History of Diabetes and the Discovery of Insulin
Diabetes has probably always been a part of human life. Historically, treatments ranged from near starvation diets that included foods high in fat and protein and low in carbohydrate. In spite of the best medical treatments known until 1921, however, diabetes always resulted in death.
The term, diabetes, comes from a Greek word meaning something which passes through (siphons), and the Latin word, mell which translates as honey. Mellitus refers to sweet urine – a fact determined by the observation that the urine of those with diabetes attracted flies and smelled sweet. The syndrome has been recognized since history has been recorded. Ancient Sanskrit literature includes descriptions of a disorder with honeyed urine. Papers from 1550 B.C. in Egypt describe dietary treatments for victims of the disease. In 170 A.D., Aretaeus, a Greek physician described "this mysterious affection...being [an inevitable] melting down of flesh and limbs into urine..." (Bloom & Ireland, 1980, p. 9). The tremendous significance of Banting and Best's discovery (described below) can be under¬stood more clearly when one recognizes that in 1921, diabetes was a long-standing, terminal disease which was especial¬ly virulent among children. Treatment regimens recommended before the discovery of insulin took a huge toll on the quality of life.
According to historical documentation, diabetes was treated in the pre-insulin era (i.e. prior to 1921) by diets of fat, rancid meat, boiled vegetables, and bran, or any combination thereof. In 1796, Dr. John Rollo, building on earlier revelations that the urine of persons with diabetes contained sugar, devised the first effective treatment of some people with diabetes. (We now know his treatment helped those with Type 2 diabetes, only.) The treatment was a diet high in animal foods (fats and meats) and low in vegetable foods (breads and grains). Until insulin was discovered in 1921, this was the only treatment for diabetes.
In 1921 (3,473 years from the first documentation of diabetes) Frederick G. Banting, MD (1891-1941) and Charles Best (1899-1978), a 22-year old medical student in need of a summer job, conducted research in Toronto, Canada that led to the discovery of, what was thought at the time to be a cure for diabetes: insulin. While it was soon discovered that insulin was not a cure, the discovery of insulin was a life-saving event met with considerable relief by the medical community of the time, not to mention by the public as well. Toronto was deluged with people who needed insulin to save their lives. Resources in Toronto produced insulin, but by July of 1922, a severe shortage of insulin had occurred. Soon thereafter, the pharmaceutical company, Eli Lilly and Company produced and distributed insulin for most western countries. Later, European pharmaceutical companies took on the challenge to mass-produce insulin.
In 1923, Dr. Banting received the Nobel Prize in Physiology or Medicine for the discovery in 1921 of insulin. The award was split with John James Richard Macleod, a Scottish physician and physiologist whose work in carbohydrate metabolism lead to his involvement in the research that led to the discovery. The award for Dr. Macleod was controversial. Dr. Banting publicly insisted Macleod's involvement in the discovery was nominal, and that Charles Best should have received the other half of the prize. Consequently, Banting voluntarily shared half of his award money with Best. While Charles Best did not receive public recognition for his part in the discovery, his name will forever be associated with it. Dr. Best died in 1978.
In 1934, Dr. Banting was knighted for his discovery of insulin, and thereafter known as Sir Frederick G. Banting. In 1941, Banting was killed in an airplane crash in Newfoundland while in route to England.
History of the Development of Insulin
At the time of the discovery of insulin (and ultimately its mass production from animal pancreases – bovine and porcine), there was known to be only one kind of diabetes. In this type of diabetes, the individual had lost his/her ability to produce insulin, thus rendering the individual entirely dependent on exogenous insulin (insulin by injection). Diabetes at that time was simply, diabetes; not Type 1 or Type 2 or anything else.
It was quickly discovered that insulin could not be administered orally due to the destructive effects of the gastric and intestinal juices on the insulin molecule. The only practical way to administer insulin was found to be by injection.
The first insulin was a fast- (onset within 30 minutes), short-acting insulin with a peak of activity in 2-4 hours, and a relatively short duration of action (6-8 hours) called simply regular insulin. It required twice daily intramuscular injections of 5-18 ml, and patients were not happy with it because of the pain and abscesses often associated with the injections and impurities in the insulin. Impurities in early insulin were mainly due to pancreatic peptides which were present in tiny concentrations. (In 1982, the problem was resolved with the development of recombinant DNA (rDNA) synthesis of insulin whereby purified insulin was produced. Recombinant DNA synthesis is the technology that allows biochemists to insert genes from one organism into another to make it produce a protein product – in this case, insulin from a harmless strain of a bacterium. Eli Lilly and Company produced the first rDNA insulin at that time).
It did not take long in the late 1920s and early 1930s for the public to clamor for a longer acting insulin that would provide extended coverage of the body's metabolic needs for insulin, and could be injected just once daily. In 1936 Protamine Zinc Insulin (PZI) was introduced, followed by NPH (Neutral Protamine Hagedorn) insulin in 1946, and the Lente insulins (Lente, Semilente, and Ultra-Lente – each with different action profiles) in 1951. Each of these preparations provided one peak time for insulin activity and long durations of actions, making them less than optimal for treatment (Bloomgarden, 2006), but the public appreciated the simpler approach to taking insulin.
Pre-mixed formulations of regular insulin or rapid-acting insulin and intermediate-acting insulin provide for convenience and improved accuracy of mixing than those mixed by patients, though there is less flexibility in dosing with these formulations. Such pre-mixed insulins available in the United States are 70/30 and 50/50 mixtures of NPH and Regular insulin, a 75/25 and 50/50 mixture of lispro insulin in its NPH-like formulation (insulin lispro protamine/insulin lispro), and a 70/30 mixture of insulin aspart with its NPH-like (insulin aspart protamine/insulin aspart).
Neither PZI nor any of the Lente insulins are on the market at present. NPH is the only intermediate-acting insulin now available. After subcutaneous injection, its onset of action is one to four hours, peak of activity is at six to twelve hours, and duration of activity is 18-28 hours (Deglin & Vallerand, 2001).
Faster in action than regular insulin, the first rapid-acting insulin analogue, insulin lispro (Humalog®) (sometimes referred to as ultra rapid-acting), was introduced in 1996, followed in 2000 by another ultra rapid-acting insulin, insulin aspart (Novolog®). The third rapid-acting insulin analogue, insulin glulisine (Apidra®) came on the scene in 2004. The onset of this rapid acting class of insulin is 5-15 minutes -- approximately twice as fast as that of regular insulin. The peak time is about one hour, and the duration of activity is approximately four hours. Each of these is made by rDNA synthesis.
In 2000, a 24 hour-acting rDNA synthesized insulin entered the market in the form of insulin glargine (manufactured by Sanofi-Aventis as Lantus®). Insulin glargine was far different from prior intermediate- or long-acting insulins. A distinct advantage of insulin glargine was that it had no discernible time of peak activity. Hence, it became known as the peakless insulin. Insulin glargine has a duration of action of approximately 24 hours so is administered subcutaneously just once per day. It is considered a basal insulin.
Not long after insulin glargine became available, insulin detemir (manufactured by Novo-Nordisk as Levemir®) came on the market. Also considered a basal insulin, this medication has no peak and is administered once every 24 hours, much like insulin glargine. Other basal insulins have come along (and will undoubtedly continue to come along) and are available for treatment of diabetes in some individuals.