Diabetes mellitus: a complete ancient and modern historical perspective

Abstract

Diabetes mellitus is one of medical conditions that have been extensively investigated. Despite these enormous developments cure for diabetes still remains virtual. The history is backdated to the Egyptian antiquity. As the history became unravelled with regard to the pathophysiological and biochemical bases, medical and surgical treatments and other management strategies, roadmap towards achieving success in curbing the menace of diabetes is promising. It is only in the 21st century that diabetes has been considered a chronic and heterogenous endocrine disorder which requires interdisciplinary and multidisciplinary approaches in its management, with the role of genetics looking exciting. However, there are lots of lessons to be learnt from the past. This review aims to explore the timeline of diabetes journey, and correct the inconsistencies in the historical perspectives of diabetes with intent to project the future.

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Article ID: WMC004831 ISSN 2046-1690
Diabetes mellitus: a complete ancient and modern
historical perspective
Peer review status:
No
Corresponding Author:
Dr. Chukwuemeka Nwaneri,
Visiting Senior Lecturer, Community & Child Health, University of Chester, Riverside Campus, CH11SL - United
Kingdom
Submitting Author:
Dr. Chukwuemeka Nwaneri,
Visiting Senior Lecturer, Community & Child Health, University of Chester, Riverside Campus, CH11SL - United
Kingdom
Article ID: WMC004831
Article Type: Review articles
Submitted on:15-Feb-2015, 10:48:54 PM GMT Published on: 17-Feb-2015, 10:12:38 AM GMT
Article URL: http://www.webmedcentral.com/article_view/4831
Subject Categories:Diabetes
Keywords:type 1 diabetes, type 2 diabetes, insulin, metformin, insulin resistance, glucose tolerance
How to cite the article:Nwaneri C. Diabetes mellitus: a complete ancient and modern historical perspective.
WebmedCentral Diabetes 2015;6(2):WMC004831
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution
License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Source(s) of Funding:
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Competing Interests:
Nil
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Diabetes mellitus: a complete ancient and modern
historical perspective
Author(s): Nwaneri C
Abstract
Diabetes mellitus is one of medical conditions that
have been extensively investigated. Despite these
enormous developments cure for diabetes still remains
virtual. The history is backdated to the Egyptian
antiquity. As the history became unravelled with
regard to the pathophysiological and biochemical
bases, medical and surgical treatments and other
management strategies, roadmap towards achieving
success in curbing the menace of diabetes is
promising. It is only in the 21st century that diabetes
has been considered a chronic and heterogenous
endocrine disorder which requires interdisciplinary and
multidisciplinary approaches in its management, with
the role of genetics looking exciting. However, there
are lots of lessons to be learnt from the past. This
review aims to explore the timeline of diabetes journey,
and correct the inconsistencies in the historical
perspectives of diabetes with intent to project the
future.
Introduction
Diabetes mellitus (DM) has been described as a
‘silent’ epidemic. Its presentation can either be a slow
onset and asymptomatic progression leading to
secondary complications, or rapidly emerging
symptoms leading to complications and/or coma. The
projection is that by year 2030, an estimated 366-438
million (i.e., 7.8% of the world population) people will
have diabetes, an increase of 54% compared to that
predicted in 2010 (Wild et al. 2004, Whiting et al.
2011). After the recognition of diabetes by the
Egyptians, various attempts were made to understand
the heterogenous nature of the disease,
pathophysiological mechanisms, appropriate therapies
and prevention strategies. As part of seeking for
answers to intriguing questions in diabetes, some
authors were more descriptive, analytic or pessimistic
rather than scientific in their search. Developmental
milestones in diabetes reflect improvements in the
understanding and management of the condition. The
overview of the history of diabetes, starting from the
ancient time to the present millennium helps to
showcase the advances that have been made in
diabetes medicine and health. An attempt is made in
this study to produce a chronologically organised,
engrossing and multi-dimensional account of diverse
documented work in diabetes. An in-depth review of
the historical timeline of diabetes shows that diabetes
has evolved over six era: era of recognition of disease,
description of causes, clinical diagnosis, biochemical
development and advancement and millennium
developments.
Discussions
Ancient time (era of recognition of disease)
The first recognition of what came to be known as DM
was documented in the Egyptian ancient papyrus,
discovered by Georg Ebers in 1862, dating back to
1550 BC which highlighted the first documented cases
of DM over 3500 years ago as stated by Ebbell, in
1937 and Tattersall in 2010. In this chronological and
hieroglyphically written document of compendium of
medical literature from 3000 BC, was noted ‘to
regulate………excessive urine’ in 1552 BC by
Hesy-Ra, an Egyptian physician. Although this may as
well represent the first recognition of diabetes, medical
historians believe that the first attempt at describing
the symptoms of diabetes was made by Aulus
Cornelius Celsus (30 BC-50 AD) of Greece (Medvei
1993, Southgate 1999, Zajac et al. 2010). Celsus had
described an ailment which presented with excessive
urination in frequency and volume, and painless
emaciations. Apollonius Memphites, an Egyptian
physician at around 230 BC had used the prefix
‘diabetes’ for the first time to denote an excessive
passage of urine and ascribed its aetiology to the
kidney (Papaspyros 1964). At that time, due to lack of
evidence, treatment had involved dehydration and
phlebotomy (bloodletting) as a method of treatment
(Papaspyros 1964, Zajac et al. 2010). In about 500 BC,
two Hindu-Indian physicians (Chakrat & Sushrut)
recognised that DM was not a single disorder, and
they made observations of the sweetness of urine
from observing ants congregating around the urine of
patients (Tattersall 2010). Although relatively
uncommon, as time went on, the recognition and
identification of diabetes became apparent. The
concept of nature showed varying and intriguing
debates and revisions.
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1st century (era of description of causes)
Diabetes, a Greek word was the term used to denote ‘
run through or siphon’ in the description of incessant
urination (Adams 1856), a word originally ascribed to
Demetrios of Apamaia in the 200-250 BC. However, at
a time, medical historians believed that Aretaeus of
Cappadocia (81-138 AD), a Greek physician
re-introduced the prefix ‘diabetes’ to describe the
wasting disease from excessive urination (Leopold,
1930). In his manuscript, Aretaeus narrated what his
knowledge of origin of diabetes was:
"The disease appears to me to have got the name of
diabetes, as if from the Greek word διαβητης (which
signifies a wine-pourer or siphon) because the fluid
does not remain in the body, but uses the man’s body
as a ladder (διαβαθρη) whereby to leave it” (Adams
1856).
Aretaeus went further to describe the features of
diabetes as
“a dreadful affliction being a melting down of the flesh
and limbs into urine. The patients never stop making
water but the flow is incessant as if from the opening
of adequeducts….and patient is short lived” (Tattersall,
2010, p.3 citing Papaspyros, 1952).
This describes the clinical picture of type 1 DM
(T1DM). Aretaeus also distinguished polyuria of DM
from diabetes inspidus, a disease in which the kidneys
are unable to conserve water. A Greek physician,
Claudius Galenus, referred to as Galen (129-200 AD)
supported the work of Apollonius of Memphis, by
attributing the pathology to the kidneys because of the
diuretic effect (Eknoyan & Nagy 2005) and called it ‘
diarrhoea of urine’ [diarrhoea urinosa] (Zajac et al.
2010). From China in 200 AD, Tchang Tchong-King
described the excessive eating symptoms seen in
these people with diabetes. The triad of polydipsia,
polyphagia and polyuria was noted in the literature as
the characteristic features of the diabetes (Lehrer
2006).
Medical historians rarely mentioned the contributions
of Aëtius of Amida, a Byzantine physician, in the
important diabetes history. He was a follower of Galen,
and his medical expertise reinforced the use of
phlebotomy, emetics and use of narcotics in the
treatment of diabetes. An approach used by many
clinicians for many years in the first half of the 6th
century (Withington 1894, Nutton 1984). In medieval
Persia, Avicenna (980-1037), an Arabian physician,
was the first to emphasise the clinical features and
some complications of DM, describing in his book ‘
Canon of Medicine’ sexual dysfunction, polyphagia
and sweet taste of urine (Sina 1593, Sina 2004,
Avicenna 1991). He had suggested that diabetes was
a disorder of the nervous system in concert with
interplay of liver dysfunction. In a quest for treatment,
Avicenna prescribed the use of emetics and exercises
to alleviate the symptoms, and discouraged the use of
diuretics (Savona-Ventura 2002). The first
documented evidence of diabetes in English literature
was the use of the word ‘diabete’, purported to be
written around 1425. Following these early records no
further progress was seen until the sixteenth century.
16th-18th century (era of clinical diagnosis)
As different researchers in Egypt, Persia, China, India,
Greece, Japan and Korea searched for appropriate
treatments of the strange and poorly understood
disease, European medical literature showed no
evidence of any documentation of the disease. In the
middle part of the 16th century, Paracelsus
(1493-1541), a Swiss German physician, was
pragmatic in his experimental search for the
pathogenesis of diabetes. He was the first to depart
from the Galenic approach to medical conditions.
Paracelsus had evaporated urine samples from people
with diabetes with resultant production of solutes
(Schadewaldt 1977). However, he did not taste it but
called it ‘salts’. In his conclusion, he stated that
diabetes was as a result of the deposition of salts in
the kidneys. The findings made him and other
researchers believed that salts were the cause of
excessive urination and thirst seen in these people.
During the period of recognition of sweetiness of urine
from people with diabetes, Thomas Sydenham
(1624-1689) proposed that ‘chyle’ from food was not
completely digested with excretion of the
non-absorbable residue. He concluded that this
diabetes was a systemic disease as a consequence of
this process (Farmer 1952). In 1674, Thomas Willis,
an Oxford-trained British physician (1621-1675),
re-echoed the presence of sweet substance in the
urine of diabetic patients in his book Pharmaceutice
Rationalis (Willis 1684, Tattersall 2010, McGrew
1985), although the actual substance was still
unknown. However, his work triggered a new interest
in diabetes research in the United Kingdom (UK). In
1682, Johann Brunner (1653-1727), aged 29 years
had carried out partial pancreatectomy in a dog, and
observed that the dog had extreme thirst, polydipsia
and polyuria. This was the first step in the recognition
of the role of pancreas in the pathogenesis of diabetes.
However, Brunner did not identify the particular organ
(Willis 1684, Farmer 1952, Mann 1971).Theophile de
Bordeu, a French physician (1722-1776) and a
pioneer in Endocrinology, in his teachings presented
the conceptual theoretical framework for glands and
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hormones. He inferred that each gland or organ of the
body produced a specific secretion which passes into
the blood and maintained the functions of the body
(Medvei 1982). In his treatise, published in 1775,
entitled Recherches Sur les maladies chroniques, de
Bordeu stated
“what I believe with certainty is that every organ
occupying its own nook…and living its own
life…diffuses about itself, into its environment and its
particular system, exhalation or certain emanations,
which have taken on its characteristics, are integral
parts of itself. I do not regard these emanations as
useless, or of purely physical necessity. I believe them
useful and necessary to the existence of the organism
as a whole. I conclude that the blood bear within itself
extracts of all organic parts, each of which component,
I repeat again, are necessary to the wellbeing of the
whole, possessing specific qualities and properties
beyond the reach of the chemist’s experiments…each
(of the organs) serves also a factory and laboratory for
a specific humor, which it returns to the blood after
having prepared it within itself and imparted to it its
own specific character” (Bordeu 1775).
He further reported that the ‘organs of the body with
several of their functions are federated with and
dependent upon each other’.
In Liverpool (UK) in 1776, Matthew Dobson
(1735-1784) confirmed the presence of sugar in blood
as well as urine of these patients. Therefore, he
surmised that the kidney only acted as an excretory
system for the sugar (saccharine). It was William
Buchan who, in 1785, described the clinical
presentations of these patients stressing the persistent
thirst, dehydration and frothy saliva, as well as
elevation in body temperature. He added that the
patients lacked energy and had poor appetite which
resulted in emaciation and wasting. Efforts aimed at
elucidating the pathogenesis of DM were spearheaded
by various pathologists including Richard Bright
(1789-1858) and Thomas Cowley in the 18th century
(Eknoyan & Nagy 2005). In addition, Cowley
performed the first autopsy in diabetes and published
his findings in the ‘London Journal of Medicine’ in
1788, suggesting a relationship between diabetes and
pancreatic disease. In same year, Cowley isolated the
sugar moiety from urine in those with diabetes. In
1798, an Edinburgh-trained surgeon of the British
Army, John Rollo (1749-1809) added the suffix ‘
mellitus’ meaning honey, to describe the sweetness of
urine in the later part of 18th century (Rollo 1797,
1798). At this stage, clinicians and researchers had no
evidence of the pathogenesis of diabetes.
Inadvertently, Rollo had felt that the gastrointestinal
tract was responsible for the excess sugar in blood
and urine, as observed by Dobson. Following Rollo’s
finding on the effects of various food substances on
urinary sugar with high carbohydrate meals producing
higher urinary glucose, whereas proteinaeous foods
caused a lower urinary sugar levels. He treated his
patients with ‘animal diets’ (Rollo 1798), and this
became the gold standard for the treatment of this rare
disease in the early part of the 19th century.
In the late1800s, chemical methods were developed to
test the presence of glucose in urine. Prior to this,
urine tasters were used to differentiate sweet urine
from tasteless and limpid ones. In order to differentiate
the two forms of disease in which urine was sweet
from the other in which it was not, Johann Frank
(1745-1821) classified diabetes into, diabetes vera
(sweet urine) and diabetes insipidus (tasteless urine).
The classification was therefore based on Avicenna’s
initial observations in patients’ who passed excessive
urine (Frank 1794).
18th-19th century (era of biochemical and
pathological differentiations)
It was between the 18th and 19th century that type 2
DM (T2DM) became known, to differentiate it from the
widely documented acutely symptomatic T1DM
(McGrew 1985). The concept of protein, fat and
carbohydrate metabolism in the body was introduced
by Justus Baron von Liebig (1803-1873), a German
chemist, who described how the body utilises
compounds for tissue growth and energy production
respectively (Barnett & Krall 2005). It was not until
Liebig’s classification of food substances, that the
physiological basis of Rollo’s experimental findings
became obvious.
In 1815, a French-born Chemist, Michael Chevreul
[1786-1889] (as cited in Barnett & Krall 2005, p.3),
revealed that the actual sugar present in the urine of
people with diabetes was glucose, as it behaved like
“grape” sugar. He proposed that glucose was not
produced in the kidneys, as was originally thought, but
was due to the failure of blood to utilise it correctly.
This raised the question of the actual site of production
of glucose and its role in the body (Chevreul 1815).
The findings by Chevreul and Liebig heralded the
explosion of intense experiments in biochemistry and
clinical chemistry in order to assay and measure the
serum glucose levels. Interestingly, Richard Bright
(1789-1858), an English physician researched
extensively on nephritis, and in his treatise ‘Reports on
medical cases selected with a view of illustrating the
symptoms and cure of diseases by a reference to
morbid anatomy’ reported on nephropathy. In 1828, he
pioneered the research into nephropathy seen in
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diabetes and Bright’s disease (Bright 1831). His
findings did not incriminate the kidney as the source of
diabetes, rather a complication of it.
William Prout (1785-1850) a renowned endocrinologist
believed that diabetes suggested a disease of the
stomach and that exposure to cold or cold drinks or
rheumatism, as well as mental anxiety and distress
were the most exciting causes of diabetes (Prout
1848). However, Prout, later described the clinical
features of what came to be known as ‘diabetic
ketoacidosis’. John Elliotson, in 1839 attributed
diabetes as a disease of the kidney, and was
published in his textbook entitled ‘Principles and
Practice of Medicine’.
One of the pioneers of modern day endocrinology was
Claude Bernard (1813-1878). A physiologist, Bernard
achieved this invaluable experimental breakthrough in
1840, after he ligated the pancreatic duct of a dog
which was followed by degeneration of the pancreas,
and resultant diabetes (Bernard 1849). He was the
first to describe the role of pancreas in glucose
production, thereafter followed inconclusive reports in
England in the mid-1800 on the ‘glycogenic theory’
i.e., formation of glycogen from glucose in the liver,
hence clarifying the understanding of glucose
metabolism (Olmsted 1953). Bernard had thought that
the liver was the site of the problems in diabetes but
not diseased in itself, and that pancreas was not the
cause of diabetes (Bernard 1853, 1857). However, he
was unable to identify the actual pancreatic substance
involved but his experimental techniques paved way
for later researchers’ discoveries. Landmark laboratory
quantitative test for estimation of urinary glucose
(Fehling’s solution) was developed by a German
chemist, Hermann von Fehling, in 1948 (Fehling
1949). At this stage, the diagnosis of diabetes was
based on the clinical features and laboratory diagnosis
of glucosuria. A decade later, Wilhelm Petters in
Germany in 1857, confirmed that urine of diabetes
contains acetone alongside glucose (Tattersall 2010).
However, it was Adolph Kussmaul (1822-1902) who
suggested that the cause of diabetic ketoacidotic
coma (DKA) was due to the presence of acetone in
the blood in these patients. Thereafter, Bernard
Naunyn (1840-1914) described the term ‘acidosis’ in
T1DM, and had treated them with bicarbonate, in his
diabetic clinic. He was the first to set up such a clinic
for people with diabetes (Naunyn 1898). By 1855,
Friedrich Theodor von Frerichs (1819-1885), a famous
German experimental pathologist, reported that in
people with diabetes, 20% had severe pathological
changes in their pancreas (Frerichs 1884). George
Harley, in 1866, formulated theories to explain the
pathophysiologies of diabetes, based on the initial
discoveries of Bernard. However, he was unable to
add much to the knowledge of diabetes at that time.
Vehemently, Frederick Pavy had disagreed with the
validity in the fundamental research by Bernard on
glycogenolytic theory, and went further to argue that
glycogenolysis had no part in diabetes (Pavy, 1869).
Little did he know that Bernard’s theory was going to
drive others to identify the enzymes responsible for
such metabolic pathway (Cori & Cori 1946). This
discovery won a Nobel Prize in Medicine. These
formed the bases for the introduction of experimental,
investigative and laboratory medicine in clinical
practice. The associations of diabetes with the
complication of the eye, retinitis and retinopathy, was
first documented by Henry Noyes in 1869. However,
even though Armand Trousseau in 1865 made a
report on people with diabetes with bronze
pigmentations of their skin, he did not suggest a
correlation. It was Friedrick von Recklinghausen in
1890 that recognised that in those patients with
haemochromatosis suffered from diabetes. On the
contrary, an English scientist, William Dickinson in
1875, postulated that diabetes was a ‘disease of the
nervous system, characterised by the secretion of
saccharine urine’.
Paul Langerhans, a German pathologist, in his thesis
in 1869, had described new ‘heaps of cells’ in the
pancreas histology, called ‘islet cells’ within the acini of
the pancreas, as an endocrine gland. However, the
role of the islet cells in diabetes was not immediately
known, as he was not able to postulate their functions
(Sakula 1988). Several researchers reported on the
outcomes of experimental tests on the pancreas in the
aetiogenesis of diabetes between 1869 and 1889,
amongst whom were Oscar Minkowski (1858-1931),
Joseph von Mering (1849-1908) and Gustave-Edouard
Laguesse (1861-1927). Minkowski and Mering in 1889
reported that following removal of the pancreas in
dogs, the clinical picture resembled ‘real permanent
diabetes mellitus’, which corresponds in every detail to
the most severe form of this disease in man
(Minkowski 1929, von Mering & Minkowski 1890).
In 1886, a German pathologist, Julius Dreschfeld
described in details the clinical features of DKA. In his
lecture presented to the Royal College of Physicians in
London, he described the chemical determinations of
acetoacetic acid, ketones and beta-hydroxybutyric
acid and their roles in DKA.
The quest to attain complete insulin independence has
resulted in trials of pancreatic or part-islet cell
transplants for people with T1DM. The first trial was in
1891, by a French scientist, Edouard Hedon, when a
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dog’s pancreatic tissue, was auto-transplanted under
the skin which prevented it from developing diabetes
even after the pancreas was excised. This experience
proved invaluable when in 1893, in London, the first
xeno-transplant was performed in a boy of 15 years.
In 1893, a French scientist, Laguesse confirmed the
initial observations of Cowley (relationship of diabetes
and pancreatic disease) and named the little ‘heaps of
cells’ seen in the pancreatic tissue as ‘islets of
Langerhans’. Despite the identification of the cells
responsible for the secretions of pancreatic substance
that regulates glucose, the actual hormone secreted
by the islets cells of Langerhans was not known or
identified. These experiments changed the entire
understanding of the disease and catapulted to an
important milestone in the history of diabetes.
Further insight into the role of sugar in the
pathogenesis of DM was highlighted by Apollinaire
Bouchardat and Moritz Traube in 1870 who observed
that consumption of carbohydrate diets increased the
sugar content of urine, while low carbohydrate diets
had the opposite effect. They began to use
personalised dietary modifications as diabetes
treatment. Bouchardat and Étienne Lancereaux in
1880, supported the earlier work of Bernard, and
implicated the pancreas in the patho-aetiology of
diabetes (Bouchardat 1852, 1875, Lancereaux 1877).
The pair had carried out a prospective study on these
patients, using the earlier findings of Rollo’s dietary
experiment and found that vegetable rich diets did not
cause elevations in urinary glucose. In furtherance,
they later described the two different clinical
presentations in patients with diabetes; obese [
diabetes gras] and lean [diabetes maigre] (Tattersall,
2010). In continuity with the dietary treatment, Arnoldo
Cantani (1837-1893), an Italian physician followed the
work of Bouchardat. He, however, made some
restrictive dietary modifications of Bouchardat’s
starvation diet, to allow patients the number of calories
that would not produce glucosuria. Cantani observed
that fatty liver was seen in people with diabetes than in
those without diabetes. These impacts of these
findings were not immediately apparent until some
years later (Lehrer 2006).
As the quest for definitive treatment heightened, Elliot
Joslin (1869-1962), from the Massachusetts General
Hospital, Boston pioneered the use of dietary
modifications, exercise and patient’s education as
tools in the improvement of glycaemic control in T2DM
(Joslin, 1915, 1921, Allen 1953) based on the
observations of Rollo on the effect of different food
substances on urinary glucose. In his publication, The
Treatment of Diabetes Mellitus, Joslin described in
details the effects of diets and exercise in the
treatment of diabetes (Joslin 1917). Frederick Allen
(1879-1964) supported the role of dietary restrictions
(starvation diets). He had used diets very low in calorie,
as low as 450 calorie/day in his patients. This
improved their diabetes symptoms and prolonged their
lives, although was associated with high mortality
especially in T1DM. These approaches are still
components of present day management of T2DM,
and have been shown to improve the quality of life in
these patients.
With advancements in knowledge of research,
physiology, biochemistry, medicine and surgery of
pancreas and the role of its secretions in glycaemic
control, many researchers began to narrow down their
studies on the pancreatic gland. These changed the
concepts and treatment of diabetes as time went on.
By the end of the 19th century, accurate and reliable
scientific methods of assessment of both blood and
urinary glucose were still not available.
19th-20th century (era of insulin development and
advancement)
Up to the 19th and early part of the 20th century,
diabetes was still considered a rarity outside Europe
due to lack of epidemiological evidence. Following the
discovery of the role of pancreas in the pathogenesis
of diabetes, clinical researchers and clinicians began
treating the patients with pancreatic extracts. In 1901,
L. W. Ssobolew (1876-1919) evidence from
experimental ligature of the pancreatic ducts showed
that even though the pancreatic ducts became
atrophic with destruction of enzyme secreting acinar
cells, the islet cells remained viable for weeks without
any resultant diabetes (Ssobolew 1902). In 1902, in
Aberdeen, Scotland, John Rennie and Thomas Fraser
extracted the pancreatic substance from Codfish. They
had injected the extract into a dog, which died soon
thereafter. The death of the dog may have resulted
from either severe hypoglycaemia or anaphylactic
shock or a combination of them. Developments in the
pancreatic extracts were undertaken by other
researchers that led to improved purities. George
Ludwig Zeulzer, a German physician, in 1908, had
treated his dying diabetic patients with pancreatic
extracts he termed ‘acomatrol’ which improved their
clinical conditions (Tripathy et al. 2012). He patented
his ‘acomatrol’ in the USA and used it to revive a
comatose diabetic patient. However, his subsequent
extracts were noticed to produce severe reactions and
complications with high mortality. Following this
outcome, Schering Pharmaceutical withdrew their
funding. Regardless of this drawback, Zeulzer
continued to work on the extracts and later on
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modified it for Hoffman-La Roche Pharmaceuticals.
Unfortunately, the newer extracts had unwanted side
effects of seizure-like attacks and consequent deaths,
presumably from severe hypoglycaemic and/or
anaphylactic shocks (Zuelzer 1908). Zeulzer’s failure
to purify his extracts and its consequent complications
led to his discontinuation of his attempts at achieving
the goal-to isolate the active substance from the
pancreatic extract (Murray 1969). It is worthwhile
noting here that knowledge of insulin was described
earlier by the Belgian physician, Jean De Meyer in
1909, as internal secretions of the islets of Langerhans
(De Meyer 1909 cited in Tattersall 2010). However, it
was in 1901 that Eugene Opie established a clear link
between the islets of Langerhans with the aetiology of
diabetes. He had documented evidence of
hyalinisation and sclerosis of islets of Langerhans in
some patients with diabetes. This assertion was
supported by an English physiologist, Edward
Sharpey-Schafer in 1910, through the outcome of his
experiments on dogs whose pancreases were
surgically removed. Without any experimental
evidence, John Homans in 1913 suggested that insulin
was produced by the β-cells of the islets of
Langerhans (Homans 1913, Papasyros 1952).
Stanley Benedict in 1911 and other researchers’ years
later developed methods of detection and estimation
of urinary glucose (using Benedict’s solution), which
helped in the prognosticating effects of treatment on
these patients (Benedict 1911). Urinary ketone bodies
were also tested using the methods of sodium
nitroprusside by Cecil Rothera in 1910 (Rothera 1908,
Fearson 1921).
As research was going on in an attempt to isolate the
active hormone responsible for glucose utilisation
present in the pancreas, the concept of islets cell
transplantation had been documented when the
English surgeon, Charles Pybus in 1916, attempted to
graft pancreatic tissue in order to cure diabetes (Pybus
& Durh 1924). As a result of high mortality recorded in
his surgical approach he surmised:
“although transplants represented the most rational
form of therapy, they would continue to fail as long as
science did not understand the principles involved”
(Schlich 2010, p.74).
In 1919, a young American biochemist and researcher
Israel Kleiner (1885-1966) published an article in the
Journal of Biological Chemistry, describing a
procedure for pancreatic extract that reduced the
blood sugar level in those with diabetes, at the
Laboratories of Rockefeller Institute for Medical
research (Kleiner 1919). However, Kleiner, working
together with his colleague, an inventive physiologist,
Samuel Meltzer (1851-1920) slowly infused pancreatic
extracts into pancreatectomised dogs and analysed
their blood glucose levels prior and after the infusions
at different time intervals (Kleiner & Melzer 1915,
Kleiner 1919). Unfortunately, the original work started
by Kleiner was not concluded after he left Rockefeller
Institute.
Despite this, in 1920, Moses Barron reiterated the
relationship between islets of Langerhans and
diabetes pathogenesis from his experimental findings.
His findings published in a paper entitled, ‘the relation
of the islets of Langerhans to diabetes with special
reference to cases of pancreatic lithiasis’ concluded
that obstruction of the pancreatic acinar, however, did
not affect the islets of Langerhans, as there were
complete preservation of the islets and no resultant
diabetes. Prior to the successful discovery of insulin by
Banting and colleagues in 1921, Nicolae Paulescu, a
Romanian physiologist in the same year had extracted
pancreatic preparations from animals (pancreine), but
the World war 1 prevented him from publishing his
work early until the 21st of August 1921, when the
Archives of Internationale de Physiologie in Liège,
Belgium published his summaries: Research on the
Role of the Pancreas in Food Assimilation. In his
conclusion he was to continue the experiments and
unfortunately, as he had patented his original work in
Romania, the saline extract was not used in humans
(Bliss 1993, Rosenfeld 2002, Paulesco 1921).
The studies on the experimental works of Kleiner (at
the Rockefeller Institute and New York Medical
College in 1919), Baron (in Minneapolis in 1920), and
the ‘near to the discovery’ works of Paulescu (in
Bucharest between 1916-1920), and the identification
and the description of the morphology of pancreatic
cells that produce the hormone insulin by Paul
Langerhans in 1869, heralded new research directions
leading to the discovery of insulin in 1921 by Frederick
Banting (1891-1941) and his colleagues in Canada:
John Macleod (1876-1935), James Collip, and Charles
Best (1899-1978), in an acid ethanol extract of
pancreas from dogs (Bliss 2007, Tattersall 2010).
They isolated and purified insulin, which was made
more available to people with diabetes. Their first trial
was on a 14 year old T1DM, Leonard Thompson in
1922 who later died after 13 years, at age 27 (Mann
1971). It was observed to reduce blood and urinary
glucose concentrations, and ketones disappeared in
urine (Banting & Best 1922, Banting et al. 1922). Their
discovery won Banting and MacLeod a Nobel Prize in
1923.
Following the effects observed by the scientists, in
1922, Eli Lilly and Company signed an agreement with
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Banting and Best of the University of Toronto for
purification and commercial production of bovine
insulin which was used to treat humans. Robert
Lawrence, an endocrinologist was diagnosed with
diabetes in 1919, and was given 4 years to live.
However, he benefitted from early insulin therapy,
soon after its discovery. He set up a Diabetes Clinic at
King’s College Hospital, London in 1923. As the
discovery of insulin was still gaining international
publicity, in the later part of 1922, a Danish Nobel
laureate in Physiology, two years earlier, for the
discovery of the mechanism of regulation of the
capillaries in skeletal muscle, had visited McLeod in
Toronto (Sulek 1967, Larsen 2007). After his return to
Denmark, he liaised with Hans Hagedorn to found
Nordisk Insulinlaboratorium, in 1922. Later on in 1923,
Novo Company and Nordisk merged forming Novo
Nordisk, which became a colossum in insulin and
pharmaceutical industry. In 1934, he also founded the
British Diabetic Association (later became Diabetes
UK), with the help of an author of ‘Time Machine’, H. G.
Wells. This was the first of such national organisation
in the world. In 1923, Novo Nordisk Insulin Laboratory
started the commercial production of insulin. This
invention brought about the evolutionary changes in
newer insulin manufacture, producing newer insulin
formulation; modified slow and fast acting regular
insulin. At the John Hopkins University in 1926, John
Abel, a biochemist prepared the first crystalline insulin
(Murnaghan & Talalay 1967), which Svedberg
determined its molecular weight in 1934.
The previously, classified obese (diabetes gras) and
lean (diabetes maigre) was later differentiated in the
1930s, based on the action and sensitivity of newly
discovered insulin, by Wilhelm Falta in 1931, and
Harold Himsworth in 1936, into ‘insulin sensitive’ and
‘non-insulin sensitive’ types. However, Himsworth’s
proposition remained unconfirmed until plasma insulin
was bioassayed and measured by Joe Bornstein and
Robert Lawrence, and thereafter with the availability of
radioimmunoassay for insulin (Bornstein & Lawrence
1951, Yalow & Berson 1961, Berson & Yalow 1963).
Invariably, this formed the basis of the present
classification of diabetes into T1DM (insulin-dependent)
and T2DM (non-insulin dependent) previously, labelled
as ‘juvenile-onset’ and ‘maturity-onset diabetes’
respectively (Tattersall 2010). Falta’s publication of his
hypothesis of insulin resistance as the cause of T2DM
heralded the pathoaetiological factors in T2DM (Falta
& Boller 1931), although T2DM does not occur without
a corresponding failure of the compensatory insulin
secretion (Nolan 2010). The need for longer acting
insulin was necessitated by repeated daily injections
and its rapid absorption. Hagedorn (Novo Nordisk) in
1936 developed the first protamine insulin (PZI) using
zinc salts that crystallised the insulin, and conjugated
the insulin with specific proteins. This preparation
slowed down the absorption and distribution of insulin
injected. As a result of the heterogenous nature of
patients with diabetes and the consequent outcomes
of treatment modalities, Harold Himsworth in 1936
postulated that insulin resistance as opposed to insulin
deficiency was the main aetiopathogenesis. In the
disease, especially T2DM, insulin resistance results in
impaired β-cell function in the pancreas (Cavaghan et
al. 2000) and impaired insulin secretion.
The increasing incidence and prevalence with
subsequent poor mortality statistics in the USA,
resulted in the formation of the American Diabetes
Association (ADA) in 1940, aimed at addressing these
challenges. Initially formed as a national Diabetes
Association but was renamed to accommodate
Canadian physicians, who did not have any
associations of such even after the discovery of insulin
in Toronto.
The ever-evolving contribution of laser surgery in
T2DM has paved way for improvements and
restoration of vision in modern management strategies.
Photocoagulation of retina was first discovered in
1940s by a German ophthalmologist,
Meyer-Schwickerath (Meyer-Schwickerath 1989).
Although diabetes is not a disease of the nervous
system as envisioned by Dickinson, similar thoughts
and eventual experiments by Housay et al. (1942)
resulted in the discovery of the role of hormones
released by the anterior pituitary lobe in the
metabolism of sugars. These findings won Housay a
Nobel Prize in Medicine in 1946.
Meyer-Schwickerath further developed a sunlight
photocoagulator in 1947, and within 1950-56, he had
used a Beck carbon arc photocoagulator for treatment
of retinopathy associated with diabetes.
After the stabilisation of people with diabetes with
insulin, there was need for an oral medication to
replace the repeated injections associated with insulin.
Sulfonylureas were the first oral hypoglycaemic agents
to be discovered by Marcel Janborn and co-workers at
the Montpellier University in France in 1942 while
studying on sulphonamide antibiotics (Janborn et al.
1942, Patlak 2002). Unexpectedly, they found that the
compound caused hypoglycaemia in animals. It was
this side effect that was investigated that led to the
production of sulfonylureas.
Different Pharmaceutical Laboratories began to source
for the possibilities of mimicking the natural patterns of
insulin actions in order to improve the quality of life of
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the patients. In 1946, Hagedorn produced the first
prolonged acting insulin (Neutral Protamine
Hagedorn-NPH), or isophane insulin, intermediate
acting insulin. Insulin research progressed at various
levels of scientific discipline. Rachmiel Levine, in 1949
discovered that insulin transports across the cells are
like a key. This finding was in concert with the
understanding of glucose metabolism.
Initially, Best in the 1950’s had made a strong
proposition for an oral insulin within the preceding 10
years after insulin discovery, however, the polypeptide
nature of insulin compound meant that it would rapidly
be digested by enzymes of the gastrointestinal system.
In quest for the discovery of an oral therapy, several
trials were conducted, including the use of aspirin and
synthalin, without any positive outcome.
Hallas-Muller and Schlichkrull in 1952 developed the
series of Lente insulin at the Novo Nordisk Laboratory.
This was a great improvement in the production of
insulin injections that led in the treatment of diabetes.
However, the concept of blood glucose measurement
and the methods available was first utilised in the early
1950s and its principle was based on the reducing
properties of glucose. This approach, inadvertently
over-estimated the actual concentration of glucose as
other reducing sugars exist in blood (King & Wootton
1957). Regardless, chemical pathologists, clinical
chemist, biochemists and physicians were able to at
least estimate the concentration of glucose in blood in
people with diabetes prior and after treatments. In
1953, glucose oxidase tablets or impregnated paper
strips was introduced in the measurement of blood
glucose (Kohn 1957). At the same time the tablets
were used in testing urinary glucose, became
available in clinical medicine (Froesch & Renold 1956,
Marks 1959). In addition, urine strips were available
for clinical use in 1960 which added reliability and
compliance to repeated testing (Cormer 1956). The
quantitative analysis of blood glucose and the
semi-quantitative detection of urinary glucose levels
revolutionised the management of people with
diabetes and their prognoses (Marks & Dawson 1965).
The evolution and developmental milestone of bariatric
surgery in obese T2DM commenced in the early
1950s and have shown dramatic contributions in the
management of the disease. In 1954, Arnold Kremen
and colleagues performed the first bariatric surgery,
which involved intestinal anastomosis (Kremen et al.
1954). They had earlier on observed loss of weight
induced by intestinal resection and anastomosis in
patients and wandered if such a procedure could be
beneficial in obese T2DM.
Thirteen years after the unexpected discovery of
hypoglycaemic effects of sulfonamides by 1955, the
German duo, Hans Franke and Jürgen Fuchs
introduced carbutamide, an oral hypoglycaemic agent
in the treatment of diabetes. Since the introduction of
carutamide as an oral hypoglycaemic agent, research
and experimental work has exponentially increased
(Franke & Fuchs 1955, Bertram et al. 1955).
At the end of 1956, Littman, Zeiss and
Meyer-Schwickerath used for the first time a xenon arc
coagulator to treat retinal vascular diseases and
anterior and posterior segment abnormal growths. The
photocoagulation produced by light of various spectra
(Bessette & Nguyen 1989, Krauss & Puliafito 1995).
Within two years, many more first generation
sulfonylureas with different potencies, tissue
distributions, duration of action and interactions were
introduced into clinical practice. These include
tolbutamide and chlorpropamide in 1957. Competition
in the pharmaceutical industry for the production of an
oral antidiabetic agent that would replace insulin
injections or similar to insulin was at its peak, and in
1957, another oral hypoglycaemic agent called
biguanides came into clinical use. The first two
biguanides to be used were metformin and phenformin,
with the former still popular till date.
Interestingly, Frederick Sanger in 1955 reported on
insulin’s molecular structure of the amino acid
sequence, and later on Dorothy Hodgkin noted in 1969,
its three-dimensional structure. In 1958, Sanger was
awarded a Nobel Prize in chemistry for his work in the
structure of proteins, especially insulin (Sanger 1958).
Hodgkin, had previously developed methods of
sequence for determining the structure of vitamin B12,
and consequently was awarded a Nobel Prize in
chemistry. Rosalyn Yalow and Solomon Berson in
1959, reported on their development of the
radioimmunoassay for insulin. Their sensitive
radioisotope method led to the observation of
antigen-antibody complexes. They demonstrated for
the first time that hormones developed
antigen-antibody reactions within 3-5 weeks of
injection of insulin. This discovery resulted in the
award of Nobel Prize to Yalow in 1977, which added
new knowledge on measuring serum insulin levels and
other serum peptides.
Theodore Maiman in 1960, discovered the first
ophthalmic laser photocoagulators, which produce a
single wavelength beams (Krauss & Puliafio 1995),
that brings about tissue specific burns as opposed to
full thickness retinal burns.
In 1961, glucagon, a hormone produced by the alpha
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cells (α-cells) of islets of Langerhans, which raises
plasma glucose (Samols et al. 1965), was introduced
by Eli Lilly and Company to treat hypoglycaemia
resulting from insulin therapy. The characteristic
developmental milestones of insulin were also seen in
its delivery apparatuses. Early insulin syringes were
initially made of glass in 1961, which were used in
multiple numbers of times after sterilisation alongside
their needles. Later on in the late 1960s, the glass
syringes were replaced by disposable plastic ones by
Becton-Dickinson. This discovery greatly reduced the
pain, sterilisation time, and infections associated with
re-use of the syringes.
Early bariatric surgery as a management approach
continued in 1963, as Howard Payne and Loren
Dewind performed a jejuno-colonic shunt and further
enhanced the procedure by doing a jejuno-ileal bypass.
Unfortunately, the latter procedure was not
unconnected with extreme intractable diarrhoea.
In 1964, McIntyre and colleagues were able to
establish the concept of role of incretins in the glucose
regulation (McIntyre et al. 1964). Initially, reported in
the 1920s, to play a role in glucose regulation. It was
suggested that following ingestion of a carbohydrate
meal and its arrival in the intestine, the cells in the
intestinal wall secrete a substance which stimulate the
pancreas to release hormones that will ultimately lead
to the regulation of glucose (Creutzfeldt & Ebert 1985,
Porte et al. 2003). This concept was dismissed as it
lacked scientific proof. Marks and Co-workers
proposed that glucagon mediated the incretin effect
(Marks 2012, Marks & Samols 1968). These brought
about the well-established understanding of the
hormonal regulations of glucose metabolism.
In the later part of the 20th century, however, the
discovery of screening methods revolutionised the
diagnosis of diabetes, to include both asymptomatic
and symptomatic patients. The World Health
Organisation (WHO) formed two decades previously,
became interested in the study of diabetes and
formed its first Expert Committee Meeting in 1964
(WHO, 1964). Following the great challenges in insulin
delivery, Novo Nordisk again in 1964, went further to
develop the first premixed insulin preparations which
were later made available for commercial purposes.
In 1968, L’Esperance reported the progress made by
the use of argon laser, which is still used to date
(L’Esperance 1968, Castillejos-Rios et al. 1992). Laser
photocoagulation has been used to provide restoration
of sight in those with retinopathies of various degrees,
and has contributed immensely in the management of
eye complications associated with diabetes.
Newer technologies improved the availability to
monitor glucose more effectively and efficiently. Ames
Diagnostics Company introduced a colour-coded
plasma glucose testing strips in 1964, whereas the
first glucometers were produced in 1969. Glucometers
brought innovations in the management of diabetes,
as it improved the blood glucose estimations, allowed
ambulatory assessments and reduced the frequency
of hypoglycaemic episodes experienced by patients
prior to its availability (O’Grady et al. 2012). It has
progressed from urine testing in the emergency room
and hospital glucose tests, to home glucometers.
The first successful pancreatic transplant was
performed in 1966, by William Kelly and colleagues at
the University of Minnesota in a procedure called
‘simultaneous pancreas-kidney transplantation’ in
T1DM (Demartines et al.2005, Kelly et al. 1967).
Pancreatic transplant was associated with high
mortality and failure rates, as it simultaneously
involved renal transplant, and this paved the way for
islet cell transplant.
Attempts at bringing down the body weights of obese
T2DM patients was heightened by Edward Mason and
Chikashi Ito in 1967 when they developed gastric
bypass procedure which resulted in minimal
complications than the earlier intestinal bypass
(Mason & Ito 1967, Nguyen et al. 2001, Mason 1982).
Mason and Henry Buchwald directed the development
of improved procedures that yielded substantial weight
loss with little complications. Different procedures
were practiced to provide limited complications and at
the same time provide sustained weight loss in obese
T2DM patients (MacDonald et al. 1997). However, in
the pharmaceutical laboratory, Donald Steiner and
Philip Oyer in1967 discovered the pro-active form of
insulin, which he called ‘pro-insulin’ and further,
described the mechanisms of insulin synthesis in the β
-cells of islets of Langerhans (Melani et al.1971,
Melani et al. 1970). It was the initial fundamental
discoveries by Bernard that propelled, a Novel Prize
winner in 1971, Earl Wilbur Sutherland, to go further to
discover cyclic adenosine monophosphate (cAMP),
and its role in the hormonal action, particularly with
counter-regulatory hormones; epinephrine and
glucagon (Sutherland 1972). Table 1 provides a
synthesised summary of further advancements in
diabetes research with the corresponding discoverers.
[Insert Table 1 here]
In 1971, Pierre Freychet discovered insulin receptors
on cell membranes (Freychet et al. 1971). These
discoveries paved the way for unanswered questions
on possible genetic variants on insulin receptors which
could account for insulin resistance in T2DM. Interests
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in the molecular basis of insulin led to the identification,
isolation and purification of the insulin receptor
proteins by Pedro Cuatrecasas in 1972.
After the discovery of insulin, there were rapid
developments in the field of diabetes research,
experiments and its treatment as well as in the
management of its complications. These brought
about a sharp reduction in morbidity and mortality from
the disease. After several years of pharmaceutical
experiments, following the discovery of insulin,
Johannes Meienhofer and colleagues, in Germany,
Panayotis Katsoyannis and colleagues in the USA,
and Y. T. Kung and colleagues in China, discovered
human insulin in the 1960s (Meienhofer et al. 1963,
Katsoyannis et al. 1966, Kung et al. 1966).
In the early 1970s, open gastrectomy was done to
provide safer outcomes. Scott Dean in 1973, modified
the bariatric surgery procedure of bypassing a
segment of the small intestine, and yet the
complications persisted (Griffen et al. 1983).
By 1974, development of the Glucose-Controlled
Insulin Infusion System (Biostator) enhanced
continuous glucose monitoring and closed loop insulin
infusion (Clemens, Chang & Myers, 1977). In addition,
in 1974 Human Leukocyte Antigen (HLA) were found
on the surfaces of cell membranes. Some of these
HLA were identified to be associated with T1DM. In
addition, in 1974, a purified form of animal insulin was
produced by chromatographic techniques (Steiner &
Oyer 1967). The impurities and allergic reactions of
the initially produced insulin led to further work in 1975
that resulted in the production of fully synthetic human
insulin in Basel, Switzerland.
The journey through the discovery of insulin, its
modifications and refinements of the bovine and
porcine extracts cannot be overemphasised. These
advancements brought about quality of life, improved
life expectancy and reduced mortality indices over the
past 100 years.
The first insulin pumps such as the Mill-Hill infusers
were invented in 1976. With weights of about 500g,
they were uncomfortable. Current pumps are much
smaller, portable and comfortable. In 1978, Wilkinson
introduced another method, gastric banding, which
was modified by Molina. In 1979, the first needle-free
insulin delivery system, weighing less than 2 pounds,
was produced by Derata, called ‘Derma-Ject’.
Variability in blood glucose readings across the globe
became a concern among clinicians and practitioners.
In order to standardise the blood sugar measurements,
glycated haemoglobin (HbA1C) test was developed in
1979. It measures blood glucose levels over 2-3
months, which corresponds to the life span of the red
blood cells (Rabhar 1968, Day 2012a).
In 1980, the duo at the University of Glasgow, John
Ireland and John Paton developed the first insulin
administration pen, called ‘Penject’. In the same year,
the outcome of the second Expert Committee Meeting
brought about the diagnosis and classification of
diabetes, and endorsement of the USA National
Diabetes Data Group (NDDG) Report on diabetes
(WHO 1980, NDDG 1979).
The classification systems of diabetes include insulin
dependent (type 1 diabetes), non-insulin dependent
(type 2 diabetes), gestational diabetes, and diabetes
associated with other syndromes or condition (Table
2).
[Insert Table 2 here]
This new categorisation and classification led to
disuse of the older terms ‘juvenile-onset’ and
‘maturity-onset diabetes’. The NDDG/WHO
classification highlighted that the diabetes syndrome is
made up of conditions of different heterogeneity which
differ in pathogenesis, natural history and treatment
and/or preventive strategies. The roles of
environmental and genetic influences in its aetiology
were also noted (Table 3 and 4). At present there are
over 50 genetic variants known to play various roles in
T2DM aetiology. Evidence suggests that the people
with these genetic variants have between 10-15%
increased risk of diabetes. The place of gene therapy
is still at its experimental and rudimentary stages.
The defining characteristic of T1DM is its abrupt onset
with severe symptoms, dependence on exogenous
insulin and tendency towards ketosis. The
pathogenesis lies in absolute insulin deficiency from β
-cell destruction, although some insulin resistance can
be present.
[Insert Table 3
here]
[Insert Table 4
here]
With improved diagnostic techniques adults have
been documented to have T1DM, with 15-30% of
T1DM being diagnosed after 30 years of age (Laakso
& Pyorala 1985, Scott & Brown 1991, Melton et al.
1983) called latent autoimmune diabetes of adult
[LADA] (Tuomi et al. 1993). Other studies reported 7%
of all insulin treated patients at onset at age 30 years
or more are T1DM (Melton et al.1983, Harris &
Robbins 1994).
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Advancements in insulin research continued with
Graham Bell in 1980 reporting on the sequencing of
the human insulin gene (Tattersall 2010, Ulrich et al.
1977, Bell et al. 1980).
The developmental milestone in pancreatic transplant
continued relentlessly, although hampered by a
significant degree of mortality. However,
improvements in graft and patients’ survival were
achieved between 1978 and 1998 with newer surgical
techniques (Gruessner & Sutherland 2002). The
modern day knowledge of islet cell transplantation is
credited to Paul Lacy in 1980, but it was Lacy and
Camillo Riordi who discovered the present enzyme
based method, collagenase-based method used
presently in islet cell transplantation (Lacy &
Kostianosvsky 1967), which led to the first successful
allo-transplantation at the University of Pittsburgh in
1990 (Tzakis et al. 1990).
As bovine insulin continued to be made available,
there was an unnecessary speculation on the
possibility of sudden scarcity of insulin in the next 10
years preceding discovery, if the demand was to
become more than the supply. The recently cloned
gene for insulin by Ulrich and colleagues was then
used to produce human insulin. This recombinant DNA
‘human’ insulin came into clinical use in 1980 (Keen et
al. 1980). This success in genetic and molecular
engineering in medicine was widely welcomed. In
addition, this invention paved way for another
milestone discovery in diabetes. In 1981, Jan
Markussen and colleagues at the Novo Nordisk
produced the first commercially available human
insulin using DNA technology (Markussen et al. 1987,
1988). This has made insulin easily accessible,
acceptable and readily affordable by many. This
innovation alleviated fears and scares of possible run
short of animal insulin injections.
The production of second generation sulfonylureas
commenced at around 1970s and became available
for patients use in 1983. The popular ones include
glibenclamide, glipizide and gliclazide.
The role of bariatric surgery continued with
modifications that produced inflatable balloon resulting
in adjustable bands (Sugerman et al.1987, Belachew
et al. 2002, O’Brien et al. 2002, Dixon & O’Brien 2002,
Ponce et al. 2004). The outcomes of bariatric surgery
in the 1980s were not only contributory to weight loss
but also led to remission of diabetes in over 83% of
patients. Consistent with the findings of other
researchers, in 1986, Doug Hess reported the
outcome of his procedure involving duodenal switch in
bariatric surgery (Hess & Hess 1998). This was
supposed to improve the outcome of obese T2DM.
By 1990, other sulfonylureas with better profile and
relatively longer half -life came into the market, called
glimepiride, Furthermore, around the 1990’s, there
were advancements in the delivery of insulin
technology with the discovery of insulin pens, which
made its administration easier and precise. In addition,
there was a breakthrough in molecular and cellular
pathology in the same year, 1990; when a 64K
autoantibody protein associated with T1DM called
glutamate decarboxylase (GAD) was identified. It was
thought that the immune system can be attacked by its
effect on GAD and resultant diabetes.
The term ‘insulin resistance syndrome’ (syndrome X)
was first used by an American endocrinologist, Gerald
Reaven in his 1988 Banting lecture. He had purposed
that a cluster of symptoms of central obesity, diabetes
and hypertension were associated with insulin
resistance and impaired glucose tolerance (Reaven
1988). More recently, syndrome X has been called
metabolic syndrome, and is it one of most extensively
investigated area in diabetes, as Reaven believed that
it is a separate entity (Reaven 2005).
As research geared up, and explanations and theories
were proposed towards the aetiogenesis and
pathophysiologies of diabetes, different scholars
continued to emerge to clarify the heterogenous
concept of diabetes. However, the total cure continued
to elude researchers. Yet the area of bariatric surgery
which was demonstrated to yield observable loss of
weight, in 1990, Kuzmak and colleagues pioneered
the modification of gastrectomy by combining it with
gastric banding (Kuzmak et al. 1990).
Edmond Fischer and Edwin Krebs won a Nobel Prize
in 1992, for their discovery of the role of the reversible
protein phosphorylation by protein kinase as biological
regulatory mechanisms (Fischer 2010).
A reflection of the achievements in diabetes treatment
and management strategies show immense progress,
yet the mortality indices continue to deteriorate. These
led to a call for research into ways to reducing the risk
and rate of progression of complications in diabetes.
The National Institute of Diabetes and Digestive and
Kidney Diseases, USA accepted and funded the study,
called Diabetes Control and Complications Trial
(DCCT) and had a full cohort of 1,441 participants
(DCCT Trial Research Group, 1993). This study was
conducted between 1983 and 1993 and an innovation
in the use of HbA1C as the index of blood glucose
estimations, which thereafter became the gold
standard in the measurement of long term glycaemic
control in diabetes. The study compared the effects of
intensive glycaemic control (HbA1C≤6%) versus
standard glycaemic control on the complications of
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cardiovascular events, retinopathy, nephropathy and
neuropathy in people aged 13-39 with T1DM across
29 medical centres in the USA and Canada. The
outcomes of the study demonstrated that intensive
glycaemic control reduced the risks of retinopathy,
nephropathy and neuropathy by 76%, 50% and 60%
respectively (DCCT Trial Research Group 1993).
Further analysis of the participants in a follow-up study,
Epidemiology of Diabetes Interventions and
Complications (EDIC) showed that intensive control
reduces risks of any cardiovascular disease event by
42% and non-fatal heart attack, stroke or CVS-related
mortality by 57% (ADA 2003, DCCT & EDIC 2005).
Although there was no evidence of reduction in fatal
CVS-related mortality, these outcomes significantly
changed the principles and course of future
management goals in diabetes.
Hess and Marceau in 1993, modified the original
bariatric surgery procedure by adding on duodenal
switch proposed by Hess himself, to improve the side
effects and produce effectively sustainable weight loss
(Hess & Hess 1998, Marceau et al. 1998). A year later,
Wittgrove and Clark performed the first successful
laparoscopic Roux-en-Y, bilio-pancreatic diversion for
the management of obese T2DM whose body mass
index (BMI) ≥35kg/m2 (Wittgrove et al. 1994, Lugan et
al. 2004, Podnos et al. 2003, Oria 1999).
In this vein, other oral hypoglycaemias were produced
which differ from biguanides and sulfonylureas.
Incretin hormone (glucagon-like peptides-1, GLP-1)
was finally discovered in 1994 and will lead to the
production of new antidiabetic agent that acts by
increasing insulin secretions in response to glucose. In
addition, alpha-glucosidase inhibitors (e.g., acarbose)
produced by Bayer Corporation and were made
available in 1996. They slow down the digestion of
carbohydrate meals therefore delaying the availability
of blood glucose.
Curiously, in 1996, Scopinaro and colleagues
performed a modified gastric bypass procedure,
involving bilio-pancreatic diversion, limited
gastrectomy with long limb Roux-en-Y and a short
common intestinal segment. Although the procedure
was supposed to be safer than jejuno-ileal bypass, it
was associated with serious side effects of
malabsorption (dumping syndrome) and stomach
ulcers (Scopinaro et al. 1996).
The improvements in insulin quality and purity
continued, in 1996, Eli Lilly and company produced the
first commercially available insulin analog called Lispro
(Humalog). Further improvements were made in the
pharmaceutical industry with the production of more
classes of antidiabetic medications.
By 1996-1997, the ADA set up an Expert Committee
to review the previous NDDG/WHO classification
(ADAEC 1997), in order to eliminate treatment based
nomenclature, and to make some modifications in the
inclusion of pathogenic findings in the diagnostic
criteria. Insulin dependent diabetes and non-insulin
dependent diabetes were withdrawn, being replaced
by aetiological based classification of T1DM and
T2DM. In addition, the fasting plasma glucose level
was reduced to 7.0mmo/l from 7.8mmol/l (126mg/dl
from 140mg/dl).
The first thiazolidinedione class of oral
hypoglycaemias approved in 1997 was troglitazone,
and it was purported to improve insulin sensitivity in
muscles. It was not quite long afterwards it was
withdrawn from clinical use because of its adverse
liver toxicity. In 1998, the first meglitinides was
developed and marketed as repaglinide. This drug
stimulates insulin secretion in the presence of glucose.
Other newer medications produced included
neteglinide.
Presently, with explosions in technology, internet and
programming, newer pumps are able to adjust delivery
of insulin doses against serum glucose. Insulin pumps
have virtually improved glycaemic control and
removed the erratic glycaemic variability. Other
modifications in insulin delivery include inhaled insulin
and oral sprays.
The recognition of the linkages between
hyperglycaemia and the development of diabetes
complications was revealed in clinical trials,
observational studies and animal experimental studies
in the last 30 years (Genuth 1995). This work included
the pioneering work of the DCCT in T1DM published in
1993, and the series of studies by the UK Prospective
Study (UKPDS) in T2DM published in 1998. The
DCCT demonstrated that lowering blood glucose as
close to normal as possible reduced the risk by
35-75%, and delayed the onset and progression of
diabetic retinopathy, nephropathy and neuropathy in
T1DM. There was also a reduction in cardiovascular
events, although of no statistical significance. The
UKPDS was the largest and longest clinical research
study ever conducted with over 5000 T2DM patients
newly diagnosed between the periods of 1977-1991 in
23 centres in the UK, with a mean follow up period of
10 years. The aims of the study were to ascertain
whether intensive glycaemic control had any beneficial
cardiovascular effects, the differential benefits of oral
hypoglycaemic drugs and insulin or otherwise, and
whether ‘tight’ or ‘less tight’ blood pressure control in
those with hypertension were of any benefits. The
study also sought to ascertain if the use of drug
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groups, angiotensin converting enzyme inhibitors
(ACEI) or beta-blockers were of any differential
therapeutic benefits over each other. The outcomes
provided robust evidence that the complications of
retinopathy and nephropathy in T2DM can be reduced
significantly (by 25%) by attaining a median HbA1C of
7%. Findings also supported evidence that elevated
blood glucose (hyperglycaemia) in part or in
conjunction with other risk factors contributes to the
microvascular complications, similar to the findings of
the DCCT. There was a significant degree of risk of
microvascular complication with glycaemic levels,
such that for every 1% decrease in HbA1C there was a
corresponding 35% reduction in the risks, 25%
reduction in diabetes related deaths, 7% reduction in
all-cause mortality and 18% reduction in myocardial
infarction deaths. The UKPDS did not show any
statistical significant benefit of lowering blood glucose
on the macrovascular complications such as
cardiovascular mortality however, there was a 16%
reduction (p-value=0.052) in the risk of myocardial
infarction. Findings on anti-hypertensive agents
showed that a reduction of blood pressure (BP) to a
mean of 144/82mmHg significantly reduced the
occurrence of cerebrovascular disease, microvascular
complications (retinopathy) and diabetes-related
mortality (with risk reduction ranging from 24-56%).
However, in comparisons of treatments types, those
on beta-blockers had slightly better controlled BP than
those on ACEI, although neither drugs showed any
superiority in any of the outcomes measured (UKPDS
1998a, 1998b, Turner, 1998, Turner et al. 1998)
The later part of the 20th century brought about the
discovery of home blood glucose monitoring making it
possible for ‘tighter glycaemic control’. Technological
developments include the introduction of insulin pens
and the development of the insulin pump (Watkins,
2008, p.vii). Evidence exists that the use of insulin
pumps improves the wellbeing and quality of life of
patients needing insulin, and reduces the rate of
hypoglycaemias (Pickup 2012, Nicolucci et al. 2008,
Hammond et al. 2007, Nuboer et al. 2008,
Scheidegger et al. 2007).
21st century (era of millennium developments)
The beginning of the millennium was when James
Shapiro and colleagues at the University of Alberta,
Canada developed an improved steroid free protocol
(the Edmonton protocol), in which patients achieved
normal glycaemic levels. Since this time, islet cell
transplantation became a more practicable and
successful procedure and operations are carried out
primarily for people with T1DM who have severe
uncontrolled diabetes associated with secondary
complications (Shapiro et al. 2000). In addition, in the
later part of 2000, Novo Nordisk and Aventis
Pharmaceuticals produced a rapid acting analog
(insulin aspart) and a long acting form (insulin glargine)
respectively. The luxury of DNA technology accorded
Novo Nordisk an opportunity to produce another long
acting insulin analog, determir, in 2003.
The 21st century, heralded the revision of the
guidelines for the diagnosis and definitions of various
stages of hyperglycaemia by the ADA in 2003 and the
WHO in 2006, and of the use of glycosylated
haemoglobin (HbA1C) as a diagnostic and prognostic
tool in diabetes (ADA 2003, WHO 2006). However, it
was not until 2011 that the WHO, International
Diabetes Federation (IDF), European Association for
the Study of Diabetes (EASD), ADA and Diabetes UK
unanimously endorsed the use of HbA1C as a
diagnostic tool (WHO 2011). New concepts were
introduced into the nomenclature of diabetes.
Prediabetes was defined as impaired fasting glucose
(IFG) and/or impaired glucose tolerance (IGT). The
IFG defines FPG of 6.1-6.9 mmol/l (100-125mg/dl) or
HbA1C =42-46 mmol/mol (6.0-6.4%), whereas IGT
defines FPG < 7.0 mmol/l (< 126mg/dl) or HbA1C=
42-46 mmol/mol (6.0-6.4%). Today, researchers have
shown those at high risk of T2DM to include IFG and
IGT. Even though they are not clinically diagnosed as
T2DM they are subject to some cardiovascular risks.
These new clinical entities brought about the
reassessment of those at increased risk of diabetes.
Newer medications were found in the 21st century,
which brought about options and choices and
consequently improved the management of T2DM.
Exenatide, a class of incretin mimetic (GLP-1) was
introduced in 2005 (Day 2012b). This originally was
designed as an oral medication, but later on an
injectable form was produced.
Innovations in 2005 brought a new modification of
laser therapy in treatment of retinopathy in diabetes,
using Pascal photocoagulator which was made
available to limit the energy dissipation by producing
an accurate and faster semi-automated laser pulses in
a rapid pre-determined fashion (Sanghvi et al. 2008).
In 2006, the first dipeptidyl peptidase-4 (DPP-4)
inhibitor, sitagliptin was approved and made available
for clinical use in T2DM. This medication enhances the
body’s ability to reduce blood sugar levels by its action
on the naturally occurring GLP-1, to increase insulin
production.
In 2008, the outcomes of Action to Control
Cardiovascular Risk in Diabetes (ACCORD), Action in
Diabetes and Vascular Disease: Preterax and
Diamicron MR Controlled Evaluation (ADVANCE) and
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Veterans Affairs Diabetes Trial (VADT) were made
public. Although large scale trials of ACCORD,
ADVANCE and VADT have not shown that glycaemic
control can reduce CVD mortality in people with high
cardiovascular risks, but observational studies
continue to demonstrate consistent correlations
between CVD risk and glycaemia (Levitan et al. 2004,
Selvin et al. 2004). However, sensitivity analyses from
VADT, ACCORD and ADVANCE trials have shown
beneficial effects of tight glycaemic control on the CVD
risk (Gerstein et al. 2008, Patel et al. 2008, Duckworth
et al. 2008), and reduction of all-cause mortality and
AMI (Holman et al. 2008). The benefits of improved
glycaemic control as identified in the UKPDS study
therefore appears to contradict the findings of the
ACCORD and ADVANCE studies in which there
seems to be no benefit from improved glycaemic
control in reducing myocardial infarction and improving
cardiovascular outcomes, even though there was an
approximately 10% reduction in primary endpoint
cardiovascular diseases (Patel et al. 2008, Gerstein et
al. 2008). Analyses of these studies showed no
benefits or improvement in cardiovascular risk and
mortality with tight glycaemia regulation (Dluhy &
McMahon 2008, Skyler et al. 2009, Duckworth et al.
2009), and can worsen cardiovascular disease events
(Meier & Hummel 2009). The deductions are that tight
glycaemic control, HbA1C≤53mmol/mol (≤7.0%) is
beneficial with regard to microvascular and
macrovascular disease risk reduction in people with
recent onset T2DM with no history of CVD and longer
life expectancy. In those with longer duration of
diabetes (>15 years), history of known CVD, and
shorter life expectancy, tight glycaemic control can be
deleterious particularly with CVD risk. The major
implications from these three studies were re-shaping
the future management of people with T2DM towards
a personalised (individualised) therapy for setting
treatment and glycaemic targets.
Around the globe, use of the ‘artificial pancreas’ is still
at the trial stages (O’Grady et al. 2012). Initially,
started in 1970s with intravascular insulin delivery, but
was later progressed to subcutaneous route in 1990s
because of increased infection risk and cost. It
involves an automated electromechanical closed-loop
insulin delivery device which mimics physiological
insulin release (Hovorka 2011, Kowalski 2009). In the
UK, this campaign is spearheaded by the Diabetes UK,
aimed at reducing the risks of hypoglycaemia and
improves overall glycaemic regulation, entails a
technique of continually glucose-responsive insulin
pumps with coupling of subcutaneous continuous
glucose monitoring in a closed loop system (Pickup
2012, 2011, Hoeks 2011).
In 2010, the controversies and inconsistencies in the
clinical laboratories estimation of HbA1C values were
resolved by the international agreement of
standardisation of values, to the present, mmol/mol
from percent (Hanas & John 2010). This rectification
and agreement brought about comparable estimations
between laboratories.
In 2013, a new class of antidiabetic medications,
sodium-glucose co-transporter 2 (SGLT-2) inhibitors
(e.g., canagliflozin) was made available for clinical use
in people with T2DM. The mechanisms of action
involves blockade of the sodium glucose transport
proteins in the kidneys thereby reducing glucose
re-uptake and increasing secretions of glucose in the
urine.
Bariatric surgery has been known to induce disease
remission. In the UK, the impact of bariatric surgery on
T2DM has necessitated the NHS to reduce the criteria
for bariatric surgery in T2DM to include those with BMI
greater or equals 30kg/m2.
Conclusions
In summary, over 3000 years have passed since the
first evidence of this chronic, heterogenous endocrine
disorder of carbohydrates, fat and protein metabolisms.
The historical developments of diabetes and its
management and its continued advances have
demonstrated emergence and evolution over a long
period of time. The DCCT, UKPDS, VADT, ADVANCE,
ACCORD and other seminal studies have
demonstrated the differential effects of different factors
on short-term and long-term outcomes, yet another
milestone in the history of diabetes. Regrettably, after
32 years, no new ground breaking discoveries have
been made to warrant a Nobel Prize despite evidence
of other advancements in diabetes investigations. The
introduction of HbA1C revolutionised the unwanted,
repeated and regular blood sugar estimations
characterising follow-up visits. It brought the
management of blood glucose more acceptability and
compliance.
As the 21st century grinds through its ‘adolescent
period’ and we approach the centenary of insulin
discovery, we do hope to drive the history forward by
cruising on the road of finding a cure to diabetes. The
future lies on the outcomes and availability of
cell-based therapy and immunotherapy alongside the
improvements in oral hypoglycaemic agents.
References
WebmedCentral > Review articles Page 15 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
Alberti KGMM 2010 The classification and1. diagnosis of Diabetes mellitus. In R. Holt, C.
Cockram, A. Flyvbjerg and R. Goldstein (Eds.),
Textbook of Diabetes (4th ed., pp. 24-30).
Blackwell Publishing.
Allan FN 1953 The writings of Thomas Willis:2. Diabetes 300 years ago. Diabetes 2 74-78.
American Diabetes Association Expert3. Committee 1997 Report of the Expert Committee
on the Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care 20 1183.
American Diabetes Association 20034. Implications of the Diabetes Control and
Complications Trial. Diabetes Care 26(suppl 1)
s25-s27.
Araetus C 1856 On causes and symptoms of5. chronic diseases. In C. F. Adam (Ed., p. 138).
London, United Kingdom: London Sydenham
Society.
Avicenna 1991 Canon of medicine. Persian6. translation by Sharafkandi, A. Volume IV, Tehran,
Soroushi.
Banting FG, Best CH, Collip JB, Campbell WR &7. Fletcher AA 1922 Pancreatic extracts in the
treatment of diabetes mellitus. Preliminary report.
Can Med Assoc J 12 141-146.
Barnett DM & Krall LP 2005 The History of8. Diabetes. In C. R. Kahn, G. C. Weir, G. L. King,
A. M. Jacobson, A. C. Moses, & R. J. Smith
(Eds.), Joslin’s Diabetes Mellitus. (4th ed., pp.
3-15). MA, USA: A Wolters Kluwer Company
Belachew M, Belva PH & Desaive C 20029. Long-term results of laparoscopic adjustable
gastric banding for the treatment of morbid
obesity. Obes Surg 12 564-568.
Bell GI, Pictet RL, Rutter WL, Cordell B, Tscher10. E & Goodman HM 1980 Sequence of the human
insulin gene. Nature 284 26-32.
Benedict SR 1911 The detection and estimation11. of glucose in urine. JAMA, LVII (15) 1193-1194.
Bergenstal RM, Tamborlane WW, Ahmann A,12. Buse JB, Dailey G, Davis SN, Joyce C, Peoples
T, Perkins BA, Welsh JB, et al. 2010
Effectiveness of sensor-augmented insulin pump
therapy in type 1 diabetes. N Engl J Med 363
311-320. (Erratum, N Engl J Med 363, 1092).
Bernard C 1849 De l’origine du sucre dans13. animale. C. R. Soc Biol 1 Mem. 121-133.
Bernard C1853 Nouvelle function du foie. Paris,14. Bailliere.
Bernard C 1857 Sur le mécanisme de la15. formation du sucre dans le foie. C R Acad Sci 44
578-586.
Berson SA & Yalow RS 1963 Antigens in insulin16. determinants of specificity of porcine insulin in
man. Science 139 844.
Bertram F, Bendfeldt E & Otto H 1955 Ube rein17. wirksames pesorales anti-diabeticum (BZ55).
Dtsch Med Wochenschr 80(40) 1455-1460.
Bessette FM & Nguyen LC 1989 Laser light: its18. nature and its action on the eye. CMAJ 141
1141-1148.
Best C & Scott MA 1923 Possible sources of19. insulin. J Metab Res 3 177-179
Bliss M 1993 Rewriting medical history: Charles20. Best and the Banting and Best myth. J Hist Med
Allied Sci 48(3) 253-74.
Bliss M 2007 The discovery of insulin. Chicago:21. University of Chicago Press.
Bonnefond A, Froguel P & Vaxillaire M 2010 The22. emerging genetics of type 2 diabetes. Trends
Mol Med 16 407-416.
Bordeu T 1775 Recherches sur les maladies23. chroniques. VI. Analyse medicinale du sang, 382,
379, Paris, Ruault.
Bornstein J & Lawrence RD 1951a Two types of24. diabetes mellitus, with and without available
plasma insulin. BMJ 1(4709) 732.
Bornstein J & Lawrence RD 1951b Plasma25. insulin in human diabetes mellitus. BMJ 2(4747)
1541-1544.
Bouchardat A 1852) Mém. Aca R Méd, Paris XVI26. 165.
Bouchardat A 1875 Dela Glycosurie ou diabète27. sucré, son tratement hygienique. Paris,
Germer-Baillière.
Bright R 1831 Reports on medical cases28. selected with a view of illustrating the symptoms
and care of diseases by a reference to morbid
anatomy, 1827-1831. Vol II, 262. London.
Buchan W 1785 Domestic Medicine or a treatise29. on the Prevention and cure of diseases by
regimen and simple Medicine. Exeter: J. B
Williams
Butler AE, Janson J, Bonner-Weir S, Ritzel R,30. Rizza RA, & Butler PC 2003 Β-cell deficit and
increased β-cell apoptosis in humans with type 2
diabetes. Diabetes 52(1) 102-110.
Castillejos-Rios D, Devenyi R, Moffat K & Yu E31. 1992 Dye yellow vs. argon green laser in
panretinal photocoagulation for proliferative
diabetic retinopathy: a comparison of minimum
power requirements. Can J Ophthal 27 243-244.
Cavaghan MK, Ehrmann DA & Polonsky KS32. 2000 Intercations between insulin resistance and
insulin secretion in the development of glucose
intolerance. J Clin Invest 106 329-333.
Chevreul E 1815 Note sur le sucre de diabetes.33. Ann Chem 95 319-320.
Clemens AH, Chang PH & Myers RW 1977 The34. development of Biostator, a glucose controlled
insulin infusion system (GCIIS), pp. 23-33 in
Blood Glucose Monitoring: Methodology and
Clinical Application of Continuous in Vivo
Glucose Analysis; Hormones Metabolic
Research Supplement Series No 7 Editors,
Krise-Jarres, J. D., & Molnar, G. D. Thieme
Stuttgart.
Collip JB 1923 Glucokinin. A new hormone35. present in plant tissue. Preliminary paper. J Biol
Chem 56 513-543.
Cori CF & Cori GT 1946 Carbohydrate36. metabolism. Annu Rev Biochem 15 193-218.
Corner JP 1956 Semiquantitative specific test37. paper for glucose in urine. Anal Chem 28
1748-1750.
Cowley T 1788 A singular case of diabetes,38.
WebmedCentral > Review articles Page 16 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
consisting entirely in the quality of the urine with
an inquiry into the different theories of that
disease. Lond Med J 9 286-308.
Cuatrecasas P 1972 Isolation of the insulin39. receptor of liver and fat call membranes. Proc
Natl Acad Sci USA 69(2) 318-322.
Currie CJ, Poole CD, Jenkins-Jones S, Gale40. EAM, Johnson JA & Morgan CL 2012 Mortality
after incident cancer in people with and without
type 2 diabetes. Impact of metformin on survival.
Diabetes Care 35 299-304.
Day A 2012a HbA1C and diagnosis of diabetes.41. The test has finally come of age. Ann Clin
Biochem 49 7-8.
Day C 2012b ADA-EASD diabetes guidance:42. individualised treatment of hyperglycaemia. Br J
Diabetes Vas Dis 12 146-151.
De Meyer J 1909 Action de la secretion interne43. du pancreas sur differents organs et en
particulier sur la secretion renale. Arch Fisiol 7
96-99.
DeFronzo RA, Tripathy D, Schwenke DC, Banerji44. M, Bray GA, Buchanan TA, Clement SC, Henry
RR, Hodis HN, Kitabchi AE, et al. 2011
Pioglitazone for diabetes prevention in impaired
glucose tolerance. N Engl J Med 364(12)
1104-1115.
Demartines N, Schiesser M & Clavien PA 200545. An evidence-based analysis of simultaneous
pancreas-kidney and pancreas transplantation
alone. Am J Transplant 5(11) 2688-2697.
Diabetes Control and Complications Trial46. Research Group 1993 The effect of intensive
treatment of diabetes on the development and
progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J
Med 329(14) 977-986.
Diabetes Control and Complications47. Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research
Group 2005 Intensive Diabetes Treatment and
Cardiovascular Disease in Patients with Type 1
Diabetes. N Engl J Med 353 2643-2653.
Dickinson WH 1875a. Diabetes. Diseases of the48. kidney. Part 1, London, Longmans, Green &
Company.
Dickinson WH 1875b Diseases of the kidney and49. urinary derangements. Part 2, 278. London,
Longmans, Green & Company.
Dixon JB & O’Brien PE 2002 Health outcomes of50. severely obese type 2 diabetic subjects 1 year
after laparoscopic adjustable gastric banding.
Diabetes Care 25 358-363.
Dluhy RG & McMahon GT 2008 Intensive51. glycaemic control in the ACCORD and
ADVANCE trials. N Engl J Med 358(24)
2630-2633.
Dobson M 1776 Experiments and observations52. on the urine in a diabetes. Med Obs Inq 5
298-316.
Drazin B 2010 Mitogenic action of insulin: friend,53. foe or “frenemy”. Diabetologia 53 229-233.
Dreschfeld J 1886 The Bradshawe Lecture on54. Diabetic Coma. BMJ 2 (1338) 358-363.
Duckworth W, Abraira C, Moritz T, Reda D,55.
Emanuele N, Reaven PD, Zieve FJ, Marks J,
Davis SN, Hayward R, et al. 2009 Glucose
control and vascular complications in veterans
with type 2 diabetes. N Engl J Med 360(2)
129-139.
Ebbell B 1937 The papyrus Ebers. (p.115).56. Copenhagen and Oxford: Oxford University
Press.
Eckhout GV, Willbanks OL & Moore JT 198657. Vertical ring gastroplasty for morbid obesity. Five
year experience with 1,463 patients. Am J Surg
152 713-716.
Eknoyan G & Nagy J 2005 A history of diabetes58. mellitus or how a disease of the kidneys evolved
into a kidney disease. Adv Chr Dis 12(2) 223-229.
Elliotson J 1839 The principles and Practice of59. Medicine. London, J. Butler.
Fajans SS, Bell GI & Polonsky KS 200160. Molecular mechanisms and clinical
pathophysiology of maturity-onset diabetes of the
young. N Engl J Med 345 971-980.
Falta W & Boller R 1931 Insularer und61. insulinresistenter diabetes. Klin Wochenschr 10
438-443.
Fearon W 1921 Acids and alkalies. Part II. Dublin62. J Med Sci 2(5) 201-207.
Fischer EH 2010 Phosphorylase and the origin of63. reversible protein phosphorylation. Biol Chem
391 131-137.
Frank JP 1794 De curandis hominum morbis64. epitome. Liber 5, 38-67. Mannheim.
Franke H & Fuchs J 1955 Ein neues65. antidiabetisches Prinzip: Ergebnisse Klinischer
Untersuchungen. Dtsch Med Wochenschr 80(40)
1449-1452.
Frerichs FT 1884 Ueber den diabetes, Berlin.66. Freychet P, Roth J & Neville DM Jr 197167. Monoiodoinsulin: demonstration of its biological
activity and binding to fat cells and liver
membranes. Biochem Biophys Res Commun 43
(2) 400-408.
Froesch ER & Renold AE 1956 Specific68. enzymatic determination of glucose in blood and
urine using glucose oxidase. Diabetes 5 1-6
Gallagher EJ & LeRoith D 2010 The proliferating69. role of insulin and insulin-like growth factors in
cancer. Trends Endocrinol Metab 21(10) 610-618.
Genuth SM 1995 The case for blood glucose70. control. Adv Intern Med 40 573-623.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr,71. Bigger JT, Buse J B, Cushman WC, Genuth S,
Ismail-Beigi F, Grimm RH Jr, et al. 2008 Effects
of intensive glucose lowering in type 2 diabetes.
N Engl J Med 358(24) 2545-2559.
Gillies CL, Lambert PC, Abrams KR, Sutton AJ,72. Cooper NJ, Hsu RT, Davies MJ & Khunti K 2008
Different strategies for screening and prevention
of type 2 diabetes in adults: cost effectiveness
analysis. BMJ 336(7654) 1180-1185.
Gough SCL, Belda-Iniesta C, Poole C, Weber M,73. Russell-Jones D, Hansen BF, Mannucci E &
Tuomilehto J 2011 Insulin therapy in diabetes
and cancer risk: current understanding and
implications for future study. Adv Ther 28(Suppl
5) 1-18.
WebmedCentral > Review articles Page 17 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
Griffen WO Jr, Bivins BA & Bell RM 1983 The74. decline and fall of jejunoileal bypass. Surg
Gynecol Obstet 157 301-308.
Gruessner AC & Sutherland DE 2002 Pancreas75. transplant outcomes for United States (US) and
non-US cases as reported to the United Network
for Organ Sharing (UNOS) and the International
Pancreas Transplant Registry (IPTR) as of
October 2002. Clin Transplant 41-77
Hammond P, Liebl A & Grunder S 200776. International survey of insulin pump users:
impact of continuous subcutaneous insulin
infusion therapy on glucose control and quality of
life. Primary Care Diabetes 1 143-146.
Hanas R & John G 2010 The 2010 consensus77. statement on the worldwide standardisation of
the haemoglobin A1C measurements. On behalf
of the international HbA1C consensus
Committee. Diabetes Care 33(8) 1903-1904.
Harley G 1866 Diabetes its various forms and78. different treatments. London, Walton and
Maberly.
Harris MI & Robbins DC 1994 Prevalence of79. adult-onset IDDM in the U.S. population.
Diabetes Care 17 1337
Hess DS & Hess DW 1998 Biliopancreatic80. diversion with a duodenal switch. Obes Surg 8(3)
267-282.
Higa KD, Ho T & Boone KB 2001 Laparoscopic81. Roux-en-Y gastric bypass: technique and 3-year
follow-up. J Laparoendosc Adv Surg Tech 11
377-382.
Himsworth HP 1936 Diabetes mellitus: its82. differentiation into insulin-sensitive and
insulin-insensitive types. Lancet 1 127-130.
Hoeks LB, Greven WL & de Valk HW 201183. Real-time continuous glucose monitoring system
for treatment of diabetes: a systematic review.
Diabetic Med 28 386-394.
Holman RR, Paul SK, Bethel MA, Matthews DR84. & Neil HA 2008 A 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med
359 1577-1589.
Houssay BA, Smyth FS, Foglia VG & Houssay85. AB 1942 Comparative diabetogenic action of the
hypophysis from various animals. J Exp Med 75
93-106.
Hovorka R 2011 Closed-loop insulin delivery:86. from bench to clinical practice. Nature Rev
Endocrinol 7 385-395.
Janbon M, Chaptal J, Vedel A & Schaap J 194287. Accidents hypoglycaemiques graves par un
sulfamidothiodiazol le VK57 ou 2254 RP.
Montpellier Med 441 21-22.
Joslin EP 1915 Present-day treatment and88. prognosis in diabetes. Trans Assoc Am
Physicians XXX, 2.
Joslin EP 1917 Treatment of diabetes mellitus.89. Philadelphia, PA: Lea and Febiger.
Joslin EP 1921 The presentation of diabetes90. mellitus. JAMA 76 79-84.
Katsoyannis PG, Tometsko A & Zalut C 196691. Insulin peptides XII. Human insulin generation by
Combination of synthetic A and B chains. J Am
Chem Soc 88186.
Keen H, Glynne A, Pickup JC, Viberti GC, Bilous92. RW, Jarrett RJ & Marsden R 1980 Human insulin
produced by recombinant DNA technology:
safety and hypoglycaemic potency in healthy
men. Lancet 2(8191) 398-401.
Kelly WD, Lillehei RC, Merkel FK, Idezuki Y &93. Goetz FC 1967 Allotransplantation of the
pancreas and duodenum along with the kidney in
diabetic nephropathy. Surgery 61(6) 827-837.
King EJ, Wootton IOP 1957 Microanaylsis in94. medical Biochemistry. Churchill, London.
Kohn JA 1957 A rapid method of estimating95. blood glucose ranges. Lancet 273 119-121.
Kowalski AJ 2009 Can we really close the loop96. and how soon? Accelerating the availability of an
artificial pancreas: a roadmap to better diabetes
outcomes. Diab Tech Therap 11(Suppl.1)
S113-119
Krauss JM & Puliafito CA 1995 Lasers in97. ophthalmology. Lasers Surg Med 17 102-159.
Krebs HA & Johnson WA 1937 Biochem J 3198. (1937) 645.
Krebs HA, Salvin E & Johnson WA 193899. Biochem J 32.
Kremen AJ, Linner JH & Nelson CH 1954 An100. experimental evaluation of the nutritional
importance of proximal and distal small intestine.
Ann Surg 140 439-448.
Kung YT, Du YC, Huang WT, Chen CC & Ke LT101. 1965 Total synthesis of crystalline bovine insulin.
Sci Sin 14(11) 1710-1716.
Kuzmak LI, Yap IS, McGuire L, Dixon JS &102. Young MP 1990 Surgery for morbid obesity.
Using an inflatable gastric band. AORN J 51(5)
1307-1324.
Laakso M & Pyörälä K 1985 Age of onset and103. type of diabetes. Diabetes Care 8(2) 114-117
Lacy P & Kostianovsky M 1967 Method for the104. isolation of intact islets of Langerhans from the
rat pancreas. Diabetes 16(1) 35-39.
Lancereaux E 1877 Note et reflexions à propos105. de 2 cas de diabète sucré avec altération du
pancréas. Bull Acad Med Paris 2(Sér 6)
1215-1240.
Larsen EH 2007 August Krogh, 1874-1949: 1920106. Nobel Prize. Ugeskrift for laeger 169(35) 2878.
Lehrer S 2006 Explorers of the body: Dramatic107. breakthroughs in medicine from ancient times to
modern science. 2nd Edition, p. 428. iUniverse,
Inc. New England: USA.
Leopold EJ 1930 Aretaeus the Cappadocian.108. Ann Med Hist 2 424-455.
L'Esperance FA Jr 1968 An opthalmic argon109. laser photocoagulation system: design,
construction, and laboratory investigations. Trans
Am Ophthalmol Soc 66 827-904.
Levitan EB, Song Y, Ford ES & Liu S 2004 Is110. nondiabetic hyperglycemia a risk factor for
cardiovascular disease? A meta-analysis of
prospective studies. Arch Int Med 164(19)
2147-2155
Lujan JA, Frutos MD, Hernandez Q, Liron R,111. Cuenca JR, Valero G & Parrilla P 2004
Laparoscopic versus open gastric bypass in the
treatment of morbid obesity: a randomized
WebmedCentral > Review articles Page 18 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
prospective study. Ann Surg 239(4), 433-437.
MacDonald KG Jr, Long SD, Swanson MS,112. Brown BM, Morris P, Dohm GL & Pories WJ
1997The gastric bypass operation reduces the
progression and mortality of
non-insulin-dependent diabetes mellitus. J
Gastrointest Surg 1 213-220.
Marceau P, Hould FS, Simard S, Hould FS,113. Lebel S, Lescelleur O, Biertho L, & Kral JG 1998
Biliopancreatic diversion with duodenal switch.
World J Surg 22 947-54.
Marks V 1959 An improved glucose114. glucose-oxidase method for determining blood,
CSF and urine glucose levels. Clin Chim Acta 4
395-400.
Marks V & Dawson A 1965 Rapid stick method115. for determining blood-glucose concentration.
BMJ 1 293-294.
Marks V & Samols E 1968 Glucose homeostasis116. pp. 111-138 in Recent Advances in
Endocrinology. Editor, James, V. H. T. Churchill,
London.
Markussen J, Diers I, Hougaard P, Langkjaer L,117. Norris K, Snel L, Sørensen AR, Sørensen E &
Voigt HO 1988 Soluble, prolonged-acting insulin
derivatives. III. Degree of protraction,
crystallizability and chemical stability of insulins
substituted in positions A21, B13, B23, B27 and
B30. Protein Eng 2(2)157-166.
Markussen J, Hougaard P, Ribel U, Sørensen118. AR & Sørensen E 1987 Soluble,
prolonged-acting insulin derivatives. I. Degree of
protraction and crystallizability of insulins
substituted in the termini of the B-chain. Protein
Eng 1(3) 205-213.
Mason EE 1982 Vertical banded gastroplasty for119. obesity. Arch Surg 117(5) 701-706.
Mason EE & Ito C 1967 Gastric bypass in obesity.120. Surg Clin North Am 47 1345-1351.
McGrew RE 1985 Encyclopedia of Medical121. history (1st ed., pp. 74-297). London, United
Kingdom: McGraw-Hall Book Company.
McIntyre N, Holdsworth CD & Turner DS 1964122. New interpretation of oral glucose tolerance.
Lancet 2 20-21.
Medvei VC 1982 The 18th century and the123. beginning of the 19th century. History of
Endocrinology (eds). pp. 149-211.
Medvei VC 1993 The Greco-Roman period. In V.124. C. Medvei (Ed.), The History of clinical
endocrinology: a comprehensive account of
endocrinology from earliest times to the present
day (pp. 34-37). New York, USA: Parthenon
Publishing.
Meienhofer J, Schnabel E & Bremer H 1963125. Synthese der Insulinketten und ihre Kombination
zu insulactiven Praparaten. Z Naturforsch 18
1120.
Meier M & Hummel M 2009 Cardiovascular126. disease and intensive glucose control in type 2
diabetes mellitus: moving practice toward
evidence-based strategies. Vasc Health Risk
Manag 5 859-871.
Melani F, Rubenstein AH & Steiner DF1971127. Proinsulin and C-Peptide in Human Serum. In
Pathophysiologie und Klinik/pathophysiology and
clinical considerations, Edited by Ernst F. Pfeiffer.
pp 159-172.
Melani F, Rubenstein AH, Oyer PE & Steiner DF128. 1970 Identification of proinsulin and C-peptide in
human serum by a specific immunoassay. Proc
Natl Acad Sci U S A 67(1) 148-155.
Melton LJ, Ochi JW, Palumbo PJ & Chu-Pin A129. 1983 Sources of disparity in the spectrum of
diabetes mellitus at incidence and prevalence.
Diabetes Care 6 427-431.
Melton LJ, Palumbo PJ & Chu-Pin CA 1983.130. Incidence of diabetes mellitus by clinical type.
Diabetes Care 6 75.
Meyer-Schwickerath GR 1989 The history of131. photocoagulation. Aust N Z J Ophthalmol 17
427-434.
Milagro FI, Mansego ML, De Miguel C &132. Martinez JA 2012 Dietary factors, epigenetic
modifications and obesity outcomes: progresses
and prospectives. Mol Aspects Med 34(4)
782-812.
Minkowski O 1929 Die lehre vom pancreas:133. diabetes in ihrer geschichtlichen Entwicklung.
Munch Med Wschr 76 311-315.
Mulnier HE, Seaman HE, Raleigh VS,134. Soedamah-Muthu SS, Colhoun HM & Lawrenson
RA 2006 Mortality in people with type 2 diabetes
in the UK. Diabet Med 23(5) 516-521.
Murnaghan JH & Talalay P 1967 John Jacob135. Abel and the crystallization of insulin. Persp Med
Biol 10 334-380.
Murray I 1969 The search for insulin. Scot Med J136. 14 286-293.
NA 1964 Historical Review. Acta Neurologica137. Scand 40 8-11. doi:
10.1111/j.1600-0404.1964.tb07422.x
Nathan DM, Singer DE, Hurxthal K & Goodson138. JD 1984 The clinical information value of the
glycosylated haemoglobin assay. N Engl J Med
310 341-346.
National Diabetes Data Group 1979139. Classification and diagnosis of diabetes mellitus
and other categories of glucose intolerance.
Diabetes 28 1039.
Naunyn B 1898 Der diabetes mellitus. Wien:140. Alfred Holder.
Neuburger M 1911 Theophile de Bordeu als141. varlaufer der Lehre vou der inneren Sekretion.
Wien Klin Wschr 39 1367.
Nguyen NT, Goldman C, Rosenquist CJ, Arango142. A, Cole CJ, Lee SJ & Wolfe BM 2001
Laparoscopic versus open gastric bypass: a
randomized study of outcomes, quality of life,
and costs. Ann Surg 234(3) 279-289.
Nicolucci A, Maione A, Franciosi M, Amoretti R,143. Busetto E, Capani F, Bruttomesso D, Di Bartolo
P, Girelli A, Leonetti F, et al. 2008 Quality of life
and treatment satisfaction in adults with type 1
diabetes: a comparison between continuous
subcutaneous insulin infusion and multiple daily
injections. Diabetic Med 25(2) 213-220
Nolan C 2010 Failure of islet β-cell compensation144. for insulin resistance causes type 2 diabetes:
What causes non-alcoholic fatty liver disease
and non-alcoholic steatohepatitis? J
WebmedCentral > Review articles Page 19 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
Gastroenterol Hepatol 25(10) 1594-1597.
Nuboer R, Borsboom G, Zoethout J, Koot HM &145. Bruining J 2008 Effects of insulin pump vs.
injection treatment on quality of life and impact of
disease in children with type 1 diabetes mellitus
in a randomized, prospective comparison.
Pediatric Diabetes 9 291-296.
O’Brien PE, Dixon JB, Brown W, Schachter LM,146. Chapman L, Burn AJ, Dixon ME, Scheinkestel C,
Halket C, Sutherland LJ, et al. 2002 The
laparoscopic adjustable gastric band (Lap-Band):
a prospective study of medium-term effects on
weight, health and quality of life. Obes Surg 12(5)
652-660.
O’Grady MJ, Retterath AJ, Keenan DB, Kurtz N,147. Cantwell M, Spital G, Kremliovsky MN, Roy A,
Davis EA, Jones TW, et al. 2012 The use of an
automated, portable, glucose control system for
overnight glucose control in adolescents and
young adults with type 1 diabetes. Diabetes Care
35(11) 2182-2187.
Olmsted JMD 1953 Claude Bernard, 1813-79.148. Diabetes 2 162-164.
Oria HE 1999 Gastric banding for morbid obesity.149. Eur J Gastroenterol Hepatol 11 105-114.
Papaspyros NS 1952 The history of diabetes150. mellitus. P.16. London: United Kingdom.
Papaspyros NS 1964 The history of diabetes. In151. G. T. Verlag (Ed.), The history of diabetes
mellitus. (pp. 4-5). Stuttgart, Germany: Thieme.
Patlak M 2002 New weapons to combat as152. ancient disease: treating diseases. FASEB J 16
(14) 1853.
Paulesco NC 1921 Recherches sur le role du153. pancreas dans I’assimilation nutritive. Arch Int
Physiol 17 85-109.
Pavy FW 1869 Researches on the nature and154. treatment of diabetes. 2nd ed., London, Churchill.
Pearson ER 2008 Recent advances in the155. genetics of diabetes. Primary Care Diab 2 67-72.
Pickup JC 2012 Insulin-pump therapy for type 1156. diabetes mellitus. N Engl J Med 366 1616-1624
Podnos YD, Jimenez JC, Wilson SE, Stevens M157. & Nguyen NT 2003 Complications after
laparoscopic gastric bypass. Arch Surg 138
957-961.
Ponce J, Haynes B, Paynter S, Fromm R,158. Lindsey B, Shafer A, Manahan E & Sutterfield C
2004 Effect of Lap-Band-induced weight loss on
type 2 diabetes mellitus and hypertension. Obes
Surg 14 1335-1342.
Prout W 1834 Chemistry, meterology and the159. function of digestion considered with reference to
natural theology, p. 100. London.
Prout W1848 On the nature and treatment of160. stomach and renal diseases. 5th ed., London,
Churchill.
Pybus PC & Durh MS 1924 Suprarenal and161. pancreatic grafting. Lancet 2 550-551.
Quastel JH & Wheatley AHM 1931The action of162. dyestuffs on enzymes: dyestuffs and oxidations.
Biochem J 25 629-638
Rabhar S 1968 An abnormal haemoglobin in red163. cells of diabetes. Clin Chem Acta 22 296-298.
Rahier J, Guiot Y, Goebbels RM, Sempoux C &164.
Henquin JC 2008 Pancreatic β-cell mass in
European subjects with type 2 diabetes. Diab
Obesity Metab 10(Suppl 4) 32-42.
Reaven GM 1988 Banting lecture 1988. Role of165. insulin resistance in human disease. Diabetes 37
1595-607.
Reaven GM 2005 The metabolic syndrome:166. requiescat in pace. Clin Chem 51 931-938.
Recklinghausen F 1890 Ueber Akromegalie.167. Virch Arch XV 42 119.
Robin ED 1979 Claude Bernard: pioneer of168. regulatory biology. JAMA 242 1283-1284.
Rollo J 1797 Account of two cases of diabetes169. mellitus with remarks as they arose during the
progress of the care. London, C. Dilly.
Rollo J 1798 Cases of the diabetes mellitus. 2nd
170. ed. London, C. Dilly.
Rosenfeld L 2002 Insulin: discovery and171. controversy. Clin Chem 48(12) 2270-2288.
Rothera ACH 1908 Note on the sodium172. nitroprusside reaction for acetone. J Physiol 37
491-494.
Sakula A 1988 Paul Langerhans-1847-1888: a173. centenary tribute. J R Soc Med 81 414-415.
Samols E, Marri G & Marks V1965 Promotion of174. insulin secretion by glucagon. Lancet 1 415-416.
Sandbaek A, Griffin SJ, Rutten G, Davies M,175. Stolk R, Khunti K, Borch-Johnsen K, Wareham
NJ & Lauritzen T 2008 Stepwise screening for
diabetes identifies people with high but
modifiable coronary heart disease risk. The
ADDITION study. Diabetologia 51(7) 1127-1134.
Sanger F 1945 The free amino groups of insulin.176. Biochem J 39 507-515.
Sanger F 1958 Nobel lecture: The chemistry of177. insulin, Nobelprize.org.
Sanger F 1960 Chemistry of insulin. Br Med Bull178. 16 183-188.
Sanghvi C, McLauchlan R, Delgado C, Young L,179. Charles SJ, Marcellino G & Stanga PE 2008
Initial experience with the Pascal
photocoagulator: a pilot study of 75 procedures.
Br J Ophthalmol 92 1061-1064.
Savona-Ventura C 2002 The history of diabetes180. mellitus: A Maltese perspective. Available at
http://staff.um.edu.mt/csav1/books/diabetes_hist.
pdf
Schafer E 1914 An introduction to the study of181. the endocrine glands and internal secretions. pp.
84-86. Palo Alto, California: Stanford University,
Schafer EA 1916 An introduction to the study of182. internal secretion. In: The Endocrine Organs.
London: Longmans, Green & Company.
Scheidegger U, Allemann S, Scheidegger K &183. Diem P 2007 Continuous subcutaneous insulin
infusion therapy: effects on quality of life. Swiss
Med Weekly 137 476-482
Schlich T 2010 Volume 18 of Rochester Studies184. in Medical History: The Origins of Organ
Transplantation: Surgery and Laboratory Science,
1880-1930, p.74. University Rochester Press.
ISBN 1-58046-353-3.
Scopinaro N, Gianetta E, Adami GF, Friedman D,185. Traverso E, Marinari GM, Cuneo, S, Cuneo S,
Vitale B, Ballari F, Colombini M, et al.1996
WebmedCentral > Review articles Page 20 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
Biliopancreatic diversion for obesity at eighteen
years. Surgery 119(3) 261-268.
Scott RS & Brown LJ 1991 Prevalence and186. incidence of insulin-treated diabetes mellitus in
adults in Canterbury, New Zealand. Diabetic Med
8(5) 443-447
Selvin E, Marinopoulos S, Berkenblit G, Rami T,187. Brancati FL, Powe NR & Golden SH 2004
Meta-analysis: glycosylated hemoglobin and
cardiovascular disease in diabetes mellitus. Ann
Int Med 141(6) 421-431.
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H,188. Lindblad R, Robertson RP, Secchi A, Brendel
MD, Berney T, Brennan DC, et al. 2006
International trial of the Edmonton protocol for
islet transplantation. N Engl J Med 355
1318-1330.
Sina AA 2004 Qanun (translated into Persian by189. Sharafkandi, A. R.). Tehran: Soroush. Book III,
175-180.
Sina I1593 Al-Qanun fi al tibb. Rome190. Typographia Mediciea 1 543-544.
Skyler JS, Bergenstal R, Bonow RO, Buse J,191. Deedwania P, Gale EAM, Howard BV, Kirkman
MS, Kosiborod M, Reaven P, et al. 2009
Intensive glycaemic control and the prevention of
cardiovascular events: Implications of the
ACCORD, ADVANCE and VA Diabetes Trials. A
position statement of the American Diabetes
Association and a scientific statement of the
American College of Cardiology Foundation and
the American Heart Association. Diabetes Care
32 187-192
Southgate TM 1999 De Medicina. JAMA 10 921.192. Steiner DF & Oyer PC1967 The biosynthesis of193. insulin by a human and a probable precursor of
insulin by a human islet cell adenoma. Proc Natl
Acad Sci USA 57 473-480.
Sugerman HJ, Starkey JV & Birkenhauer R 1987194. A randomized prospective trial of gastric bypass
versus vertical banded gastroplasty for morbid
obesity and their effects on sweets versus
non-sweets eaters. Ann Surg 205 613-24.
Sulek K 1967 Nobel prize for August Krogh in195. 1920 for his discovery of regulative mechanism
in the capillaries. Wiadomosci lekarskie (Warsaw,
Poland: 1960) 20(19) 1829.
Sutherland DER, Steffes MW, Mauer SM &196. Najarian JS 1974 Reversal of secondary lesions
of diabetes in rats by pancreatic islet
transplantation. Surgical Forum 25 309-311.
Sutherland EW 1972 Studies on the mechanism197. of hormone action. Science 177 401-408.
Tattersall RB 2010 The history of Diabetes198. Mellitus. In R. Holt, C. Cockram, A. Flyvbjerg & R.
Goldstein (Ed.), Textbook of Diabetes (4th ed.).
Blackwell Publishing
Teuscher A 1979 The biological effect of purely199. synthetic human insulin in patients with diabetes
mellitus. Schweiz Med Wochenschr 109 743-747.
Tripathy BB 2012 Landmarks in the history of200. diabetes. In RSSDI Textbook of Diabetes
Mellitus, Edited by Chandalia HB, Das AK, Rao
PV, Madhu SV & Mohan V. 2nd ed. Vol. 1 & 2.
Jaypee Broters Medical Publisher (P) Ltd. India.
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ,201.
Knowles W & MacKay IR 1993 Antibodies to
glutamic acid decarboxylase reveal latent
autoimmune diabetes mellitus in adults with a
non-insulin-dependent onset of disease.
Diabetes 42(2) 359-362.
Turner R 1998 Intensive blood glucose control202. with sulphonylurea or insulin compared with
sulphonylureas or insulin compared with
conventional treatment and risk of complications
in patients with type 2 diabetes (UKPDS: 33).
Lancet 352(9131) 837-853.
Turner R, Holman R, Stratton I, Call C, Frighi V,203. Manley S, Matthews D, Neil A, McElroy H,
Kohner E, et al. 1998 Tight blood pressure
control and risk of macrovascular and
microvascular complication in type 2 diabetes:
United Kingdom Prospective Diabetes Study
(UKPDS: 38). BMJ 317 703-713.
Tzakis AG, Ricordi C, Alejandro R, Zeng Y, Fung204. JJ, Todo S, Demetris AJ, Mintz DH & Starzl TE
1990 Pancreatic islet transplantation after upper
abdominal exenteration and liver replacement.
Lancet 336(8712) 402-405.
Ulrich A, Shine J, Pictet R, Tischer E, Rutter WJ205. & Goodman HM 1977 Rat insulin genes:
construction of plasmids containing coding
sequences. Science 196 1313-1319.
United Kingdom Prospective Diabetes Study206. Group 1998a Efficacy of atenolol and captopril in
reducing risk of both macrovascular and
microvascular complications in type 2 diabetes
(UKPDS: 39). BMJ 317(7160) 713-720.
United Kingdom Prospective Diabetes Study207. Group 1998b Effect of intensive blood glucose
control with metformin on complication in
overweight patients with type 2 diabetes (UKPDS:
34). Lancet 352(9131) 854-865.
von Mering J & Minkowski O 1890 Diabetes208. mellitus nach pankreasexstirpation. Arch Exp
Path Pharmacol 26 371-387.
Watkins PJ (Ed.) 2008 Introduction. ABC of209. Diabetes (5th ed.). London, United Kingdom:
British Medical Journal Publishing.
Whiting DR, Gurriguata L, Weil C & Shaw J 2011210. IDF Diabetes Atlas: Global estimates of the
prevalence of diabetes for 2011 and 2030.
Diabetes Res Clin Pract 94(3) 311-321.
Wild S, Roglic G, Green A, Sicree R & King H211. 2004 Global prevalence of diabetes: estimates
for the year 2000 and projections for 2030.
Diabetes Care 27(5) 1047-1053
Willis T 1684 Pharmaceutice rationalis. London,212. Dring.
Wittgrove AC, Clark GW & Tremblay LJ 1994213. Laparoscopic gastric bypass, Roux-en-Y:
preliminary report of five cases. Obes Surg 4(4)
353-357.
World Health Organisation 1964 Expert214. Committee on Diabetes Mellitus. First Report:
Technical Report Series 310. Geneva: World
Health Organisation
World Health Organisation 1999 Report of the215. WHO Consultation. Definition, diagnosis and
classification of diabetes mellitus and its
complication 1. Diagnosis and classification of
diabetes mellitus. WHO/NCD/NCS/11.2. Geneva:
WebmedCentral > Review articles Page 21 of 26

WMC004831 Downloaded from http://www.webmedcentral.com on 17-Feb-2015, 10:12:40 AM
World Health Organisation.
World Health Organisation 2006 Definition and216. diagnosis of diabetes mellitus and intermediate
hyperglycaemia. Report of the WHO/IDF
Consultation. Geneva: World Health
Organisation.
World Health Organisation 2011a International217. Statistical Classification of Diseases and Related
Health Problems, 10th Revision; edition 2010.
Volume 2 Instruction Manual, 3V.
World Health Organisation 2011b Use of218. glycated haemoglobin (HbA1C) in the diagnosis
of Diabetes Mellitus. Report of a WHO
Consultation. Geneva: World Health
Organisation.
World Health Organization 1980 Second report219. of the WHO expert committee on diabetes
mellitus. Technical report series no. 646. Geneva,
Switzerland.
Yalow RS & Berson SA 1959 Assay of plasma220. insulin in human subjects by immunological
methods. Nature 184(Suppl 21) 1648-1649.
Yalow RS & Berson SA 1961 Immunoassay of221. plasma insulin in man. J Clin Invest 39
1157-1175.
Zajac J, Shrestha A, Patel P & Poretsky L 2010222. The main events in the history of diabetes
mellitus. In L. Poretsky (Ed.), Principles of
diabetes mellitus. Springer Publishing.
Zuelzer GL 1908 Uber versuche einer223. specifischen fermentherapie des diabetes.
Zeitshrift Fur Experimentalsische Pathologie und
therapie 5 307-318.
Zuelzer GL 1982 Cited by Michael Bliss. The224. discovery of insulin. University of Chicago Press.
Willis T 1684 Pharmaceutice rationalis: or, an225. excercitation of the operations of medicines in
humane bodies, in his practice of physick,
London, During, 1684; sect 3: chapt.3.
Farmer L 1952 Notes on the history of Diabetes226. Mellitus. Bull NY Acad Med 28 408-416.
Mann RJ 1971 Historical vignette: Honey urine to227. pancreatic Di-abetes, 600BC-1922AD. Mayo
Clinic Proceedings 46 56-58.
Withington ET 1894 Medical History from the228. Earliest Times: A Popular History of the Healing
Art. Scientific Press. p. 130.
Nutton V 1984 From Galen to Alexander:229. Aspects of Medicine and Medical Practice in Late
Antiquity. Dumbarton Oaks Papers 38(2) 1-14.
Schadewaldt H 1977 Paracelsus and diabetes230. mellitus. Medizinische Klinik 72(19) 875-878.
Paulesco NC 1921 Recherche sur le role du231. pancreas dans l’assimilation nutritive. Arch
Internationales de Physiologie, Tome XVII.
Kleiner IS 1919 The action of intravenous232. injections of pancreas emulsions in experimental
diabetes. J Biological Chem 40 153-170.
Kleiner IS & Meltzer SJ 1915 Retention in the233. circulation of dextrose in normal and
depancreatized animals and the effect of an
intravenous injection of an emulsion of pancreas
upon this retention. Proc Nat Aca Sciences 1(6)
388-341.
Banting FG & Best CH 1922 The Internal234.
Secretion of the Pancreas. J Lab Clin Med 7 251.
Banting FG, Best CH, Collip JB & Macleod JJR235. 1922 Preliminary studies on the physiological
effects of insulin. Trans Royal Soc Canada 4 1.
Homans J 1913 Partial pancreatectomy and236. insulin concentration. Proc Roy Soc B 85 73.
Ssobolew LW 1902 Zur normalen und237. pathologischen Morphologie der inneren
Secretion der Bauchspeicheldrüse. Archiv für
pathologische und anatomie und physiologie und
für klinische medizin 168 91-128
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Illustrations
Illustration 1
Table 1 Short summary of important advancements in diabetes research
Illustration 2
Table 2 Classification of disorders of glycaemia based on aetiology
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Illustration 3
Table 3 Specific conditions associated with T2DM
Illustration 4
Table 4 Other specific conditions associated with T2DM
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