjects who had baseline fasting blood glucose levels of less than 100 mg/dl. The study concluded that higher fasting glucose levels within the normoglycemic range, i.e., less that 100 mg/dl, constitute an independent risk factor for type 2 diabetes among young men, and that the sustaining of normal fasting blood glucose levels did not exclude the subsequent occurrence of type 2 diabetes. *diabetic retinopathy symptoms*
A question you may now ask is what is diabetes? The subsequent chapters will answer that question.
3 DIABETES IN ANCIENT TIMES
TO GAIN AN appreciation of increased insulin (hyperinsulinemia) and increased glucose of diabetes mellitus, one must begin with an awareness of the history of diabetes. In the Ebers papyrus dating back to the seventeenth dynasty (1650-5132 BC), there is testimony to a long history of diabetes before it was ever given a name. This papyrus was found in a tomb in Thebes in 1862 and named after the Egyptologist George Ebers. It contained descriptions of various diseases, including a polyuric state (frequent urination) resembling diabetes mellitus, as we now know it. The papyrus also contained a four-day treatment course consisting of a decoction of bones, wheat, grain, grit, green lead, and earth. This has been described as being no more bizarre and no less successful than that which had been prescribed over the next thousand years.
We must never forget, however, that whenever the cause and effect of a clinical condition is not definitive, speculative creativity results under the guise of research. This is true in the present as well as in ancient times. The term “diabetes,” which is Ionian Greek and means “to run through”or a “siphon,” was first used by Aretaeus of Cappadocia in the second century AD as a generic description for a condition causing increased urine output. Aretaeus described this condition accurately, which is immediately recognizable today. His description is so remarkable that I will now cite it in part from Papaspros, N. S. ed. 1964. The History of Diabetes Mellitus, 2nd ed. Stuttgart: Georg Thieme Verlag.
Diabetes is a dreadful affliction, not very frequent among men, being a meltdown of the flesh and limbs into urine. The patient never stops making water and the flow is incessant, like opening an aqueduct. Life is short, unpleasant and painful, thirst unquenchable, drinking excessive and disproportionate to the large quantity of urine, for yet more urine is passed.
One cannot stop them either from drinking or making water. If for a while they abstain from drinking, their mouths become parched and their bodies dry; the viscera seem scorched up; the patients are affected by nausea, restlessness, and burning thirst, and within a short time, they expire.
The Roman physician, Claudius Galenus (Galen: 125-199 AD), like Aretaeus, thought diabetes to be a rare disease and apparently had encountered only two cases. Galen employed alternative terms for diabetes, including “diarrhea urinosa” and “dipsatos,” the latter emphasizing the cardinal symptoms of excessive thirst and drinking. The association of polyuria with a sweet-tasting substance in the urine was first reported in the Sanskrit literature dating from the fifth to sixth centuries AD. The urine of the polyuric patients was described as tasting like honey, being sticky to the touch, and strongly attracting ants and flies.
It is most interesting that the Indian physicians of this time suggested two forms of diabetes—one affecting older, fatter people and the other thin people who did not survive long. During this era, Chinese and Japanese physicians also described this polyuric condition with the sweetness of urine which attracted small animals, including dogs. They also observed that these individuals were prone to develop boils, a condition which even today prevails in those with diabetes. *peripheral diabetic retinopathy*
The fact that diabetic urine tasted sweet was subsequently emphasized in Arabic medical texts during the centuries when Arabic medicine was at its peak of achievement. The most influential Arabic contributor to medicine was Avicenna (980-1037 AD), whose standing in both Islam and Christendom was equal to that of Galen. Until the mid-seventeenth century, the curriculum of the Christian universities, including those in the British Isles, was based on Avicenna’s writings. He described accurately the clinical features of diabetes. He specifically mentioned two complications of the disease—gangrene and the collapse of sexual function—both of which prevail today worldwide in the diagnosed and undiagnosed diabetic population. Both conditions must have been of significant incidence to have
been judged worthy of note by Avicenna. While the gangrene was objective, the sexual dysfunction was totally subjective. Sexual dysfunction, now known as penile erectile dysfunction (PED), must have been of grave concern to the men at the time of Avicenna, just as it is today to me worldwide.
PED is a personal physical manifestation of hyperinsulinemia, type 2 diabetes, even in those with “normal” fasting blood sugars. All PED must be considered hyperinsulinemia, type 2 diabetes until proven otherwise by oral glucose tolerance with insulin assays.
4 HIPPOCRATES: THE FATHER OF MEDICINE
THE PURPOSE OF the Egyptian papyri was to provide physicians with instruction of methods to be applied in curing diseases and in preparing medicine, with no particular emphasis or discussion of differential diagnosis or etiology. It remained for the ancient Greeks to initiate this gigantic step and to endeavor to establish a theoretical basis for treatment. The first instance of medicine deserving of the adjective “scientific” was in ancient Greece. It was connected with the name Hippocrates.
The Alexandrian accounts of the life of Hippocrates are rich in detail, noting that he was born in the year 460 BC, descended from Hercules as well as from Asclepious. Hippocrates studied medicine and philosophy with famous teachers and traveled over the entire Greek world. He died at an advanced age, estimated to be at or near 100 years. His tomb could still be seen in the second century AD, according to Celsus Cornelius (circa AD 30). A medical writer of renown, Hippocrates was as eminent for his eloquence as for his knowledge. *peripheral diabetic retinopathy*
There is one saying that has achieved universal use, and only a few who quote it today are aware that Hippocrates was referring to the art of the physician. It has been referenced as the first of his aphorisms.
“Life is short and the art is long; the occasion fleeting; experience fallacious and judgment difficult.”
The Hippocrates figure as the legendary Father of Medicine soon replaced the historical Hippocrates. More than sixty books or manuscripts are assumed to have originated from Hippocrates’ time, i.e., fourth and fifth centuries, BC. Presumably, they were compiled in the second century AD as Corpus Hippocraticum. This now goes by the name Hippocratic Collection. *retinopathy without diabetes*
It remains even to this day an important compendium of the medical science of antiquity. Specific symptoms of diabetes are not identified. The writings of Hippocrates are truly exceptional on physician behavior. The Hippocratic Oath is the known document associated most widely with his name. This famous testament contained both affirmations and prohibitions targeted for the physicians of his time when abortion and assisted suicide prevailed:
“I will neither give a deadly drug to anybody if asked for it. Similarly, I will not give a woman an abortion remedy. In purity and holiness, I will guard my life and my art.”
The earliest reference to the oath occurs in the first century AD. Later, it was adapted to Christianity by substituting God, Christ, and/or saints for the name Asclepius and his family. Gradually, medical students for centuries have stood to swear to the provisions of this oath. Self-evident today in the practice of medicine is the present and ongoing, never-ending, worldwide need of continuous renewal of moral and virtuous principles based upon natural law unaltered by secularism.
The emphasis that Hippocrates placed on nutrition must not be overlooked. In the oath, he further states, “I will apply dietetic measures for the benefit of the sick according to my ability and judgment.” Based on his recognition of the importance of nutrition as a method of treatment in medicine, Hippocrates has also been credited as the Father of Dietetics. For many succeeding generations, Hippocrates was the ideal physician. Several hundred years later, Galen, a distinguished Roman physician, venerated Hippocrates as one “… who with purity and holiness lived hislife and practiced his art.” I have previously referred to Galen as the one who employed the alternative terms of diarrhea urinosa and dipsakos for diabetes. Galen is a most interesting person. At the beginning of his career, he had been a physician to gladiators. Later, he became the personal physician to the emperor, Marcus Aurelius. Galen acknowledged that Hippocrates was truly a man of virtue. *peripheral diabetic retinopathy*
5 DIABETES HISTORY: SIXTEENTH TO NINETEENTH CENTURIES
SEVERAL CENTURIES APPARENTLY elapsed before European physicians made observations that diabetic urine was sugary. The sixteenthcentury Swiss physician, von Hohenheim (1493-1591), who humbly accorded himself the name “Paracelsus” in self-recognition of his own scientific achievements, reported that diabetic urine contained an abnormal substance which remained as a white powder after evaporation. He concluded that this substance was a salt and that, in diabetes, this was due to a deposition of salt in the kidneys causing “thirst” of the kidneys and hence polyuria.
It was not until the seventeenth century that Thomas Willis (1621-1675) made reference to the sweet taste of the diabetic urine and thereby duplicated the observations which had appeared over a thousand years before in the Egyptian and Eastern writings. Dr. Willis made several other astute observations about diabetes. He wrote that diabetes had been rare in classical times, “… but now, we meet with examples … I may say daily of this disease … wherefore the urine of the sick is so wonderfully sweet … or hath an honied taste.. “ Willis continued: “As to what belongs the cure . it
seems a hard thing in this disease to draw propositions for curing, for that its causes lies so deeply hid, and hath its origin so deep and remote.” Hundreds of years later, into this twenty-first century, the cure has not yet
been fully unveiled. *diabetic retinopathy blurred vision*
Another celebrated physician of the seventeenth century was Dr. Thomas Sydenham (1624-1684) who speculated that diabetes was a systemic disease in which the blood contained products of incomplete digestion of food, and its non-absorbed residue had to be excreted. About a century later, Dr. Matthew Dobson (1735-1784), a Liverpool physician,
published in 1776 a series of experiments on his nine patients with diabetes that the blood serum as well as their urine contained a substance with a sweet taste. Furthermore, he proved that the substance was sugar. He concluded that this had previously existed in the serum rather than being formed in the kidney. This was the first evidence that diabetes might be a generalized disorder. *peripheral diabetic retinopathy*
A few years after Dr. Dobson’s important paper, another English physician, Dr. John Rollo, published his study on two cases of diabetes (1809) in which he was the first to use the adjective “mellitus.” This word was derived from the Latin and Greek roots for “honey.” It was used to distinguish the condition of diabetes with its characteristic sweet urine from another poly-uric disease in which sugar was absent in the urine. The Latin term insipidus was applied to this condition and designated “diabetes insipidus.” This disease, which still prevails today, has no relationship to diabetes mellitus. Dr. Rollo made another significant observation. He reported the greater association of cataracts in some diabetics and the notation of the odor of acetone (which he compared to like decaying apples) on the breath of somediabetic persons. The latter is now known as “ketosis.”
In 1855, French physiologist Claude Bernard demonstrated that the sugar that appears in the urine of diabetics was stored in the liver in the form of glycogen. Coma was first recognized as a complication of diabetes by Dr. W. Prout (1785-1859), an English physician at Guy’s Hospital. An American ophthalmologist, Dr. H. D. Noyes, in 1869 published a report that a form of retinitis occurred in glycosuric patients. In 1869, while working on his doctorate dissertation, Paul Langerhans (1847-1888) had noted small clusters of cells in his tissue preparations of pancreas which were separable from the surrounding exocrine and ductal tissue. Langerhans simply described these structures without speculating in
his thesis as to their possible function. *diabetic retinopathy hemorrhage*
In 1874, Professor A. Kussmal (1821-1902) of Freiberg University in Germany described the “air hunger” of ketoacidosis in diabetes. Even to this day, very rapid breathing implies a condition known as metabolic acidosis occurring in diabetes and is named Kussmal Breathing. He had observed, by gentle palpation, increased pressure within the jugular veins occurred upon deep inspiration and returned to normal upon exhaling.
Failure to return to normal he judged to be indicative of increased venous pressure throughout the body. Dr. Kussmal reported that the increased venous pressure could be identified before the clinical symptoms—mainly edematous swelling of the legs, increased fluid (ascites) in the abdominal cavity, and congestion of the liver—were identified. This observation has been named the Kussmal Sign. *diabetic retinopathy blurred vision*
In 1890, Oskar Minkowski and Josef von Mering reported their experimental work, which firmly established the role of the pancreas in causing diabetes. The experiment was performed at the University of Strasbourg. The pancreas of a dog was removed to determine whether it was essential for life. After the operation, the animal unexpectedly displayed the typical signs of severe diabetes. The dog was hyperglycemic and glycosuric. The dog was now diabetic. The long-sought answer regarding the structural origin of diabetes was now answered.
In 1893, Edouard Laguesse (1861-1927) suggested that the clumps of cells described by Langerhans be named the Islets of Langerhans, and that they might constitute the endocrine tissue of the pancreas. This concept was continued by a Belgian physician, Dr. Jean de Meyer, who in 1909 gave the name “insulin” (Latin insula or island) to the glucose-lowering hormone. At that time, the existence of a glucose-lowering hormone was still hypothetical. Dr. de Meyer had postulated that this hormone was produced by the islet tissue. Insulin, therefore, became a substance, an entity, which
was named before it was actually discovered.
Minkowski and Von Mering’s discovery in 1890 that dogs developed severe diabetes immediately after pancreatectomy stimulated the idea of treating diabetes with pancreatic tissue. Many researchers reported negative or inconclusive results. Some claimed to have isolated pancreatic extracts which could reduce the sugar in the urine and the glucose in the blood when given to diabetic patients. However none could repeat their experimental work nor convince the medical community of their results. *diabetic retinopathy hemorrhage*
6 DISCOVERY OF INSULIN
THE DISCOVERY OF insulin with clinical application is a story in itself. The following is a very brief review of the highlights leading to one of the most dramatic impacts in the entire ongoing history of medicine. In 1920, Dr. Frederick Grant Banting (1891-1941), a practicing physician and surgeon in London, Ontario, was convinced that if one could ligate the ducts of the pancreas, it would cause the gland to shrink and degenerate, leaving the Islets of Langerhans. An extract of the remaining tissue, hopefully containing the islets, would be injected into a diabetic person. If the sugar spilling into the urine would be immediately relived, Dr. Banting postulated that this would prove his hypothesis that insulin came from the islets. Dr. Banting convinced J. W. Macleod, PhD (1876-1935), of the merit of his concept. In 1921, Dr. Macleod provided Banting with the experimental facilities plus a medical student as an assistant, Charles H.
Best (1899-1978). Their initial experiments were only partially successful. Finally, after much discouragement, Dr. Banting requested help. Dr. Macleod invited a skilled biochemist, James B. Collip, PhD (1892-1962) to join the team. Even though their experimental results were not conclusive, Banting and Best presented their preliminary report at a meeting of the American Physiological Society on December 30, 1921. The paper was severely criticized. *diabetic retinopathy blurred vision*
Meanwhile, Dr. Collip, working independently, developed an extraction technique which removed the toxic contaminates of the crude extract of Banting and Best. Nevertheless, Banting and Best, convinced of the quality
of their extract, gave it to a fourteen-year-old boy dying of diabetes in Toronto General Hospital on January 12, 1922. It failed! On January 23, 1922, a separate extract made by Dr. Collip was given to the same fourteenyear-old boy. The results were immediate and dramatic. Collip’s extract reduced the blood sugar to normal, abolished the excretion of sugar in the urine, and ended the ketonuria. Hereby, the use of insulin in the treatment of diabetes mellitus was inaugurated. That fourteen-year-old patient had juvenile diabetes, i.e., he was severely deficient in producing his own
insulin in sufficient amounts. This form of diabetes is now designated type 1 diabetes mellitus. The Collip technique was crude, inconsistent, and capable of only limited production. These problems were not solved until there was collaboration with the chemists of the Eli Lilly Company of Indiana. A commercially viable extraction technique involving isoelectric precipitation was developed. By October 1923, insulin became widely available in North America and Europe. *diabetic retinopathy hemorrhage*
In 1923, the Nobel Committee, with unprecedented promptness, awarded Banting and Macleod the prize in physiology/medicine for the discovery of insulin. The controversy over who should also have been recognized was never officially resolved. However, the formal winners shared their prize money with Best and Collip. Thus we come to the end of an era and the beginning of another.
History references and suggested readings:
- Hutchins, R. M., ed. 1952. Great Books of the Western World, vol. 10. Chicago: Encyclopedia Britannica.
a) Hippocrates and Galen, p. 131
b) Aphorisms, xi
- Lyons, A. S., and R. J. Petrocelli, eds. 1987. Medicine: An Illustrated History. New York: Abrams.
a) Ancient Egypt, pp. 77-104
b) Medicine in Hippocratic times, pp. 195-215
c) Medical sects and The Center at Alexandria, pp. 219-230
d) Galen, pp. 250-261
e) Ancient India, pp. 105-120
- Pickup, J. C., and G. Williams, eds. 1997. “History of Diabetes Mellitus.” In Textbook of Diabetes, 2nd ed., vol. 1. (London: Blackwell Science), 1-21. *diabetic retinopathy blurred vision*
7 THE YALOW-BERSON CONTRIBUTION: THE RADIOIMMUNOASSAY OF INSULIN
INSULIN WAS PREPARED from the pancreas glands of cows and pigs. It became of clinical concern that, over a period of time, there was an unexplained increased requirement of the insulin units needed per day by the patients. This increased requirement was arbitrarily defined as “insulin resistance.” It was applied whenever a daily requirement of 200 units or more was necessary to maintain normal metabolic stability. Fortunately, the incidence of insulin resistance requiring very high doses of insulin greater than 1,000-25,000 units per day are now rare. *diabetic retinopathy hemorrhage*
A quantitative measurement of the patient’s insulin was not yetavailable but was being sought by many. It must be noted that the clinical concept at that time was that diabetes mellitus was total or eventually a total insulin deficiency. There are some who hold to this concept even today, which I will subsequently address. In the 1950s, Solomon A. Berson, MD, Director of Radioisotope Unit, Veterans Administration Hospital, Bronx, NY, and Rosalyn Yalow, PhD, a
physicist also at the V. A. hospital, pioneered the study of the behavior of iodine-131 labeled insulin. In 1951, J. Bornstein and R. D. Lawrence published a bioassay technique demonstrating insulin in a small number of diabetic patients (Br Med J 2:144-5). Their bioassay and other similar insulin bioas-say procedures were neither practical nor applicable to clinical medicine. As a consequence, they received little attention. Yalow and Berson’s study of radioactive labeled insulin (iodine-131 labeled insulin) made several important observations that led to the development of a radioimmunoassay for plasma insulin. (Yalow, R. S., and S. A. Berson.
1960 Immunoassay of endogenous plasma insulin in man. J Clin Invest 30:1157-75.) (Yalow, R. S., and S. A Berson. 1960. Plasma insulin concentrations in nondiabetic and early diabetic subjects. Diabetes 9:254- 60.) They observed that when patients were treated with insulin, insulinbinding antibodies were formed to the injected insulin. This accounted for
the so-called “insulin resistance.” It was this principle of antigen-antibody reaction that Yalow and Berson applied to their iodine-131 labeled insulin studies. They produced insulin antibodies by injecting guinea pigs with insulin. They subsequently observed that unlabeled-insulin displaced radioactive-labeled insulin from the insulin antibody. This became the basis of radioimmunoassay. For this procedure development in analytic clinical chemistry, Dr. Yalow shared with others a 1977 Nobel Prize. Dr. Yalow also shared her financial prize with Dr. Berson, who was her husband.
8 THE ATOMIC ENERGY ACT OF 1945 AND LABORATORY MEDICINE
THE ATOMIC ENERGY Act of 1945 decreed that atomic energy was to be applied and utilized in medicine. A requirement of the Act stated that before a physician could be allowed utilization of any radioactive material, he must first be certified by a PhD physicist, primarily for safety training regarding exposure to radioactivity. The intent of the Atomic Energy Act was handcuffed by this requirement. First of all, the amount of radiation exposure with radioisotopes was minute. Secondly, the physicists were of limited number and were the first to acknowledge their lack of knowledge in matters of medicine. Modification of this requirement occurred by authority of the Atomic Energy Commission (AEC) formed in 1947. In 1955, the College of American Pathologists conjointly with the American Society of Clinical Pathologists initiated a workshop on atomic energy safety, in cooperation with the Atomic Energy Commission. I was privileged to attend this workshop, which was small in the number of participants. It was under the direction of Oscar B. Hunter, Jr., MD, director of the Oscar B. Hunter Memorial Laboratory and Professor of Clinical Pathology at Georgetown University in Washington, DC. Upon completion of the workshop, the AEC licensed each of the participants to obtain radioisotope material available at that time for clinical laboratory testing. The utilization of radioisotopes was an exciting new dimension in laboratory medicine. It was an adjunct to the clinical chemistry already in place. As an extended tool of analytical chemistry, the utilization of radioisotopes yielded unprecedented accuracy, specificity, and reproducibility in clinical laboratory medicine. Without question, the leading clinical pathologist into this new frontier of diagnostic laboratory medicine was Dr. Oscar B. Hunter. At that time, I was Pathologist and Director of Laboratories at St. Francis Hospital in Peoria, Illinois, where we had been provided a scintillation gamma counter for radioisotope testing. I say we, because Ernie P. Elzi, MD—my co-director and very best friend—and I began our adventure into radioassay medicine together.
9 OAK RIDGE INSTITUTE OF NUCLEAR STUDIES
IN 1957, MARSHAL Brucer, MD, Medical Director of the Oak Ridge Institute of Nuclear Studies (ORINS) in Oak Ridge, Tennessee, initiated a comprehensive program in radioisotope technology. The faculty was from the Institute, all of whom were experts and pioneers in their fields. The course was two weeks, with a separation of three months between the first and second week. It was a five-day program, 7:00 a.m. to 9:00 p.m., with lectures and hands-on workshops. The purpose of the three-month separation was to give each of us an opportunity to apply what we had learned and hopefully to share our experiences in the next session. The number of participants in this program was limited to 20, and I was fortunate to have been included. Like me, all participants were clinicalpathologists who had previously obtained the basic AEC licensure. Dr. Brucer, who was a physician with a specialty in medical radiation physics, directed his programs to clinical pathologists for very definite reasons:
- Radiologists were not basically trained in standardizations and
quality control in laboratory medicine.
- Clinical pathologists, by their very essence, were so trained, and
it remains the core of the specialty even today.
- Radioisotope procedures are laboratory examinations.
The labeling of red blood cells for identification of sub-clinical hemolytic anemias, the labeling of vitamin B-12 for the identification of pernicious anemia, and oleic acid labeling for malabsorption studies were all laboratory procedures. These were the first of the many radioassay procedures that followed. The one test that was not a laboratory procedure was the external counting of radioactivity from radioactive-labeled iodine emitted from the thyroid gland for the determination of hyperthyroidism.
Whereas iodine is an essential metabolite of the thyroid gland, it was quite logical, therefore, that radioactive-labeled iodine would be captured by the thyroid gland. The emission of radioactivity within the thyroid gland could thereby be measured over the thyroid gland area. Theoretically, therefore, the external counting by an appropriate gamma-ray scintillation counter could identify normal and/or the increased uptake of hyperthyroidism. This procedure was initially performed within departments of radiology. It is important to know that the gamma-ray emission of radioisotopes has a different spectrum than that of the x-ray emission. The iodine uptake via radioassay is not an x-ray emission examination. What frustrated Dr. Brucer without end was the total failure of departments of radiology, irrespective of their locations, to employ standardized procedures. In the absence thereof, the results in one institution were devoid
of relative value in other institutions. Without standardization and quality control, these procedures in the departments of radiology, according to Dr. Brucer, were virtually worthless.
A highlight of the ORINS program was that it gave a preview of organ imaging by external counting of radioisotopes. They demonstrated that images could be produced on Polaroid film, photographic paper, and x-ray film by the external counting of radioactivity. They further demonstrated that by utilizing an iodine crystal varying from one to four inches in diameter, a highly sensitive detection unit was available. The iodine crystal has its peak sensitivity at 140 keV. This means that any radioisotope whose peak activity is at or near the 140 keV becomes an ideal match with the
crystal detector, thereby achieving optimal efficiency. Radioactive iodine131 with a keV of 145 fulfills this criterion perfectly.
The first radioisotope organ imaging was the thyroid gland. Under standardized conditions, the crystal was to be moved at a controlled rate over the thyroid gland area. The term “scan” was now being introduced into medical usage. We must now move on to St. Joseph Hospital in Chicago, Illinois.
10 HISTORY OF THE INSULIN ASSAY ST. JOSEPH HOSPITAL, CHICAGO, ILLINOIS 1972-1998
FROM 1965 TO 1978, I was a member of the clinical faculty of the Department of Pathology at the University of Illinois, School of Medicine, Chicago Campus. This was during the tenure of Professor Cecil Krakower, MD, the chairman of the Department of Pathology. One afternoon a week during the school year, I would be assigned 25-30 second-year students to discuss and review their microscopic pathology slides. Dr. Krakower’s emphasis on basic pathology was reflected year after year in the National Board Examinations where his students were always in the top percentile. In 1967, Dr. Krakower assigned me the lecture subject “Diabetes,” to be given the following year to the sophomore class of 200+ students. This was an interesting challenge, which I readily accepted.
In my review of the world literature on diabetes, I encountered the nowfamous work of R. S. Yalow and S. A. Berson, Immunoassay of Endogenous Plasma Insulin in Man. 1960. J Clin Invest 30:1157. It was not until 1970 that Pharmacia Diagnostics AB, in Uppsala, Sweden, made available their product, Pharmacia Insulin RIA, based upon World Health
Organization standards for the quantitative measurement of insulin in serum. When this product became available to us with regularity, the insulin assay was applied to our oral glucose tolerance examinations. It became our routine procedure in 1972. The insulin assay became a part of the Department’s research and development program.
In 1972, the adventure of the insulin assay with the oral glucose tolerance (100-g load) began. The following are presentations and publications that highlighted this adventure: