Discovery, treatment and management of diabetes
S.P. Lasker1, C.S. McLachlan2, L. Wang3, S.M.K.
Ali4, H.F. Jelinek1
Author Affiliations:1 School of Community Health, Charles Sturt
University, Australia; 2 University of Technology, New South Wales, Australia, 3
School of Biomedical Sciences,Charles Sturt University, 4 Institute of Nutrition
and Food Science, University of Dhaka.
The history of diabetes started in Egypt, Arab and Asia 3,500 years ago. From the
16th - 18th century diabetes has been diagnosed and treated
more methodically starting in Europe but the remedy for the diabetes was only discovered
in the last century. Discovery of insulin for the treatment of diabetes represents
one of the major humanitarian and scientific milestones of the 20th century.
But health care providers have no awareness of the history of diabetes. Knowledge
of the history provides a better understanding of contemporary issues and a clearer
vision for the future. Ancient physicians recorded their observations in an attempt
to better understand the nature of the ailment, its origin, and treatment. Diabetes
was recognized in antiquity but its history has been characterized by numerous cycles
of discovery, neglect and rediscovery.
Diabetes, History, Treatment and management
Diabetes is a chronic disorder affecting carbohydrate, fat and protein metabolism
due to defective production and action of the hormone insulin characterized by hyperglycemia.
Typically people with diabetes have a long term risk of developing progressive disease
such as blindness, end stage renal disease, heart disease, cerebro-vascular disease,
and peripheral vascular disease as well as peripheral neuropathy. In fact there
is hardly any organ system or tissue that is spared by diabetes mellitus
The prevalence of the diabetes mellitus is increasing rapidly and standing as a
major threat to mankind. There are about 100 million (3% of world population) diabetic
patients in the world today
By the year 2025, 6.3% of the global population will have diabetes (334 million).
Each year 6 million people develop diabetes
It is now recognized as the third leading cause of death in adults after heart disease
A remedy for diabetes was discovered in the 20th century though diabetes
mellitus was first described 3500 years ago. The discovery of insulin for the treatment
of diabetes represents one of the major humanitarian and scientific milestones of
the 20th century
However health care providers receive very little information on the history of
diabetes during their training. Historical concepts of causes and the nature of
diabetes have a vital role to play if we are to understand and deal with the current
diabetes epidemic. In addition there is only sparse literature available on the
history of diabetes. Thus the present work was undertaken to compile a comprehensive
history on diabetes.
The history of diabetes is divided into four periods that reflect the understanding
and management of the disease in different historical periods
Discovery of Insulin
This period was witness to the first clinical description and complication of diabetes
mellitus by Egyptian physicians 3,500 years ago who had been striving to diagnose
and treat diabetes. Egyptian medicine influenced the medical practices of neighboring
cultures; including the culture of ancient Greece
From the first century AD, the Greeks described the disease as "a melting down of
the flesh and limbs into urine
Hippocrates did not specifically mention diabetes in his writing but his disciples,
Galen and Aretaeus contributed much to the description of diabetes
Around 250 BC Apollonius of Memphis probably coined the name "diabetes" from Ionian
Greek. The literal translation, is "to go through" or siphon, reflecting the early
understanding of a disease that drained patients of more fluid than they could consume
Aretaeus of Cappadocia first used the term diabetes in the 2nd century AD and he
concluded that it was due to a fault in the kidney, a generic description for conditions
that are instantly recognizable today. Galen (AD 131 – 201), a Roman physician,
proposed the same notion but he used an alternative term for diabetes including
“diarrhea urinosa”- excessive urinary output, and “dipsakos” - excessive thirst
Dating from the 5th – 6th centuries AD, Sushruta and Charuka,
two notable Indian physicians, first reported a sweet tasting substance (Madhumeha)
present in the urine of patients with polyuria, being sticky to touch and strongly
Indian description of this time appear to distinguish two forms of diabetes one
affecting older, fatter people and the other thin people who did not survive long,
that resemble the present day subdivision of type I and type II diabetes
At the same time, Chinese (Chen Chuan) and Japanese (Li Hsuan) physicians also described
the sweetness of diabetic urine, which apparently attracted dogs. Their recommended
treatments included the avoidance of wine, sex and salty cereals
That diabetic urine tasted sweet was subsequently emphasized by Arabic Medical
Texts during the 9th – 11th centuries, when Arabic medicine
was at its peak of achievement. Avicenna (AD 960 - 1037) described accurately the
clinical feature of diabetes and mentioned two specific complications of the disease
namely “gangrene” and “fall down” of sexual function. He recommended treatment of
a mixture of lupin, fenugreek and zedoary seeds that possess mild hypoglycemic activity
From the 16th to 18th century the diabetic medicine falls
into the diagnostic period and was recognized as a separate disease entity centred
largely in Europe
In the 16th century, the Swiss physician Von Hohenhein (Paracelus) suggested
that diabetic urine contains white powder, due to deposition of salt in the kidney
that causes thirst. It was not until the 17th century that Thomsas Wills
(1674), a physician and anatomist describing diabetes as the ‘pissing evil’, made
reference to the sweet taste of diabetic urine and reiterated the same observation
that was first discovered in Asian and Hindu writings over 1000 years before
Thomas Sydenham then proposed that diabetes was a systemic disease. Mathew Dabson
(1776) finally indicated that the sweet substance in urine is sugar, and that it
is not present in the kidney but in serum.
In 1809, John Rollo, an apothecary and chemist, first used the term “mellitus”,
the Latin and Greek root for honey and documented excess sugar in the blood as well
He differentiated diabetes mellitus from a polyuric disease which is tasteless (Insipidus).
He also concluded that diabetes causes cataract and an odor of acetone (decaying
apples) on the breath of some patients. He treated his patients with meat rich carbohydrate
restricted diet, and sometimes supplemented this with an anorectile compound including
antimony, opium and digitalis like the starvation diet of Allan and others a century
In the last part of the 18th century Thomas Cawley described that diabetes
may follow damage to the pancreas
Experimental period (Mid to late 19th century)
During this period the glucoregulatory role of the pancreas became clear, and the
biochemical mechanism was recognized. Knowledge of diabetes and its associated effect
on metabolism dramatically improved in this era
Claude Bernard (1813-1878) believed that the sugar present in diabetic urine was
stored in the liver as glycogen. He also found that the central nervous system was
involved in controlling blood glucose concentration while stimulating vagal motor
nuclei by pricking the medulla of rabbits with a needle
In 1869, Paul Langerhans (1847 – 1888), aged 22, while working for his doctorate
in Berlin noticed small clusters of cells in the pancreas. Langerhans simply described
these structures without speculating as to their possible function. In 1889, Osker
Minikowski and Joseph Von Mering who were assistants of Albert Naunyn, the foremost
European clinician in diabetes in Strassburg at that time, removed the pancreas
from dogs to discover whether it had an effect on blood sugar levels. After the
operation, dogs unexpectedly displayed typical signs of severe diabetes with polyuria,
polyphagia, thirst, wasting and death in ketoacidotic coma. This observation firmly
established the role of pancreas in diabetes
It was only in 1893 that Edouard Laguesse (1861 – 1927) suggested that these clumps
of cells in pancreas might constitute the endocrine tissue of the pancreas, which
he named the Islets of Langerhans (named after Paul Langerhans)
This theme was continued further by the Belgian physician, Jean de Meyer, who in
1909 isolated glucose lowering hormone from the pancreas and gave it the name insulin
(Latin, insula= Island, as it was produced by islet cells
Discovery of insulin
As soon as the link between the pancreas and diabetes was recognized, researchers
focused on treating diabetes with pancreatic extracts. Several workers including
Georg Ludwig Zülzer (Germany), Nicolas Paulesco (Romania), EL Scott and Isael Kleinter
(North America) were actively trying to search for the active principal of insulin.
In the early 1900s, Zülzer experimented with pancreatic compounds and made an injection
called "acomatrol" into a dying diabetic patient. The patient improved but later
died when Zülzer’s acomatrol supply was exhausted
Later, in 1911, a European pharmaceutical company funded a small laboratory and
some workers to help Zulzer, who took out an American patient on his "Pancreas Preparation
Suitable for the Treatment of Diabetes”. But Zulzer’s laboratory was turned over
to the military during World War 1
In the early years of 20th century purification, removal of toxic products
and demonstrations consisting of biological activity were the principal problem.
Professor John James Rickard Macleod, a physiologist at the University of Toronto,
continued to pursue his work on carbohydrate metabolism. In 1921, Frederick G. Banting
was hired and Charles Herbert Best, a 21 year old student was recruited for assisting
Banting, who proved that it is an active substance of the pancreas that is associated
with hypoglycemia in diabetic dogs under Macleod’s patronization. James Bertram
Collip, a biochemist, later joined the team, and improved the extraction and purification
of insulin. The most important demonstration was that the pancreatic extract enabled
the diabetic liver to store glycogen and it could clear ketouria7. Discovery of
insulin for the treatment of diabetes represents one of the major humanitarian and
scientific milestone of this century. It was a momentous advance in medicine
On 1 January 1922, the insulin extract made by Banting and Best was first injected
into Leonard Thompson, a 14 year old boy who weighed only 64 pounds, dying of diabetes
in Toronto Hospital. Leonard was given a 5 -10 mL injection in each buttock. But
it failed to relieve the symptoms. Abscesses developed at the injection sites, and
Leonard became even more acutely ill. However, his blood glucose level dropped initially.
On 23rd January another insulin extract injection refined by Collip reduced
Thompson’s blood sugar to normal (from 520-120 mg/dL) in about 24 hours and abolished
his glycosuria and ketonuria. He began to gain weight and regain strength. Leonard
lived a relatively healthy life for 13 more years but died of pneumonia at the age
About the time that insulin was being developed, the treatment of diabetes was centered
Frederick Allen, the leading American diabetologist, believed that since the diabetic's
body could not use food, he limited the amount of food to his patients to reduce
the strain. The outcome was better than ever seen before for type II diabetes, but
for those with type I, death from "inanition" was not uncommon. Fortunately, Allen's
treatment did allow a number of young people to survive to become the first insulin
Allen's treatment was so rigid that he put one of his patients named Elizabeth Evans
Hughes on diet. This diet almost lead to starvation, and she hated these "nightmares"
during her treatment period. But Elizabeth clung to life until Banting agreed to
see her in August 1922
Banting was astonished to see the girl, who weighed only 45 pounds and was scarcely
able to walk, was still alive. He began insulin at once, injecting 1 mL twice daily
and increasing her calorie allowance by 100 calories each day. Elizabeth went on
to live a happy and productive life. She did not tell anybody about her diabetes
not even her future husband until after they became engaged. Elizabeth probably
had about 43,000 insulin injections before she died suddenly of a heart attack at
Her recovery was hailed around the world as a true medical miracle.
Interestingly, after the successful use of insulin isolated by Leonard Thompson,
Collip, who had agreed to share all information with Banting and Best, but he decided
not to tell them how he had improved the insulin extraction. Because he was thinking
about patenting his refined insulin himself. This led to an unsavory encounter (a
physical fight actually) between Banting and Collip. A cartoon published at the
time, and unfortunately now lost, showed Banting sitting on Collip, choking him.
The caption read "The Discovery of Insulin”
Though, insulin was discovered by the team of four, the credit for the discovery
of insulin is given to Banting and Macleod who won the Noble Prize in 1923. In an
attempt to remedy this injustice Banting publicly acknowledged Best’s role in the
discovery of insulin and Banting shared the prize money equally with Best while
Macleod agreed to do the same with Collip
Although conflicts were resolved sufficiently to allow the four key players to continue
their work, Banting lost trust in his coworkers and eventually began to withdraw
from the team. Privately and bitterly, the men feuded over priorities and who did
what for the next two decades
Life of four heroes:
Macleod died in 1935 in Scotland
while Banting immediately reached heroic proportions in the medical community and
among the general public. He later became the Head of the Research Institute at
Toronto University. Banting died in a plane crash in Newfoundland in 1941. Best
outlived everyone in this drama, dying in 1978 after a distinguished career at the
University of Toronto, where he eventually took over Macleod's job
Collip also achieved recognition for his pioneering work in purifying insulin
Within a year of the first successful extraction, insulin was sufficiently purified
for therapeutic administration to patients with diabetes mellitus. Chemical identification
of insulin was first prepared by Abel in 1926
In 1928, Wintersteiner and his colleagues described insulin as a protein composed
of amino acids
Fredrick Sanger et al. proposed the structure of insulin that consists of two protein
chains connected by a disulfide bond in 1945
and sequenced the protein of insulin in 1955
In 1958, Sanger was recognized with a Noble Prize in chemistry
The major breakthough in the development of insulin was the development of the radioimmunoassay
for insulin level measurement by Rosalyn Sussman Yalow and Solomon Berson in 1959.
This work was also rewarded with the Nobel Prize
The chemical synthesis of the A and B chain of insulin and the combining of a synthetic
and natural chain of the active insulin was achieved by Du et al. (Germany), Katsoyanis
(USA) and Kung (China) in1963
Proinsulin was first synthesized by Donald Steiner et al. in 1967
However, the total synthesis of human insulin, starting from peptides with intact
disulfide bridges was achieved by Sieber and his colleagues at Ciba Geigy laboratory
in Basel in 1974
For many years, beef/pork insulin was the only source of insulin. The first commercial
product of human insulin was developed by recombinant DNA technology in 1979 by
Goeddel et al.
and human insulin was first prepared by Graham Bell et al. in 1980
DNA technology, which freed manufacturers from the demands of collecting huge stockpiles
of animal pancreatic tissue allowed synthesis of a "human" type of insulin. In July
1996 the Food and Drug Administration approved the first recombinant DNA human insulin
analogue, Lispro (Humalog). At present, more than 300 insulin analogues have been
identified, including about 70 animal,, 80 chemically modified , and 150 biosynthetic
In 1939, Himsworth reported that some patients required higher insulin doses to
lower their blood glucose concentration. This observation laid the foundation for
the concept of impaired insulin action, which is now known to be a crucial factor
in pathogenesis of non insulin dependent diabetes mellitus (NIDDM). However, in
1979, Deborah Doniach and GianFranco Battazo suggested that autoimmune attack directed
against β cell mass causes Insulin dependent diabetes mellitus (IDDM)
Another type of diabetes occurs only during pregnancy (gestational diabetes) predisposing
to type II diabetes
The diabetic control controversy
After the discovery of insulin many physicians felt that tight control of diet along
with insulin was of paramount importance in managing the deadly disease of diabetes.
Other practitioners however believed that with the advent of insulin using specific
diets as treatment could be liberalized
Considering the value of loose or tight control led to a long term prospective clinical
trial with insulin, oral hypoglycemic agents and diet by the University Group Diabetes
Programme (UGDP) in 1970. But this study failed to show that the “improved control”
prevented or slowed the development of complications
A decade later, the National Institute of Diabetes, Digestive and Kidney Diseases
developed a study called the Diabetes Control and Complications Trail (DCCT) by
insulin therapy only on patients with type 1 diabetes. In 1993 the results of the
DCCT reported that intensive control of the blood sugar over a 7 year study interval
reduced the progression of diabetic complications retinopathy, nephropathy and neuropathy
but also resulted in a threefold increased risk of serious hypoglycemia. The relationship
between the control and complications in type 2 diabetes was also evaluated by United
Kingdom Prospective Diabetic Study (UKPDS). Following an average decade of follow
up on 5,000 newly diagnosed patients, the study concluded that a 1% decrease in
glycosylated Haemoglobin A1c causes a 35% reduction of microvascular complications.
These two studies at the end of the 20th century gave physicians and
patients a solid confirmation of the benefit of good control and thus ending the
nearly 50 years of divisiveness and confusion
Traditional medicine for managing diabetes
Spices, herbs and indigenous plants have been used for treating diabetes in Egypt,
India, and China from thousands of years ago
Plants with sufficient evidence for blood glucose level lowering activity in diabetes
jamon (Eugenia Jambolana)
neem, methi (Trigenella foenum grceum), Karela (Memordica Chantia) and Kalonji (Nigella
Oral administration of the aqueous extract of the whole Ocimum sanctum plant is
beneficial against the development of insulin resistance in fructose fed rats
In 1923, Collip found that onion has a hypoglycemic effect in fasting and depancreatized
Histopathological findings suggested that some of these plants also increased the
number of B cells in experimental animals
Hypoglycemic medicinal plants are about 75 per cent as active as the synthetic medicine
Medicinal plants are cheap, easily available and have no additional side effect
and thus might be considered as another choice in treating diabetes.
Oral hypoglycemic agents
An oral drug is a far more convenient and comfortable way instead of delivering
insulin. Among the millions of type 2 diabetes, about 40% use insulin , 50% use
oral agent and 10% use a combination of two
The first oral hypoglycemic agent was discovered serendipitously in 1942 by M.J.
Janbon, Professor of Pharmacology, while working on sulfonylurea for typhoid disease
in Montpellier in France. He asked August Loubaieres, Professor of Medicine to try
this agent on diabetic patients. Sulfonylurea produced an undoubted fall of blood
glucose but it was ineffective in animals after pancreactomy. Ten years later, Franke
and Fuchs in Berlin rediscovered the sulfonylurea as oral hypoglycemic agent and
applied it clinically
Other oral agents followed with the biguanide, metformin succeeding over phenformin
due to its side effect, lactic acidosis. Glucosidase inhibitors became more widely
used in the 1980s.The thiazolidinediones were introduced in the 1990s, although
troglitazone was rapidly withdrawn for its hepatic toxicity. However, pioglitazone
and rosiglitazone are now in widespread use. Recent additions include non sulfonylureas
repaglidine and nateglinide similar to sulfonylureas but have a short half-life
In late 2005, Emisphere initiated a 90-day Phase II study to evaluate the efficacy
and safety of fixed doses of oral insulin in patients with type 2 diabetes
National institute of Health (NIH) has launched a nationwide clinical study to determine
whether oral insulin (capsule of insulin crystals) can prevent or delay onset of
type I diabetes
The oral insulin trial failed to prevent type 1 diabetes in at-risk people. The
European Nicotinamide Diabetes Intervention Trial (ENDIT) also failed to prevent
or delay type 1 diabetes with nicotinamide, a vitamin present in small amounts in
a normal diet. Another NIH oral insulin clinical trial was conducted with more close
supervision under Type 1 Diabetes TrialNet, a collaborative network of more than
100 medical centers across the United States, Canada, Finland, United Kingdom, Italy,
Germany, Australia and New Zealand that came into existence for the prevention of
type 1 diabetes and preserving insulin production in new-onset patients
The first trials were started in 2003. One Trial Net study sought to turn off the
immune attack on beta cells with Rituximab, a monoclonal antibody that binds to
and temporarily destroys a specific class of immune cells. Another under way study
is testing whether mycophenolate mofetil (MMF) or MMF plus daclizumab (DZB), drugs
approved by FDA to prevent rejection after an organ transplant, can slow or arrest
the autoimmunity of type 1 diabetes
Life expectancy of people with diabetes
Prior to advent of insulin, most patients with diabetes died shortly after diagnosis
but the good news is that we have learned a lot about the value of careful control
in diabetes management over the past 85 years. The recently conducted Diabetes Control
and Complications Trial (DCCT) provided information about how to maintain near-normal
blood glucose levels and lower the risk of complications by almost 75%
Life expectancy of people with diabetes has increased. In 1897, the average life
expectancy for a 10-year-old child diagnosed with diabetes was 1 year. Diagnosis
at age 30 carried a life expectancy of 4 years, while a 50-year-old with a new diagnosis
could expect to live 8 more years. By 1945, a newly diagnosed 10-year-old had a
45-year life expectancy; a 30-year-old had 30 or more years, and a 50-year-old 15
and more years to live. Today's life expectancy for people with diabetes is still
lower than that for the general population by about 15 years but better control
is leading to longer and healthier lives
The discovery and therapeutic application of insulin in the 1920s was a miraculous
development in the treatment of diabetes that enabled individuals affected by this
disease to live an almost-normal life. Type II patients could control blood glucose
with diet and exercise, and increase their life expectancy
As people began to live longer, they experience complications that had not previously
been seen. People with diabetes are at increased risk for the development of serious
complications, including blindness, kidney failure, heart disease, stroke, and amputations
Great strides were made in insulin pump technology, and implantable pumps are now
an option for some patients. A new class of medications called insulin sensitizers,
which stimulate a gene to produce more insulin-controlled proteins, has been released.
These proteins remove glucose from the bloodstream, essentially improving the availability
of insulin. It also decreases the body's glucose production
Pancreatic or islet cell transplantation is also under way for type I diabetes
The U.S. Food & Drug Administration (FDA) approved the first inhaled insulin Exubera
or insulin human (rDNA origin) inhalation in January 2006 for both type 1 or type
2 diabetes. Inhaled insulin is one of the greatest breakthroughs for people who
must take short-acting insulin
Oral-Lyn is an oral spray formulation of human insulin indicated for the treatment
of type 1 and 2 diabetes. Generex Biotechnology started it clinical use of Oral-Lyn
in type 2 diabetics in Ecuador in 2005
Taiwan scientists Sung et al. reported the success in early tests of an oral insulin
solution in diabetic rats
They bundled insulin with chitosan -- a chemical derived from the shells of shrimp,
crabs and lobsters into tiny particles called nanoparticles. They then put these
nanoparticles in an oral solution, which they tested on diabetic male rats. Laboratory
tests showed that the insulin reached the rats' blood stream and lowered their blood
This historical review shows that the most of advancement in discovery, treatment
and management of diabetes have occurred in the 20th century and that
has given the greatest benefit to mankind in the form of longer life. In 20th
century much of the morbidity and mortality of diabetes has been reduced by discovery
of insulin and aggressive treatment with diet and exercise. Effective use of oral
insulin is the target of the21st century. Perhaps one day, injecting
insulin will become a thing of the past. Clinical trials on medicinal plants may
be put to thought for alternative oral medication. However, increased understanding
of the pathophysiology of diabetes with continuous advancements in the prevention
and treatment of diabetes and its complications may cure diabetes through genetic
corrections before they emerge in 21st century.
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