Grabbing the golden ring

Insulin, glucose meters and the control of an ancient disease

Mary Beth Gardiner
Published: July, 2003

Pictured above: Dr. Frederick Banting (top) and Charles H. Best, co-discoverers of insulin.
Photos courtesy of Eli Lilly and Company Archives
A century ago a diagnosis of diabetes was a death knell. There was little a physician could offer in the way of help, other than home remedies and desperation diets that only slowed the inexorable wasting of flesh to skin and bone. Opium dulled the anguish.

The discovery of insulin in 1921 was as close to a medical miracle as humanity has seen. The Lazarus-like recovery following injection of the pancreatic extract into a child lying literally on his or her deathbed seemed surreal. Within weeks, hollow cheeks turned plump and pink, frail limbs supple and sturdy.

Initial exuberance was tempered, however, as it became clear that although insulin might pull a person from the brink of death, it was not a cure. And the treatment wasn’t perfect — the injections caused bruising and painful abscesses. Maintenance of the syringes was elaborate and time-consuming. Monitoring of urine sugar levels was crude and cumbersome. And because nutritional thinking of the day said that carbohydrates could not be tolerated, physicians exhorted patients to drink quarts of cream and eat thrice-boiled vegetables, saccharin-flavored agar, and up to 60 grams of meat a day to restore vitality.

Managing the disease left little time for enjoying life.

Today, there is still no cure, but living with diabetes isn’t nearly the struggle it once was. Thanks to the efforts of countless basic and clinical researchers over the past hundred years, what we know about the disease — what goes awry in the body and how to prevent or control it — has expanded remarkably.

The long line of incremental discoveries that brought us to our current understanding of diabetes extends back more than two thousand years. The Ebers’ Papyrus, which dates from 1552 B.C. Egypt and is our oldest preserved medical document, noted the most prominent symptom of the disease, frequent and voluminous urination accompanied by excessive thirst and emaciation. In the first century A.D., Aretaeus coined the name diabetes from the Greek word for “pipe-like,” and described the affliction as a “melting down of flesh and limbs into urine.”

The association between sugar and diabetes was initially recognized in the sixth century by an Indian physician, Susruta, who wrote of diabetes as the honey urine disease. Gradually, the Latin word for sweet — “mellitus” — was added to distinguish the disease from Diabetes insipidus, a pituitary disorder in which large volumes of sugar-free urine are passed.

In the seventeenth century, English physician Thomas Willis added a urine taste test to the criteria for diagnosing diabetes. It wasn’t unusual for physicians to first suspect diabetes in men by noting the presence of crystals on their shoes. With the beginnings of modern chemistry in 1775, the source of the sweetness was identified as sugar, and by 1815 it was known to be glucose.

During these years, the only therapeutic advice was dietary. The nineteenth-century French physician Apollinaire Bouchardat, who required daily urine analysis of his patients, recognized that fasting reduced sugar levels and prescribed a spare diet. Observing that exercise increased carbohydrate tolerance, he admonished his patients, “You shall earn your bread by the sweat of your brow.”

Yet the real breakthrough in treatment was to come not from dietary prudence but from basic physiological studies of glucose metabolism that began in the latter half of the nineteenth century.

In 1869 a German pathologist, Paul Langerhans, discovered the existence of two systems of cells in the pancreas: the acinar cells, secreting the pancreatic juice into the digestive system, and islets floating between the acini, with some as yet unknown function. In 1889 Oscar Minkowski and Joseph Von Mering removed the pancreas from a dog and witnessed symptoms indistinguishable from diabetes.

The two German physiologists went on to eliminate acinar cell secretion as the culprit when, after tying off the ducts that feed digestive juices from the pancreas to the gut, diabetes did not develop. By the early twentieth century, a direct link had been made between diabetes and damage to the islet cells.

Failure piled upon failure as scientists from around the world went in search of the “internal secretion” responsible for diabetes. The gold ring was finally grabbed by a Canadian surgeon and a medical student in the summer of 1921. Dr. Frederick Banting and Charles H. Best, in collaboration with J.J.R. Macleod and J.B. Collip, successfully reversed diabetes in a depancreatised dog by injecting a concoction of pancreatic extracts, which the researchers later named “insulin.”

The discovery was front-page news around the world. Appeals from families of diabetic patients poured in, and after Banting and Best tested the extract on themselves and found it safe, the first insulin injection in a diabetic patient was given to 14-year-old Leonard Thompson in January 1922. Thompson, who had been surviving on the “starvation” diet, weighed less than 65 pounds and was near death. Insulin saved his life.

Since 1922, much has been done to better insulin therapy, both in terms of improved insulin preparations and ease of use. Purification of insulin reduced adverse reaction at the injection site, and modification of the insulin molecule has led to greater control over the duration of its effects, which translates to fewer injections.

Initially, all insulin was isolated from either beef or pork pancreas tissue. Before long, demand for insulin was outgrowing the supply of slaughterhouse pancreases. It was a great relief when, in 1979, recombinant DNA techniques made high-volume production of human insulin possible. The U.S. Food and Drug Administration approved the use of the new insulin — called Humulin — in 1982.

Meanwhile, the years between 1950 and 1970 saw leaps in our understanding of glucose metabolism and insulin’s role in it. Vanderbilt was one of the foremost places in the world for metabolism research, due in large part to the efforts of Charles “Rollo” Park, a physician scientist who helped define how insulin “carries” glucose into cells. Assuming the helm of a physiology department of only two scientists, he set out to build a program centered on metabolism of sugars.

Park’s work and reputation attracted an impressive array of talent to Vanderbilt, including Nobel laureate Earl Sutherland, Jr., and diabetes clinician Oscar B. Crofford.

In the 1970s and 1980s, research discoveries and therapeutic innovations came fast and furious. For diabetic patients, the horizon glimmered with hints of an improved ability to monitor and control glucose levels. The means for measuring hemoglobin A1c, a way of monitoring longer term glucose control, was developed in 1977, and the first insulin pump was introduced in 1979. In that same year, trials for the use of laser photocoagulation in the treatment of diabetic retinopathy began. In the early ‘80s, other methods of insulin delivery were being explored — including microencapsulated islet cells and nasal insulin — and new, more powerful blood sugar lowering drugs entered the market.

By this time, a series of publications from a number of laboratories had suggested that tight control of blood-glucose levels could prevent or retard the onset of diabetic complications. As a result of these reports, in 1983 the government launched the Diabetes Control and Complications Trial. Widely considered the best-run clinical trial every carried out, the DCCT showed unequivocally that rigorous control of blood sugar reduces the risk and severity of long-term complications.

Improvements in insulin delivery and glucose monitoring were essential to conducting the DCCT, and by the time the results from the study became public in the early 1990s, diabetic patients had gained the ability to measure blood sugar levels at home, rather than having to go to a doctor. This newfound self-sufficiency allowed the tighter control that the DCCT touted, but patients soon found that freedom came at a price: a greater risk of hypoglycemic episodes. Innovations such as non-invasive glucose meters and implantable insulin pumps are helping to overcome the risk, however, making insulin-dependence an easier condition to bear.

And so the efforts continue. Yet with all that that’s been discovered about diabetes, much remains to be learned. To achieve a world without diabetes, whether through prevention or by cure, is the ultimate goal of these many efforts. At this rate, perhaps a second miracle is not too much to hope for.

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