Journal of The Association of Physicians of India Vol.

63 October 2015 51

review article

Pancreas and Diabetes Mellitus: The Relationship

between the Organ and the Disease
Saumya Menon, Gopalakrishna Rajesh, Vallath Balakrishnan

was mention of the organ in the

Abstract Anathoma of Mondino de Luzzi
Diabetes mellitus has been a fascinating disease from the dawn of medical published in 1487 in Padua, Italy.
history. The first breakthrough in its treatment came in 1922, with the When Greek civilization gave
discovery of insulin which was extracted from the pancreas of a dog. way to the Romans, many Greek
Even earlier, a relationship between pancreas and diabetes mellitus had physicians flocked to the capital of
been suspected by medical scientists. However, the study of diabetes the New Empire. Galen, physician
mellitus is much more than its relationship with the pancreas. On the of the gladiators and to the Roman
other hand the pancreas has been known to be a very reclusive organ Emperor, was notable among them.
Once a year, he and his students
that is hidden away from physicians and surgeons for centuries. In recent
cut open a dead pig to study
times, it has become more accessible and has yielded some of its secrets.
its anatomy. Galen viewed the
The relationship between the pancreas and diabetes mellitus is a story
pancreas as a cushion overlying
full of complexities and surprises. This article attempts to reveal some
and protecting the large vessels
of the important events and persons in the story and the controversies
behind it. Because of his formidable
surrounding them. reputation as a medical authority,
his views, many of them disproved
later, were to hold sway for the
Introduction the complex relationship between next several centuries and blocked
this little organ and a disease that independent scientific thinking and

T he pancreas, hidden in
a posterior recess of the
abdominal cavity, with its relative
is today overwhelming mankind.

Anatomy
pursuits till nearly the 18 th century.
Andreas Vesalius, who in 1531,
at the age of seventeen, left his
inaccessibility, rightly fits into home in Brussels to study medicine
The earliest recognition of the
the description of a riddle in Paris provided a more realistic
pancreas is believed to be by the
wrapped in an enigma having description of the pancreas. Sylvius
Greeks. The first description of
s h yl y e va d e d t h e a t t e n t i o n o f a disciple of Galen was his teacher.
the organ has been attributed to
meddling anatomists and surgeons Vesalius wished to dissect the
Herophilus of Chalcedon, born in
for several centuries. From its human body, but would have been
336 BC on the Asiatic side of the
secretive nature it could very well burned or hanged if he did. While
Bosporus. 1 He has been considered
be a Scorpio! This mysterious organ working in Padua, he completed
Father of anatomy who practiced
has been having a long-standing his medical masterpiece-De
dissection, even on living criminals,
affair with diabetes mellitus, part humani corporis fabrica - Fabric of
in Alexandria in ancient Egypt.
of which has been revealed to us the Human Body, divided into
Rufus of Ephesus (1 st or 2 nd century
now. On the other hand, the story seven volumes. 2 Vesalius in his
AD), the Greek physician and
of diabetes mellitus is one of the illustration of the pancreas, seemed
anatomist gave the name pancreas
most fascinating chapters in the to be more impressed with the
to the organ (pan=all; creas=flesh,
history of medicine. One of the vessels running through the gland
derived from the Greek) since
major events in its history was the since he had cut away most of the
there was no bone or cartilage in
way its relationship to pancreas gland to expose the vessels. He
it and its uniform consistency. 2
was brought out in 1922, by Banting thought that the gland afforded a
In the thirteenth century there
and Best, a story in itself with the protective cushion for the stomach.
punch of a cloak and dagger
mystery. In this article we attempt
Department of Gastroenterology, Amrita Institute of Medical Sciences, Kochi, Kerala
to capture some of the exciting
Received: 15.04.2014; Revised: 10.06.2014; Accepted: 15.07.2014
people and events of the story of
52 Journal of The Association of Physicians of India Vol. 63 October 2015
Vesalius was assisted in his work
by his student Gabriele Fallopio
(1523-1562). Even though the term
pancreas is not mentioned by
Vesalius in his book, the English
translation mentions the synonym
sweetbread. 2
Johann George Wirsung, a
German migr, living in Padua,
described in 1642, the structure
of the main duct of the pancreas.
He wondered whether it was an
artery or a vein. A colleague gave
his name to the duct. It seems
he got the idea from his student
Hoffman who had noticed such
a duct in the rooster. The first
known picture of pancreas was
produced by the Roman anatomist
Bartolomeo Eustachio (1520-1574).
He showed the posterior aspect of
dogs pancreas with duodenum
and the common bile duct. The
discovery of the pancreatic duct
established the role of pancreas
as a secretory gland nullifying
the previous theories such as
cushion of stomach and a pad
supporting vessels. His pictures
were published 140 years after
his death by Lancisi. The credit
for the discovery of the accessory
pancreatic duct is usually given
to Giovanni Domenico Santorini
(1681-1737). However, there were
at least 8 observations of the minor
duct prior to Santorini. Santorini
wished to publish a book on his
findings of the minor pancreatic
duct. However he died before his
work could be published. Michele
Girardi, 38 yrs after Santorinis
death, published the drawings
under the title Jo. Dominci Santorini
anatomici summi septemdicum
tabulae which means- Giovanni
Domenico Santorini, the excellent
anatomists seventeen drawings.
D.Moyse, (1852) a French student
was the first to pictorially depict
the microscopic structure of the
pancreatic acini in a dissertation
he submitted. 3
Physiology
The famous Dutch physician
Franciscus de Le Boe (Sylvius) did
several experiments on digestion
and on the role of pancreatic juice
and bile in the digestive process.
Many of his hypotheses were later
questioned by John Conrad Brunner
who believed that the duodenal
glands secreted the main digestive
juice, and is the first recorded
person to resect a pancreas. His
experiments were published in a
book entitled Experimenta nova circa
pancreas [New experiments on the
pancreas]. Regnier de Graaf (1641-
1673) was a student of Sylvius who
assisted Sylvius in his studies of
the digestive process. De Graaf
investigated the pancreatic juice of
a dog by collecting it though a quill
inserted into the pancreatic duct.
He tasted the pancreatic juice and
observed that the juice was insipid
and of an acid-salt (acidic) type. He
collected the pancreatic juice from a
dead sailor later, and noticed it was
similar to that of the dog.
Leopold Gmelin and Friedrich
Tiedemann discovered in 1826, that
the pancreatic juice was alkaline
and not acidic like gastric juice
and that it contained proteins. It
was the classic work of Claude
Bernard (1813-1878), the great
French physiologist that brought
out the dominant role of the
pancreatic juice in digestion. He
clearly demonstrated that gastric
digestion was only a preparation,
and that further breaking up of
starch and proteins took place
by the effect of the pancreatic
juice. Bernards complete studies
including the anatomic studies,
comparative anatomy and
physiology, and his experiments
with the pancreatectomized dogs
were published in 1856. 4
It was the celebrated Russian
p h y s i o l o g i s t , I va n Pe t r o v i c h
Pavlov from St. Petersburg, who
through his studies of pancreatic
fistulae in dogs, demonstrated
the vagal control of pancreatic
secretion. Pavlovs group found
that introduction of acids into the
duodenum stimulated pancreatic
juice secretion and also described
enterokinase that activated
pancreatic juice. Pavlovs book,
The Work of the Digestive Glands
comprising his lectures at the
Imperial Institute for Experimental
Medicine in St. Petersburg was first
published in 1897 and remains a
classic work in physiology. 5 His
work on conditioned reflexes
earned him outstanding acclaim and
reputation. Pavlov was awarded
the Nobel Prize in Physiology or
Medicine in the year 1904.
Bayliss along with Starling, who
was his brother-in-law, working
in University College, London,
discovered a chemical substance
released from the proximal small
intestine in response to acid
which stimulated secretion from
the pancreas. They named this
substance secretin and suggested
the term hormone, from the Greek
word meaning I set in motion.
Secretin was the first hormone
to be discovered and Bayliss
and Starlings epoch-making
paper appeared in the Journal of
Physiology in 1902. 6 The second
hormone to be released from the
duodenum and the intestinal
m u c o s a wa s c h o l e c y s t o k i n i n ,
discovered years later in 1928-29 by
Ivy and Oldberg which stimulated
the contraction of gall bladder and
also increased pancreatic protein
secretion. In the year 1928, Ivy
and Oldberg had demonstrated
a hormone with the action of
contracting the gallbladder and
relaxing the sphincter of Oddi. 7,8
This was labeled cholecystokinin
(CCK) in 1943. Harper and Raper
discovered pancreozymin, a
hormone that influenced pancreatic
enzymatic secretion. 9 A few years
later, Jorpes and Mutt proved that
cholecystokinin and pancreozymin
were the same substance, which is
now known as cholecystokinin. 10
Diabetes Mellitus
The term diabetes is derived
from Latin and ancient Greek and
literally means a passer through;
a siphon. The term diabetes,
meaning running through a siphon
is based on traditional belief that

in this disease all fluids consumed
rapidly run through the body to
be passed in urine, thus causing
polyuria. The word mellitus comes
from Latin and means honey-
sweet. It was Thomas Wills in 1675
who added the word mellitus to
diabetes as the urine of diabetic
patients had a sweet taste. This
s we e t t a s t e h a d h o we ve r b e e n
previously commented upon by
ancient Greeks and Indians.
In 1552 BCE, the Egyptian
physician Hesy-Ra of the 3rd
Dynasty makes the first known
mention of diabetes found on the
Ebers Papyrus and lists remedies
to combat the passing of too much
urine. Demetrius of Apamaia, a
Hellenistic physiologist of the
Herophilian school, seems to have
used the name diabetes towards
the beginning of the Common Era.
Aretaeus of Cappadocia (81-138
CE), a Greek physician, follower
of Hippocrates, who practiced
in Rome and Alexandria, gave a
detailed description of the disease
which went by the name diabetes. 11
Aretaeus believed the cause of
diabetes lies in the stomach, Galen
implicated the kidneys and Claude
Bernard, the celebrated French
physiologist, in the middle of the
19 th century, favored the liver.
Johann Conrad Brunner (1653-
1727), who studied medicine in
the University of Strasburg, in his
studies observed that dogs could
survive partial pancreatectomies.
Brunner also found that the dogs
suffered from polyuria, polydypsia,
polyphagia and bulimia but did not
associate it with diabetes. This had
to wait another 200 years for Oskar
Minkowski and Joseph von Mehring
to describe it. It took a few more
years before the pancreas - diabetes
connection was established. In
1674, Thomas Willis, a physician,
anatomist and professor of natural
philosophy at Oxford, discovered,
by tasting, that the urine of diabetic
p e r s o n s wa s s we e t . H o we ve r ,
Charaka and Susruta of India had
predated him by nearly fifteen
centuries when they described
Journal of The Association of Physicians of India Vol. 63 October 2015
Madhu Meha (diabetes) in
their Samhitas (Treatises). 12 The
Susruta Samhita deals with diabetes,
an d it s sy mpt oms in det ail. It
elaborates on the symptoms such
as overabundance and sweetness
of urine, weight loss, impotence
and ulcers. It also differentiates
b e t we e n t h e e a r l y on se t t h i n
diabetes and later-onset fat
diabetes, thus being forerunners
to type 1 and type 2 diabetes. 13,14 In
1776, Mathew Dobson of England
showed that diabetics excrete sugar
in their urine. Cawley reported in
1788 the observation of a shrunken
pancreas in a diabetic at autopsy,
p erhaps t he first aut opsy in a
diabetic. 15 Eteienne Lancrereaux (in
1877) was the first to recognize that
diabetes mellitus was definitely
related to pancreas. Before insulin
wa s d i s c o ve r e d , t r e a t m e n t f o r
diabetes consisted of a diet low
in carbohydrates and by feeding
fresh veal pancreas by mouth.
John Rollo, Surgeon-General to the
Royal Artillery treated a patient by
dietary restriction in 1806.
In 1899, Joseph von Mehring and
Oscar Minokowski of Strasbourg,
demonstrated that extirpation of
the pancreas of the dog caused
diabetes. The two were arguing
whether dogs would survive
pancreatectomy, when their chief
Naunyn suggested that they
better try out the experiment and
verify it. After the experiments,
a laboratory attendant noticed
t h e p r e s e n c e o f f l i e s o ve r t h e
urine of the depancreatectomized
dogs, but not over the urine of
the control dogs. Following this
tip, Minkowski found out that the
urine of the depancreatectomized
dogs contained sugar. It was the
first practical demonstration that
pancreatectomy in dog caused
diabetes.
Paul Langerhans (1849-1888),
a medical student working in
Rudolf Virchovs institute in Berlin,
presented a thesis on clear cell
clusters (Zellhaufen) in the gland
in 1869, describing the structure
of the pancreatic islands. In the
53
forward to his doctoral thesis,
which was entitled Contributions
to the microscopic anatomy of the
pancreas, Paul Langerhans wrote:
the purpose of these lines can be
at best to help in drawing greater
attention to the pancreas than has so
far been paid by anatomists. There
was no follow-up to Langerhans
work during the next few decades,
so that Naunyn stated: Nothing is
more boring than the autopsy of a
diabetic- except the autopsy of two
diabetics (Schadewaldt, 1975). It
was not until 1893 that Laguesse,
a French worker, suggested,
probably under the influence of
the epochal work of Mehring and
Minkowski, that the assumed
internal secretory function of the
pancreas may be ascribed to the
islets of Langerhans. In the
year 1893, Laguesse described the
granules of the islet cells of the
pancreas. Eugene Opie (1901), a US
pathologist proposed the common
channel theory and the role of
bile reflux in the causation of acute
pancreatitis. He also described
consistent hyaline changes in the
islets of Langerhans in diabetic
patients, the first evidence of islet
cell damage in diabetes. 16 About the
same time as Opies observation on
the islets, Ssobolew and Schulze
independently demonstrated that
following ligation of the pancreatic
duct, the gland atrophies, but the
islets are spared and diabetes did
not develop. Moses Barron (1883-
1974) in a paper The Relation of
the Islet of Langerhans to Diabetes
with special Reference to Cases
o f Pa n c r e a t i c L i t h i a s i s m a d e
the landmark observation that
in pancreatic disease without
islet involvement, there was no
diabetes. 17
S i r E d wa r d A l b e r t S h a r p e y -
Schafer (1850-1935) theorized that
diabetes resulted from deficiency
of a single substance produced by
the pancreas. He, in the year 1910,
dubbed the chemical produced by
the pancreas insulin. The great
break-through came in diabetes
with the discovery of insulin in
54 Journal of The Association of Physicians of India Vol. 63 October 2015
1921. Frederick Grant Banting
studied in Toronto for his MB and
during the war became a private in
the army and won a Military Cross
for gallantry in action in 1918.
Afterwards he tried to establish
a practice while lecturing part
time. It was while working as
a lecturer in pharmacology in
Toronto University that he got
interested in diabetes after reading
a paper on the pancreas in diabetes.
He approached John James
Rickard Macleod, the professor
of physiology at the University
of Toronto, a leading diabetes
researcher, for facilities to work on
diabetes. Macleod provided him
with a few dogs and basic facilities.
Charles H Best a medical student
was assigned to assist him. When
Macleod was on leave, Banting and
Best prepared isletin, an extract
prepared from the pancreas of a
dog whose duct had been ligated
earlier. The extract was injected
into another depancreatectomized
diabetic dog in a moribund
condition and in diabetic coma.
Following the injection, the dog
dramatically recovered. By now
Macleod had returned from leave
and he too got excited by the results
and provided the young workers
better facilities. The new substance
was purified and standardized by
J.B.Collip, a biochemist who had
joined their team. The pure extract
was labeled insulin. A 14 year-
old boy, Leonard Thompson, dying
of diabetes was saved by giving an
injection of the newly discovered
hormone. 18 In 1923, the Nobel Prize
in Medicine was jointly awarded to
Banting and Macleod. Banting was
furious that Best was left out; he
shared his prize money with Best.
Macleod shared his part of the prize
money with Collip. This award and
subsequent comments by the key
players led to a bitter controversy
about who really deserved the
credit for the discovery of insulin
and have been the substance
o f s e ve r a l c o n f l i c t i n g a r t i c l e s .
Banting died in 1941 in a plane
crash in Newfoundland. Best later
succeeded Macleod as Professor
of Physiology in the University
of Toronto and died in 1978 after
a long and a productive scientific
c a r e e r . 19 S i n c e 2 0 0 7 , B a n t i n g s
birthday (14 th November ) has been
observed as World Diabetes Day.
There was great excitement and
tremendous demand for the new
drug. The researchers gave the
patent rights to the University of
Toronto and refused financial gain.
The university laboratory could
not cope up with the demand.
Commercial production of insulin
on a large scale started and was
soon made available in the market.
There was further controversy
s u r r o u n d i n g t h e d i s c o ve r y o f
insulin by Banting and Best. In
1916, Nicolae Paulescu, a Romanian
scientist had developed an
aqueous pancreatic extract which
normalized the blood sugar level
in a diabetic dog. His experiments
were interrupted by the event
of the World War I. However,
in 1921 he published a research
paper Research on the Role of the
Pancreas in Food Assimilation. 20
His discovery was even patented
on April 10, 1922 by the Romanian
Ministry of Industry and Trade.
Thus Paulescus work preceded that
of Banting and Best. Despite this
fact, sufficient acknowledgement
was not recorded by the Toronto
group to Paulescus work in any of
their writings. 21
Frederick Sanger of England
received the Nobel Prize in
chemistry (1958) for his discovery
of the complete sequence of the
two polypeptide chains of the
insulin molecule. Sanger later
developed the dideoxy method
for sequencing DNA, also known
as the Sanger method, for which
he was awarded a second Nobel
Prize in chemistry in 1980. Radio-
immuno assay of plasma insulin
was reported by Solomon Berson
and R.A. Yallow in 1977. 22
In the 1923, Kimball and Murlin
studied pancreatic extracts and
found an additional substance
with hyperglycemic properties.
This substance was identified as
glucagon. The amino acid sequence
o f g l u c a g o n wa s d e s c r i b e d b y
Bromer et al in 1957. A more
complete understanding of its role
in physiology and disease was not
forthcoming until the 1970s, when a
radioimmunoassay was developed.
Type 1 diabetes was
distinguished from type 2 diabetes
by Sir Harold Percival Himsworth
in an article in Lancet in 1936. 23 He
was the Professor of Medicine in
London University and delivered
the Goulstonian Lecture at the
Royal College of Physicians on
Mechanisms of Diabetes Mellitus
in 1936.
Diabetes in Pancreatitis
Harley in 1862, reported a case
of acute pancreatitis exhibiting
glycosuria; and Atkinson in 1895,
and Korte, in 1911, described
several similar cases. Fitz,
curiously enough, made no
mention of diabetes in his original
contributions to the literature of
acute pancreatitis, but Shumacker,
in 1940, estimated that 11 per cent
of patients with acute pancreatitis
had glycosuria during some phase
of the acute attack.
De Graaf in the second edition
of his book 24 in 1668 described
p a n c r e a t i c c a l c u l i w h i c h wa s
probably the first pathological
description of chronic pancreatitis.
The first association of diabetes
with pancreatic calcification was
d e s c r i b e d b y T h o m a s C a wl e y
in 1788 after observations at the
postmortem of a very obese man.
However, he considered kidneys
to be the cause for this disease.
The significance of the association
between the disease and the organ
was reported by Richard Bright in
a patient having pancreatic cancer
and diabetes. Arnaldo Cantani
observed that fatty changes and
shrinking was more common in the
pancreas of a diabetic than non-
diabetics. Diabetes due to chronic
pancreatitis is characterized by the

low incidence of ketosis and the
high incidence of insulin-induced
hypoglycemia. 25
Insulins
The last 90 years have witnessed
tremendous progress in insulin
therapy, from the initial crude, yet
life-saving, animal insulin extracts
to novel human insulin analogues.26
In 1922, bovine insulin was first
given to humans. For more than
six decades, insulin from different
animal sources was used, until the
breakthrough in biotechnology
made it possible to produce human
insulin in sufficient amounts. The
first insulin was a quick and short
acting soluble or regular insulin.
In 1936, protamine was used to
develop slow-release insulin. The
effect of protamine zinc insulin
(PZI) lasted for 24-36 hours. In 1950
isophane NPH (neutral protamine
Hagedorn) insulin was developed
with maximal effect of 24 hours. In
1951 the amorphous lente insulins
(IZS) semilente, lente, and
ultra-lente were developed. The
following decades were to witness
the development of human insulins
and analogues. Recombinant
D N A h u m a n i n s u l i n wa s f i r s t
used in the 1980s. The advances
i n i n s u l i n d e l i ve r y s y s t e m s
syringes, pens, pumps, patches,
etc. over the years have also been
remarkable. Efforts are currently
focused towards developing non-
invasive insulin delivery systems,
and there are several competing
technologies in different stages of
development. Novel approaches to
mimic the endogenous release and
kinetics of insulin, and also many
i m p r o ve d a n a l o g u e s d e s i g n e d
t o a c h i e ve b e t t e r c o n t r o l a n d
effective treatment of diabetes are
anticipated.
Oral Anti-diabetic Drugs
The most widely used
antidiabetic drugs are insulin
secretagogues which stimulate beta
cells to release insulin. 27 Insulin
secretagogues can be divided into
Journal of The Association of Physicians of India Vol. 63 October 2015
two subclasses: sulfonylureas and
non-sulfonylureas. The first oral
hypoglycemic agent, sulfonylurea
was identified in 1942. These drugs
were found to stimulate insulin
secretion by residual beta cells in
type 2 diabetes. Sulphonylureas
have been used since the 1950s and
their efficacy is well-established.
However, they are being superseded
by newer agents. First-generation
sulfonylurea compounds became
w i d e l y a va i l a b l e i n 1 9 5 5 . T h e
second-generation sulfonylureas
were introduced in 1984.
Sulfonylureas that are currently
available are gliclazide, glimepiride,
glyburide, and the older agents:
chlorpropamide and tolbutamide.
The last two are now rarely used. In
1970, during the University Group
Diabetes Program, the largest and
longest diabetes research project at
the time it was found that patients
taking the oral diabetes medication
tolbutamide had a higher rate of
cardiovascular death than patients
on placebo or insulin. Non-
sulfonylureas are a relatively new
class of medications: repaglinide
is a benzoic acid derivative, and
nateglinide is a phenylalanine
d e r i va t i ve . T h e m e c h a n i s m o f
action of these drugs is similar
to that of the sulfonylureas but
they act at a different receptor.
The glinides have a faster onset
and shorter duration of action
than the sulphonylureas. They are
associated with a reduced risk of
hypoglycaemia, cause less weight
gain, and are metabolized and
excreted by the liver, and so can
be used in patients with impaired
renal function.
Some other agents besides
sulfonylureas (including
biguanides and alpha-glucosidase
inhibitors) have been available for
the treatment of type 2 diabetes
for a long t ime. Acarb ose and
miglitol are drugs in the class of
-glucosidase inhibitors which
lowers postprandial glucose levels.
In the 1950s various biguanides
(e.g., metformin, phenformin,
buformin) were used in different
55
countries for the treatment of
diabetes. All but metformin were
removed from the international
market in the 1970s because of
the associated high risk of lactic
acidosis. Metformin is the sole
agent in clinical use in this class.
Metformin improves insulin
sensitivity especially in skeletal
muscle, and is an ideal first-line
agent particularly in overweight
patients. Metformin may also
improve other cardiovascular risk
factors; and may have a role as a
novel anti-cancer drug.
Thiazolidinediones were
identified as an effective insulin
sensitizer in 1990s. While
metformin acts mainly on the
muscle and the hepatocyte,
TZDs act predominantly on the
adipocyte and the muscle. The
2 t hiazolidinediones curren t l y
available in are rosiglitazone and
pioglitazone. Troglitazone, an
e a r l i e r t h i a z o l i d i n e d i o n e wa s
removed from the world market
in 1997 because of an unacceptable
risk of fulminant hepatic failure.
Thiazolidinediones improve insulin
sensitivity, particularly in the
peripheral tissues. Scientists from
the Cleveland Clinic analyzed data
from more than 15,000 patients and
12,000 controls. They discovered
an increased risk of cardiovascular
e ve n t s a m o n g p a t i e n t s t a k i n g
rosiglitazone. Furthermore,
increased risk of cancer of urinary
bladder has been reported in
patients using pioglitazone. There
has been a decline in popularity of
TZDs and currently pioglitazone
is third-line of treatment in many
guidelines.
Incretins and DPP4 Inhibitors
After the discovery of secretin
by Bayliss and Starling, oral
administration of extracts of
intestinal mucosa failed to help
several patients with type 1 diabetes.
In 1932 La Barre proposed the name
incretin for a hormone extracted
from the upper gut mucosa, which
caused hypoglycemia and proposed
possible therapy for diabetes.
Incretins are gut-derived peptides
56 Journal of The Association of Physicians of India Vol. 63 October 2015
secreted in response to meals. The
two major incretins are glucagon-
like peptide (GLP-1), which is
produced by the neuroendocrine
L cells of the ileum and colon, and
glucose-dependent insulinotropic
peptide, which is produced by
the K cells of the duodenum and
jejunum. In 1970, JC Brown isolated
and sequenced GIP from intestinal
mucosa. Originally named
gastric inhibitory peptide, GIP
was renamed glucose-dependent
insulinotropic peptide in 1973 after
Brown and Dupre showed that
GIP stimulates insulin secretion.
(GLP)-1 is a gut hormone that
stimulates insulin secretion, gene
expression, and -cell growth.
Together with the related hormone
glucose-dependent insulinotropic
polypeptide (GIP), it is responsible
for the incretin effect, the
augmentation of insulin secretion
after oral as opposed to intravenous
administration of glucose. The
effects of endogenous incretins
are short-lived because of rapid
degradation and inactivation by
the enzyme dipeptidyl peptidase-
IV (DPP-4). Endogenous GLP-1
has a short half-life (<2 min). To
counteract this, agents that are
resistant to DPP-4 degradation
such as exenatide and liraglutide
have been developed. There
are two commercially available
GLP-1 agonistsexenatide and
liraglutide. Exenatide is derived
from the naturally occurring
peptide, exendin-4, which
was isolated from the salivary
secretions of the lizard Heloderma
suspectum (Gila monster ). This
lizard eats once a month and
the function of exendin-4 is to
rapidly increase the production
of insulin in response to nutrients
entering the gut. Liraglutide
provides greater improvements
in glycaemic control, induces
weight loss, improves obesity-
related risk factors, and reduces
pre-diabetes. Animal studies have
shown an increased occurrence
of thyroid medullary cancer with
high doses of liraglutide but the
clinical relevance is unclear. In
2007 a question was raised about
the causal relationship between the
first of the glucagon-like peptide 1
receptor agonists, exenatide, and
p ancreat it is, as post mark et ing
reports of pancreatitis in patients
treated with this agent had been
received by the Food and Drug
Administration (FDA). Early clinical
trials of liraglutide suggested an
increased incidence of pancreatitis.
A n o t h e r a p p r o a c h wa s t h e
development of Inhibitors of DPP-4
to prevent the inactivation of GLP-1
and prolong the activity of the
endogenously released hormone. In
contrast to GLP-1 receptor agonists,
these drugs are available orally and
have a longer duration of action,
requiring only once daily dosing.
T h e d r u g s c u r r e n t l y a va i l a b l e
are sitagliptin, saxagliptin, and
v i l d a g l i p t i n . T h e r e h a ve b e e n
reports of acute pancreatitis in
patients receiving sitagliptin.
Incretin therapy appears to
offer an effective alternative to the
currently available hypoglycaemic
agents. Continued evaluation and
further long-term studies will
confirm its safety and clinical role.
Recently sodium-glucose
transporter 2 (SGLT-2) inhibitors
like dapagliflozin and sergliflozin
have been developed to produce
glucosuria and reduce the plasma
glucose concentration. Inhibition
of the SGLT2 transporter is an
effective and novel strategy
to control the plasma glucose
concentration in T2DM subjects
These oral antidiabetic agents
h a ve t h e p o t e n t i a l t o i m p r o ve
glycemic control while avoiding
hypoglycemia, to correct the
glucotoxicity, and to promote
weight loss. Because these agents
have a distinct mechanism of action
t h a t i s i n d e p e n de n t o f i n su l i n
secretion or the presence of insulin
resistance, the efficacy of this
class of drugs is not anticipated
to decline with progressive -cell
failure or in the presence of severe
insulin resistance. Furthermore,
this class of drugs can be used
in combination with all other
antidiabetic medications with
anticipated additive efficacy on
g l y c e m i c c o n t r o l . T h e S G LT 2
inhibitors are also effective as
monotherapy in newly diagnosed
diabetic patients. Currently
available data indicate that the
S G LT 2 i n h i b i t o r s h a ve a g o o d
safety profile.
Other therapies in development
include glucagon receptor
antagonists, glucokinase activators
and sirtuins.
Bariatric Surgery
An exciting development has
been ever increasing popularity
of bariatric surgery procedures
initially started as treatment for
morbid obesity. Bariatric surgery
results in significant weight loss
and remission of diabetes in most
patients.28,29 After surgery, glycemic
control is restored by a combination
of enforced caloric restriction,
enhanced insulin sensitivity, and
increased insulin secretion. An
enhanced incretin effect was found
to contribute independently to
i m p r o ve d g l u c o s e l e ve l s a f t e r
bariatric surgery. Prospects of
reversal of diabetes and freedom
from hypoglycemic agents after
bariatric surgery are very bright for
obese patients with type 2 diabetes.
Pancreatic and Islet Cell
Transplantation
After the discovery that
pancreatectomy leads to diabetes,
Ssobolew had speculated that
transplantation of the pancreas can
be a treatment for human diabetes.30
In 1893, Hedon from France,
performed the autotransplant of a
free, nonvascularised fragment of
pancreas in a 10 kg dog. This dog
was induced to have diabetes after
doing a total pancreatectomy. This
lead to a reduction in glucosuria
as well as blood glucose levels.
The first successful pancreatic
transplant was done on December
17, 1966 at University of Minnesota
b y K e l l y e t a l . 31 T h e r e c i p i e n t
was a 28 year old lady, diabetic

since the age of 9 who developed
terminal renal failure. However,
the still functioning graft had to be
removed because of rejection and
sepsis, and she died shortly after.
Moskaleweski in 1965 showed
that islet cell could be separated
from the exocrine tissue by
collagenase in 1967 Lacy suggested
that for separation, mechanical
mincing of the pancreas was a much
better method. The Minneapolis
group 32 in 1977-78 did the first
islet cell transplant in ten patients.
Seven out of them required insulin
in lesser doses; however none of
them could do away with insulin
completely. In 1978 another new
approach was carried out by the
Minnesota group. They resected
around 96% of the pancreas of a
39 year old woman with chronic
pancreatitis. This tissue was then
minced, digested with collagenase,
islets separated and re-injected
into the spleen of the woman. She
showed significant improvement
during the follow up period of
s i x m o n t h s . 33 F r o m D e c e m b e r
16, 1966, through December 31,
2010, more than 37,000 pancreas
transplantations have been
reported to the International
Pa n c r e a s T r a n s p l a n t R e g i s t r y
(IPTR), including more than 25,000
from the US and more than 12,000
from outside the US.
Pancreatic islet transplantation
is a minimally invasive treatment
that has the potential to prevent
diabetes after total pancreatectomy
for chronic pancreatitis (islet
autotransplantation) and to reverse
diabetes in those with type 1
diabetes (islet allotransplantation).
While pancreas transplantation
is not considered experimental
anymore, there is often reluctance
to recommend this procedure to
patients because of its complexity
and risks, especially for solitary
pancreas transplants. However
i m p r o ve d s u r g i c a l t e c h n i q u e s
and newer immunosuppressive
regimens contributed significantly
to better graft survival. Exocrine
pancreas transplantation is a
Journal of The Association of Physicians of India Vol. 63 October 2015
treatment of choice for patients
with diabetes mellitus complicated
by end-stage renal disease.
Pa n c r e a s t r a n s p l a n t a t i o n s i n
diabetic patients may be divided
into 3 categories: those performed
simultaneously with a kidney
(SPK), those given after a previous
kidney transplantation (PAK), and
pancreas transplantation alone
(PTA). Recently, the performance
of pancreas transplant was shown
to be feasible laparoscopically
under robotic assistance using the
da Vinci Si high definition (SiHD)
surgical system.
Stem Cell in Pancreas
Since the discovery of embryonic
stem cells, several researchers
have been studying the possibility
that human embryonic stem cells
could be developed as a therapy
for treating diabetes. In 2000,
Spanish workers engineered
mouse embryonic stem cells to
allow selecting cells that were
differentiating into insulin-
producing cells. 34 Ron McKay (in
2001) and his colleagues described
a series of experiments in which
they induced mouse embryonic
cells to differentiate into insulin-
secreting structures that resembled
pancreatic islets. 35
The worlds first study on
cell therapy for type 1 diabetes
o n h u m a n s wa s p e r f o r m e d b y
a research team (2003) from the
Divisions of Immunology and
Endocrinology, University of Sao
Paulo, Brazil. 36 The Scientists at
University of Wisconsin isolated
stem cells from the inner cell mass of
human blastocysts and grew them
in culture for prolonged periods
of time. In 2006, a Chinese group
from the University of Naijing,
infused stem cells, 50% into the
peripheral vein and 50% directly
into the pancreas through arterial
catheterization. Five patients were
treated by following this protocol,
4 became insulin-independent (2
for short time) and one improved
requiring 50% decrease in the
insulin dose. 37 The scientists from
57
the University of North Carolina
at Chapel Hill School of Medicine
in 2008, transformed cells form
human skin into cells that produce
insulin. 38
Mario Capecchi and Eugenio
S a n g i o r g i 39 f r o m t h e C a t h o l i c
University of Rome in 2009
reported a method for marking and
isolating stem cells in the pancreas.
This involved use of a special
fluorescent protein, produced in
the pancreas under the stimulus
of a molecular switch, a piece of
DNA. Capecchi was the co-winner
of the Nobel Prize for Physiology
or Medicine, for his discovery
of a method for introducing
homologous recombination in
mice using embryonic stem cells
along with Martin Evans and Oliver
Smithies.
The modern era in diabetes
mellitus owes a lot to that grand
man of diabetes, Elliot P Joslin.
He, more than anybody else in
our times, has contributed to the
practice, teaching, education and
research on diabetes mellitus.
He maintained a database of all
the patients he began to see in
large books, which was the first
of its kind diabetes registry. He
compiled the first textbook on
diabetes, The Treatment of Diabetes
Mellitus. The International
Diabetes Federation (IDF) is one
of the biggest non-governmental
organizations involved in a
mission to promote diabetes care,
prevention and a cure worldwide
since 1950. The campaign for a
United Nations Resolution on
diabetes was a response to the
diabetes pandemic. The United
Nations passed Resolution 61/225
World Diabetes Day on December
20 th 2006. Since 2007, Bantings
birthday (14 th November ) has been
observed as World Diabetes Day.
The IDF brought out the blue circle
symbol as a global symbol for
diabetes in 2006.
58 Journal of The Association of Physicians of India Vol. 63 October 2015
Conclusion
The hide and seek relationship
between this small organ and an all
encompassing disease are the stuff
of mystery and suspense. Diabetes
is not all about the pancreas. The
metabolism of glucose and the
actions of insulin in the human
body are far more complex and are
still to be unfolded fully. Diabetes
leaves its foot prints on all the
tissues and organs of the body
that it touches. The future should
be pregnant with many more
surprises.
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