The Internal Secretion of the Pancreas

Insulin Extracted to Treat Diabetes

Journal article

By: Frederick Grant Banting and Charles Herbert Best.

Date: February 1922

Source: Journal of Laboratory and Clinical Medicine 7 (February 1922): 256-271.

About the Author: Canadian scientist Frederick Grant Banting (1891–1941) discovered insulin, along with his colleague Charles Herbert Best (1899–1978). Banting was born in Ontario, Canada, and earned his medical degree and surgical certification from the University of Toronto. Banting began to conduct experiments on the pancreas in the laboratory of a colleague, John Macleod, in 1921. Best, then a graduate student, became Banting's assistant, and the two scientists isolated insulin during the summer of 1921. The Nobel Prize was awarded to Banting and Macleod in 1923 for the discovery of insulin. Banting shared half of his prize with Charles Best, who earned doctorate degrees in both medicine and physiology. Best became a professor of physiology at the University of Toronto, where his further accomplishments included isolating heparin, an anti-coagulant drug.

INTRODUCTION

Insulin is a hormone secreted by the beta cells of the islets of Langerhans (specific groups of cells in the pancreas) as a response to increased glucose (sugar) levels in the blood stream. It promotes the entry of glucose into cells and a drop in blood glucose levels. When the body does not make enough insulin, or when it has difficulty using the insulin that it does make, elevated blood sugar (hyperglycemia) and excess sugar in urine (glycosuria) result—both characteristics of the disease called diabetes mellitus.

Canadian scientists Frederick Grant Banting and Charles Herbert Best were the first to obtain—from extracts of pancreas—a preparation of insulin that could serve to replace a deficiency of the hormone in the human body. In their article, "The Internal Secretion of the Pancreas," published in 1922, they described the successful results of their experiment to treat diabetes in dogs.

Previously, in 1889, scientists had demonstrated the importance of the pancreas in carbohydrate metabolism. They removed the entire pancreas of a dog and observed all the symptoms of severe diabetes in that animal. Subsequently, physiologists and clinicians tried to obtain an internal secretion from the pancreas, now known as insulin, which would be of value in the treatment of diabetes mellitus.

Many researchers tried various forms of pancreatic extracts, using water, saline, alcohol, and glycerin. The extracts obtained were administered by mouth, subcutaneously (injected just beneath the skin), intravenously, or by rectum. These attempts all failed, presumably because the insulin in these extracts was destroyed by trypsin, the proteolytic enzyme of the pancreas found in the digestive juice. Researchers did not know about the action of trypsin on insulin at the time these experiments were carried out.

In 1920, Frederick Banting visited the University of Toronto to speak to John Macleod, the newly appointed head of the department of physiology. Macleod had studied glucose metabolism and diabetes and Banting had a new idea on how to find not only the cause, but also a treatment for the so-called "sugar disease."

While reading the article "The Relation of the Islets of Langerhans to Diabetes, with Special Reference to Cases of Pancreatic Lithiasis" by Moses Barron, Banting had an inspired idea. He suspected that the pancreas's digestive juice was destroying the islets of Langerhans's hormone before it could be isolated. If he could stop the pancreas from destroying the islets, he should be able to isolate insulin. He presented this idea to Macleod, who at first scoffed at it. Banting badgered him until finally Macleod gave him lab space and ten experimental dogs.

On April 14, 1921, Banting began working on this idea in the Physiological Laboratory of the University of Toronto. Professor Macleod allotted him Dr. Charles Best as an associate. The first step was to tie the pancreatic ducts in a number of dogs. At the end of seven weeks these dogs were chloroformed. The pancreas of each dog was removed and all were found to be without trypsin-producing cells. This material was cut into small pieces, ground with sand, and extracted with normal saline. This extract was tested on a dog rendered diabetic by the removal of the pancreas. Following the intravenous injections, the blood sugar of the diabetic dogs was reduced to a normal or subnormal level, and the urine became sugar-free. There was a marked improvement in the general clinical condition of the dogs—they became stronger and more lively, their wounds healed, and their lives were undoubtedly prolonged. Insulin had been isolated.

However, the extract was still impure and could not be injected into humans. In order to obtain a pure insulin extract, J. B. Collip, a biochemist, was brought on board. With his help, the first human patient, Leonard Thompson, was treated with the purified insulin extract in January 1922. The trial resulted in the well-documented revival of the young fourteen-year-old diabetic.

Banting's involvement in the experimental work was less evident during the winter and spring of 1922. However, he did treat diabetic patients, as insulin became more readily available. Sometime in April, with the help of Dr. Joseph Gilchrist and the support of the Department of Soldiers' Civil Reestablishment, Banting established a diabetic clinic at the Christie Street Hospital. He also opened his own practice at 160 Bloor Street West to treat private patients. One of these patients, Jim Havens of Rochester, became the first American citizen to be injected with insulin. In late May, after an agreement was reached with Eli Lilly & Company to distribute insulin on a larger scale, the research entered the clinical testing phase.

Banting and Macleod were awarded the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin, a prize they later shared with Best and Collip.

PRIMARY SOURCE

The hypothesis underlying this series of experiments was first formulated by one of us in November 1920, while reading an article dealing with the relation of the isles of Langerhans to diabetes. From the passage in this article, which gives a résumé of degenerative changes in the acini of the pancreas following ligation of the ducts, the idea presented itself that since the acinous, but not the islet tissue, degenerates after this operation, advantage might be taken of this fact to prepare an active extract of islet tissue. The subsidiary hypothesis was that trypsinogen or its derivatives was antagonistic to the internal secretion of the gland. The failures of other investigators in this much-worked field were thus accounted for….

In this paper no attempt is made to give a complete review of the literature. A short résumé, however, of some of the outstanding articles, which tend to attribute to the isles of Langerhans the control of carbohydrate metabolism, is submitted.

In 1889 Mering and Minkowski found that total pancreatectomy in dogs resulted in severe and fatal diabetes. Following this, many different observers experimented with animals of various species and found in all types examined, a glycosuria and fatal cachexia after this operation. The fact was thus established that the pancreas was responsible for this form of diabetes….

Lewaschew believed that the islets were modified acinous cells. Laguesse, an anatomist, first suggested that the islets of Langerhans might be the organ of pancreatic internal secretion. He showed that there were comparatively more islets in the fetus and the newborn than in the adult animal. Opie and Sscobolew independently furnished the first clinical foundation for the belief that the islets were involved in pancreatic diabetes.

W. G. MacCallum, in 1909, ligated the pancreatic ducts draining the tail third of the pancreas. After seven months he excised the remaining two-thirds. This was followed by a mild glycosuria. Three weeks later he removed the degenerated tail third. This second operation resulted in an extreme and fatal glycosuria….

Murlin prepared an alkaline extract of pancreatic tissue and after the injection of this solution, a reduction in sugar excreted by a diabetic animal was observed. Kleiner has pointed out that the reduction secured by Murlin might be due to the alkali per se. Kleiner himself has shown that "unfiltered-water extracts of fresh pancreas diluted with 90 percent NaCl when administered slowly usually resulted in a marked decrease in blood sugar." There was no compensating increase in urine sugar, but rather a decrease, which Kleiner suggests may be partly due to a temporary toxic renal effect. Hemoglobin estimations made during the experiment showed that the reduction in blood sugar was not a dilution phenomenon. Paulesco has demonstrated the reducing effect of the whole gland extract upon the amounts of sugar, urea and acetone bodies in the blood and urine of diabetic animals….

From the work of the above-mentioned observers we may conclude: (1) that the secretion produced by the acinous cells of the pancreas are in no way connected with carbohydrate utilization; (2) that all injections of whole-gland extract have been futile as a therapeutic measure in defects of carbohydrate utilization; (3) that the islands of Langerhans are essential in the control of carbohydrate metabolism. According to Macleod there are two possible mechanisms by which the islets might accomplish this control: (1) the blood might be modified while passing through the islet tissue, i.e., the islands might be detoxicating stations and (2) the islets might produce an internal secretion.

We submit the following experiments, which we believe, give convincing evidence that it is this latter mechanism, which is in operation….

METHODS:

The first step was to tie the pancreatic ducts in a number of dogs. At the end of seven weeks these dogs were chloroformed. The pancreas of each dog was removed and all were found to be without trypsin producing cells. This material was cut into small pieces, ground with sand, and extracted with normal saline. This extract was tested on a dog rendered diabetic by the removal of the pancreas. Following the intravenous injection, the blood sugar of the depancreatized dogs was reduced to a normal or subnormal level, and the urine became sugar-free.

RESULTS:

In the course of our experiments we have administered over seventy-five doses of extract from degenerated pancreatic tissue to ten different diabetic animals. Since the extract has always produced a reduction of the percentage sugar of the blood and of the sugar excreted in the urine, we feel justified in stating that this extract contains the internal secretion of the pancreas. Some of our more recent experiments, which are not yet completed, give, in addition to still more conclusive evidence regarding the sugar retaining power of diabetic animals treated with extract, some interesting facts regarding the chemical nature of the active principle of the internal secretion. These results, together with a study of the respiratory exchange in diabetic animals before and after administration of extract, will be reported in a subsequent communication.

We have always observed a distinct improvement in the clinical condition of diabetic dogs after administration of extract of degenerated pancreas, but it is very obvious that the results of our experimental work, as reported in this paper do not at present justify the therapeutic administration of degenerated gland extracts to cases of diabetes mellitus in the clinic.

CONCLUSIONS:

The results of the experimental work reported in this article may be summarized as follows:

Intravenous injections of extract from dog's pancreas, removed from seven to ten weeks after ligation of the ducts, invariably exercises a reducing influence upon the percentage sugar of the blood and the amount of sugar excreted in the urine….

The extent and duration of the reduction varies directly with the amount of extract injected.

Pancreatic juice destroys the active principle of the extract….

The presence of extract enables a diabetic animal to retain a much greater percentage of injected sugar than it would otherwise….

We wish to express our gratitude to Professor Macleod for helpful suggestions and laboratory facilities and to Professor V. E. Henderson for his interest and support.

SIGNIFICANCE

The discovery of insulin for therapeutic use was a milestone in medicine. Before the discovery and extraction of insulin, diabetes was a slow death sentence that usually struck children and adults under thirty. Physicians treated their diabetic patients with a diet low in carbohydrates and sugar and high in fat and protein. People with diabetes often had constant thirst and insatiable appetites, but lost weight when they could not process their food.

There are two major forms of diabetes: insulin-dependent diabetes and insulin-independent diabetes. After Banting's and Best's discovery, people with insulin-dependent diabetes were given cow or pig insulin, which differs very little from the human hormone. Thanks to recombinant (genetic engineering) technology, people with diabetes now are given human insulin.

The isolation of insulin was also a highly publicized medical achievement, and after news of the initial success, the demand for insulin was immediately widespread. Production of insulin was given a high priority after pharmaceutical companies received permission to manufacture insulin without payment of royalties. Scientists hurried to determine proper dosages and to develop manufacturing processes capable of producing sufficient quantities of insulin of consistent strength and purity. By 1923, roughly one year after it was successfully tested in a human, insulin was widely available to a grateful public. One year the disease was an automatic death sentence; the next, people with diabetes—even children—had the hope of living full and productive lives.

FURTHER RESOURCES

Books

Bankston, John. Frederick Banting and the Discovery of Insulin. Hockessin, Del.: Mitchell Lane, 2001.

Bliss, Michael. The Discovery of Insulin. Chicago: University of Chicago Press, 1982.

Yuwiler, Janice M. Insulin. Detroit: Lucent Books, 2005.

Periodicals

Rosenfeld, Louis. "Insulin: Discovery and Controversy." Clinical Chemistry 48 (2002): 2270-2288.

Web sites

New Tecumseth Public Library. "Banting Digital Library." 〈http://www.newtecumseth.library.on.ca/banting/main.html〉 (accessed April 17, 2005).

Sir Frederick Banting Educational Committee. "The Discovery of Insulin." 〈http://www.discoveryofinsulin.com〉 (accessed April 22, 2005).

The Nobel Foundation. "Frederick G. Banting—Nobel Lecture." 〈http://nobelprize.org/medicine/laureates/1923/banting-lecture.html〉 (accessed April 16, 2005).

Audio and Visual Media

Diabetes: Towards the Cure, created by Richard Simpson, R. Fraser, and Chris Simpson (Special originally aired on the CanWest Global Network, 2001). BTV Communications, 2001 (VHS).