Insulin – structure, discovery and obtaining.

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Insulin is a hormone central regulating
carbohydrate and fat metabolism in the body.
Insulin causes liver cells, muscle cells and fat
tissue to take up glucose from the blood and
store it as glycogen in the liver and muscle.
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Insulin is producted by the pancreas, which
has two important functions :
1. Producing hormones – insulin and
glucagon which regulate blood sugar levels.
2. Producing pancreatic digestive enzymes.
Insulin is released when any of the several
stimuli are detected– stimuli include ingested
protein and glucose in the blood from
digested food.
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Insulin and its related proteins have been
shown to be produced inside the brain, and
reduced levels of these proteins are linked to
Alzheimer’s disease.
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Insulin is a peptide hormone composed of 51
amino acids and has a molecular weight of
5808 Da.
Insulin is
produced and
stored in the
body as a
hexamer , while
the active form
is the
monomer.
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Hexamer is more stable then the monomer,
which is better for practical reasons.
Monomer is a much faster-reacting drug, it
means that insulin injections do not have to
precede mealtimes by hours.
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Insulin is produced by beta cells in the islets
of Langerhans, which release insuln in two
phases: The first phase release is triggered in
response to rising or increased blood glucose
levels. The second phase is a sustained, slow
release of newly formed vesicles triggered
independently of sugar.
Beta cells in the islets of Langerhans take up
as much as 60%-80% of all the cells.
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Mutations in the insulin gene can cause type I
or type II diabetes. Reserchears have found at
least 10 mutations - they suspect that the
mutations alter the way insulin folds during
its synthesis. Reserchears suggest that these
improperly folded proteins interfere with
other cellular processes in ways that
eventually kill the cells that produce insulin.
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Most strongly influenced by insulin are the
muscle cells and fat cells. These cells are
important because of their central role in
movement, breathing and circulation.
Together these cells account about twothirds of all cells.
Avarage life of insulin is 3-6 min.
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Control of the cellural intake of certain
substances.
Increase of DNA replication and protein
sythesis.
Modification of the activity of numerous
enzymes.
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Insulin is being produced biosynthetically
using recombinant DNA technology. More
recently, reserchers have succeded in
introducing the human insulin gene into
plants and in producing insulin in them. This
technique is set to reduce production costs.
Before it was possible to produce insulin
biosynthetically it wa aquired from animals
and purified so it could be used as injections.
Although insulin
which is aquired
biosynthetically is
a precise copy of
the human insulin
gene, they have
been designed to
have an effect
much faster.
Paul
Langerhans
Paul Langerhans was
a medical student in
Berlin in 1869. He was
studying the structure
of pancreas under the
microscope when he
noticed tissue clumps
scatarred throughout
the pancreas. He
named them as the
islets of Langerhans.
Oscar
Minkowski
In 1889, Polish-German
physician Oscar
Minkowski in
collaboration with
Joseph von Mering,
removed the pancreas
from a healthy dog to
test its assumed role in
digestion. On testing
the urine , they found
sugar in the dog’s urine,
establishing for the first
time a relationship
between the pancreas
and diabetes.
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In 1916, a Romanian professor of physiology
Nicolae Paulescu, was the first to isolate
insulin.
In 1921. Nicolae published four papers
explaining his research.
8 months later his work was confirmed by
doctor Frederick Grant Banting and
biochemist J.J.R. Macleod, who were later
awarded the Nobel prize.
Nicolae
Paulescu
Nicolae Paulescu
was the dicoverer
of insulin,
however because
of his anti-semitic
views he has been
ereased from the
history of
medicine as the
discoverer of
isnulin.
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In 1920, Canadian Frederick Banting was reading one
of Mikowski’s papers and concluded that it was the
digestive secretions that Minkowski had originally
studied that were breaking down the islet secretions,
thereby making it impossible to extract successfully.
The idea was the pancrea’s internal secretions, which,
it was supposed, regulates sugar in the bloodstream,
might hold the key to the treatment of diabetes. A
surgeon by training, Banting knew certain arteries
could be tied off that would lead to atrophy of most
the pancreas, while leaving the islets of Langerhans
intact.
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In 1921, Banting travaled to Toronto to
explain his idea to J.J.R.Macleod, who was
Professor of Physiology at the University of
Toronto. He asked Macleod if he could use his
lab to test his idea. Eventually he agreed to
let Banting use his lab and supplied him with
ten dogs on which to experiment and a lab
assistant Charles Best.
John James
Rickard
Maclod
When the Professor
returned from his
summer vacation to
the University of
Toronto and saw the
progress Banting and
Best had made, he
decided to let Banting
contionue his
research, supplied
him with more dogs,
bigger lab and
pointed out the flaws
in his research.
Frederick
Banting
After Bantings
discovery, the
Canadian
goverment
funded Bantings ,
so he could
continue his
research. King
George V
crowned Banting
Ser.
Chales Best
Macleod supplied
Banting with two lab
assistants – Charles Best
and Clark Noble. Since
Banting required only
one lab asisstant, Best
and Noble flipped a coin
to see which would
assist Banting for the
first half of the summer.
Best won, and took the
first shift as Banting’s
asisstant. Unfortunate
for Noble Banting
decided to keep Best for
the entire summer.
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The first insulin injection was made on January
11, 1922, Leonard Thomson, a 14-year-old
diabetic who lay dying at the Toronto General
Hospital. However, the extract was so impure
Thompson suffered a severe allergic reaction,
and further injections were canceled. Over the
next 12 days, Collip developed a second dose –
purified exctract, which Banting injected
Thompson on January 21. The second injection
was succesful, with no side-effects and also in
completely eliminating the glycosuria sign of
diabetes.
James Collip
James helped
Banting to purify
the insulin
exctract, but
Banting, Best and
Collip didin’t work
well together so
after a year Collip
left the group.
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In 1922, Best managed to improve his
techniques to the point where large
quantities of insul could be exctracted on
demand, but the preparation remained
impure. The drug firm “Eli Lily and Company”
united with Basting and in November, “Eli Lily
and Company” made a major breakthrough
and were able to produce large quantities of
highly refined insulin. Insulin was offered for
sale shortly after.
Herbert Boyer
Herbert Boyer
was the scientist
first who
succeded in
making a
synthetic
“human” insulin
through geneengeneering in a
laboratory in 1977.
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“Eli Lily and Company” partnered up with
“Genetech” the company founded by Boyer,
went on in 1982 to sell the first
commercionally available biosynthetic
human insulin under the brand name
“Humilin”.
The patent for insulin was sold to the
University of Toronto for one half-dollar.
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In 1923 the Nobel prize committee awarded
Frederick Banting and J.J.R.Macleod. They
were awarded the Nobel Prize in Physiology
for the discovery of insulin. Banting, isulted
that Best was not metioned, shared his prize
with him and Macleod immediately shared
his with James Collip.
Frederick Banting and his lab
partner Charles Best
Dorothy
Crowfoot
Hodgkin
In 1969, Dorothy
determined the
spatial
conformation of the
molecule, the socalled tertiary
structure. She had
been awarded a
Nobel Prize in
Chemistry in 1964
for the
development of
crystallography.
Frederick
Sanger
In 1958 british molecular
biologist Frederick
Sanger determined the
primary structure of
insulin. It was the first
protein to have its
sequence be
determined. He was
awarded the Nobel Prize
in Chemistry for his
work.
Rosalyn
Sussman Yalow
1977 Rosalyn
received the Nobel
Prize in Medicine
for the
develpoment of
radioimmunoassay
for insulin.
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http://nobelprize.org/educational/medicine/insulin/dia
betes-insulin.html
http://stemcells.nih.gov/info/scireport/chapter7.asp
http://wwwnews.uchicago.edu/releases/07/070910.insulin.shtml
http://www.novonordisk.com.au/documents/article_p
age/document/History.asp
http://nobelprize.org/nobel_prizes/chemistry/laureate
s/1980/sanger-autobio.html
http://www2.chemistry.msu.edu/Portraits/PortraitsH
H_Detail.asp?HH_LName=Sanger
http://nobelprize.org/nobel_prizes/medicine/laureates
/1923/banting-bio.html
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http://www.shalinimusic.com/2011/06/29/frederi
ck-banting/
http://en.wikipedia.org/wiki/Charles_Herbert_Be
st
http://particle.physics.ucdavis.edu/bios/Best.ht
ml
http://en.wikipedia.org/wiki/James_Collip
http://www.folio.ualberta.ca/36/01/07.HTM
http://www.discoveriesinmedicine.com/HuMor/Insulin.html
http://care.diabetesjournals.org/content/32/1/12
3.full.pdf
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http://nobelprize.org/nobel_prizes/medicine/laur
eates/1977/yalow-autobio.html
http://www.chemistryexplained.com/VaZ/Yalow-Rosalyn-Sussman.html
http://nobelprize.org/nobel_prizes/chemistry/lau
reates/1964/hodgkin-bio.html
http://www.chm.bris.ac.uk/motm/vitaminb12/ho
dgkin.htm
http://nobelprize.org/nobel_prizes/medicine/laur
eates/1923/macleod-bio.html
http://simple.wikipedia.org/wiki/File:J.J.R._Macl
eod_ca._1928.png
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http://www.accessexcellence.org/RC/AB/BC/Her
bert_Boyer.php
http://en.wikipedia.org/wiki/Nicolae_Paulescu
http://www.romanialibera.ro/cultura/aldine/nicol
ae-paulescu-savantul-nedreptatit-168760.html
http://en.wikipedia.org/wiki/Oskar_Minkowski
http://www.bookrags.com/biography/paullangerhans-wob/
http://en.wikipedia.org/wiki/Insulin
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