Diabetes mellitus Dietary intervention Remedies for diabetes before the mid-1800s often consisted of blends of ingredients, bloodletting, and
opium (which was still being mentioned by
William Osler in 1915). Another treatment that prevailed into the 20th century was to provide the patient with extra nourishment to compensate for the loss of nutrients to urine. Patients under this regimen were advised to eat as much as possible; sometimes, to eat extra large quantities of sugar. This was misguided advice that resulted in early deaths. Meanwhile, greater success at controlling diabetes was found as physicians began to notice that
fasting, not overfeeding, seemed to improve the symptoms of diabetes. Dietary restriction was first reported successful by
John Rollo in 1797, and later by
Apollinaire Bouchardat, who observed the disappearance of
glycosuria in his patients during the rationing while
Paris was besieged by the Germans in 1870. A variety of sugar-free,
low-carbohydrate diets (occasionally involving physical restraint of patients lacking self-discipline) became increasingly popular. Among others,
Frederick Madison Allen's "starvation diet" was notoriously spartan, but was shown to extend life expectancy.
Elizabeth Hughes Gossett, later among the first people to be treated with
insulin, was among Allen's patients.
Pancreatic extracts before insulin The limit to early diabetes control was partly due to the common-sense assumption that the stomach was wholly responsible for nutrient
metabolism. As physiologists came to better understand the metabolic role of other organs, they began to hypothesize alternative causes for the disease. Through accumulating evidence, it was established that the "cause" of diabetes could be localized to the pancreas, then to its
internal secretion (see:
History of diabetes#Pathophysiology#Role of the pancreas). These findings fueled attempts to treat diabetes in animals and humans with direct extracts from the pancreas, by no less than 400 researchers according to historian
Michael Bliss. In the early 1900s,
Georg Ludwig Zuelzer experimented extensively with pancreatic extracts. After initial tests on rabbits, he injected his extracts (which he called
acomatol) on humans to clear but inconsistent success and severe side-effects. He nonetheless took out an American patent on his yet-problematic extracts. Unfortunately, Zuelzer was ultimately unable to purify the extract due to difficulty obtaining pancreases, a lack of funding, and interruption by
World War I.
Ernest Lyman Scott, studying at the
University of Chicago between 1911 and 1912, also obtained some promising results but was discouraged from continuing. In 1913,
John MacLeod, at the time several years into research in the area of
carbohydrate metabolism and blood sugar behaviour, synthesized the state of research in
Diabetes: Its Pathological Physiology. He concluded that there was an internal secretion of the pancreas, but suggested several reasons why it may never be captured in a pancreatic extract. Between 1910 and 1920, techniques for measuring blood sugar (
glucose test) were rapidly improved, allowing experiments to be conducted with greater efficiency and precision. These developments also helped establish the notion that high blood sugar levels (
hyperglycemia), rather than
glycosuria, was the important condition to be relieved. Working at the
Rockefeller Institute for Medical Research between 1915–1919,
Israel Kleiner reported convincing results on the effect of ground pancreas solutions on blood sugar levels, using rigorous
experimental controls which "theoretically... support[ed] the internal secretion hypothesis of the origin of diabetes" and "practically... suggest[ed] a possible therapeutic application." He discontinued this work upon leaving Rockefeller institute in 1919, for reasons not clearly known. Romanian scientist
Nicolae Paulescu, another notable figure in the search for the anti-diabetic factor, began experimenting in 1916 using a slightly
saline pancreatic solution like Kleiner's. After being interrupted by the
Battle of Bucharest and the postwar turmoil, he published his first results in French in 1920 and 1921. His extracts resulted in clear reduction of blood and urinary sugar in the tested dogs, but had no immediate effect in his human patients (through
rectal injection) that could not be duplicated by doses of saline alone. Paulescu took out a Romanian patent on his solution (which he called "pancréine") and method of production, but during the next year, made no further progress with his work due to a lack of funding.
Insulin In October 1920,
Frederick Banting took interest in
carbohydrate metabolism while preparing a talk he was to give his physiology students at
Western University in
London, Ontario. He encountered an article by
Moses Barron which reported an autopsy of a patient whose pancreatic
stone had obstructed the main pancreatic duct, but most of the
islet cells had survived intact. Banting wrote a note on October 31 of that year describing his thinking: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these to relieve glycosurea [
sic]" On November 8, 1920, Banting met with
John Macleod, a senior professor of
physiology at the
University of Toronto, to ask if he might mount a research project on the internal secretion of the pancreas. Banting lacked experience in physiological research and had superficial knowledge of the subject. Nonetheless, Macleod took some interest and accepted Banting's request to work in his lab. On account of what may have interested Macleod,
Michael Bliss considers the following:Speculation is in order here and is permissible because we have some idea of Macleod's knowledge of the literature. Whether he and Banting were discussing grafting or extracting, what must have appealed to Macleod as "never having been tried before" was the idea of somebody experimenting with degenerated or atrophied pancreas. Now there was nothing new in the idea of producing degeneration or atrophy of the
acinar tissues by
ligating the pancreatic ducts—all sorts of researchers had done this. Their interest, however, had been almost entirely in measuring the relative amounts of degeneration that took place in the various components of the pancreas, particularly the relative changes in the acinar and islet cells... Nobody had either tried to prepare a graft or administer an extract using a fully degenerated pancreas. And yet, theoretically, if there was an internal secretion, and if it did come from the
islets of Langerhans, and if it was the acinar cells but not the islets that degenerated after the ducts were ligated, and if two or three other conditions held good, then perhaps some interesting results would follow. Even if the results were negative, it was the kind of experiment that ought to have been tried long ago, if only for completeness's sake. Banting, Macleod, and student assistant
Charles Best began the first experiment on May 17, 1921. On June 14, Macleod left for Scotland and advised remotely through the summer, returning on September 21. During this time, Banting and Best obtained mixed but encouraging results. Since they began with the hypothesis (months later
falsified through their own work) that it was necessary to avoid the external secretion in order to obtain the internal secretion, they first used degenerated pancreas, then used foetal pancreas obtained from slaughterhouses. Progress accelerated through December 1921 as it was clarified that pancreatic extracts could be used without removing the external (digestive) secretion. As the group prepared for clinical trials, biochemist
James Collip joined the team at Banting's request to help purify the extract for human injection. On January 23, 1922,
Leonard Thompson was successfully treated with Collip's extract at
Toronto General Hospital. Six more patients were treated by February 1922 and quickly experienced an improved standard of life. Other notable early recipients of insulin included
Elizabeth Hughes,
Constance Collier,
James D. Havens, and
Theodore Ryder. In April 1922, the Toronto group jointly authored a paper summarizing all work thus far, and formally proposed to name the extract "insulin". In October 1923, Banting and Macleod were awarded the
Nobel Prize in Physiology based on a nomination by
August Krogh for "the discovery of insulin
and their exploration of its clinical and physiological characteristics". Banting and Macleod publicly shared the prize with Best and Collip, respectively. A diabetes clinic was established at
Toronto General Hospital that summer to increase capacity for treatment by Banting and collaborating physicians. The non-commercial
Connaught Laboratories collaborated with researchers to scale production. Once limits were reached, Toronto contracted with
Eli Lilly and Company beginning May 1922 with some caution regarding the commercial nature of the firm (see:
Insulin#Patent).
Nobel Prize controversy The 1923
Nobel Prize in Physiology awarded to
Frederick Banting and
John Macleod—publicly shared with
Charles Best and
James Collip, respectively—sparked controversy as to who was due credit "for the discovery of insulin". Early mass-reproduced accounts of the discovery often emphasized the role of Banting and Best's work, sidelining Macleod and Collip's contributions. This
lopsided narrative persisted due to limited availability of documentary evidence and sustained differences in researchers' attitudes toward claiming recognition. During their lifetime, Banting (d. 1941) and Best (d. 1978) were more active—and in some ways, more obviously placed—than Macleod (d. 1935) and Collip (d. 1965) in emphasizing their contributions to the work. However, the criteria advanced to prioritize the pair's early work alone (before the extract was purified) would itself run into challenges in the 1960s and 1970s as attention was drawn to successes in the same year (
Nicolae Paulescu) or earlier (
George Ludwig Zuelzer,
Israel Kleiner). was made possible through the joint effort of team members, and built on the insight of researchers who came before them. In 1954, American doctor Joseph H. Pratt, whose lifelong interest in diabetes and the pancreas went back well before the Toronto discovery, published a "reappraisal" of Macleod and Collip's contributions in refining Banting and Best's flawed experiments and crude extract. Notably, Bliss's account reviews the nominations and Nobel Prize committee's own investigations that culminated in the 1923 decision.
Metformin In 1922, metformin was developed for the treatment of type 2 diabetes mellitus.
Further developments Other notable discoveries since the early development of insulin and metformin include: • Development of the long acting insulin NPH in the 1940s by
Novo Nordisk • Identification of the first of the
sulfonylureas in 1942 • Reintroduction of the use of
biguanides for type 2 diabetes in the late 1950s. The initial
phenformin was withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis and
metformin was first marketed in France in 1979, but not until 1994 in the US. • The determination of the
amino acid sequence of insulin (by Sir
Frederick Sanger, for which he received a Nobel Prize). Insulin was the first protein that the amino acid structure was determined. • The
radioimmunoassay for insulin, as discovered by
Rosalyn Yalow and
Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine) • The three-dimensional structure of insulin () • Dr
Gerald Reaven's identification of the constellation of symptoms now called
metabolic syndrome in 1988 • Demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose levels approach 'normal'
in a large longitudinal study, and also in type 2 diabetics in other large studies • Identification of the first
thiazolidinedione as an effective insulin sensitizer during the 1990s In 1980, U.S. biotech company Genentech developed biosynthetic human insulin. The insulin was isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing synthetic human insulin), which produce large quantities of insulin. The purified insulin is distributed to pharmacies for use by diabetes patients. Initially, this development was not regarded by the medical profession as a clinically meaningful development. However, by 1996, the advent of insulin analogues which had vastly improved
absorption, distribution, metabolism, and excretion (ADME) characteristics which were clinically meaningful based on this early biotechnology development. In 2005, a new drug to treat type 2 diabetes, derived from the
Gila monster, was approved by the
Food and Drug Administration. The venom of the lizard contains exendin 4, which triggers one of the insulin-releasing pathways.
Diabetes insipidus In 1913, researchers in Italy (A. Farini and B. Ceccaroni) and Germany (R. Von den Velden) reported the
anti-diuretic effect of the substance extracted from the posterior lobe of the
pituitary gland. The hormone responsible for this effect was later isolated and named
vasopressin. Even while the
pathophysiology of diabetes insipidus was being further clarified, these findings made possible a relatively simple and effective treatment such that physicians could begin to control the disease. Various preparations of the extract were produced and made commercially available by the
pharmaceutical industry through the 20th century. In 1928, Oliver Kamm and his colleagues posited two active principles in the pituitary extract: one with antidiuretic and
pressor properties (
vasopressin), and another with
uterotonic properties (
oxytocin). In a series of landmark achievements between 1947 and 1954 which culminated in a
Nobel Prize in Chemistry (1955),
Vincent du Vigneaud isolated, sequenced, and synthesized oxytocin and vasopressin. Today, synthesized and modified vasopressin is used to treat the condition. == Notes ==