Insulin is a
hormone that
has extensive effects on metabolism and other body functions, such
as vascular compliance. Insulin causes cells in the
liver,
muscle, and
fat tissue to take up
glucose from the
blood, storing
it as
glycogen in the liver and muscle, and
stopping use of fat as an energy source. When insulin is absent (or
low), glucose is not taken up by body cells, and the body begins to
use fat as an energy source, for example, by transfer of lipids
from
adipose tissue to the liver for
mobilization as an energy source. As its level is a central
metabolic control mechanism, its status is also used as a control
signal to other body systems (such as
amino
acid uptake by body cells). It has several other
anabolic effects throughout the body. When control
of insulin levels fails,
diabetes
mellitus will result.
Insulin is used medically to treat some forms of diabetes mellitus.
Patients with
Type 1 diabetes
mellitus depend on external insulin (most commonly
injected subcutaneously) for their
survival because the hormone is no longer produced internally.
Patients with
Type 2 diabetes
mellitus are
insulin
resistant, and because of such resistance, may suffer from a
relative insulin deficiency. Some patients with Type 2
diabetes may eventually require insulin when other medications fail
to control blood glucose levels adequately.
Insulin is a
peptide hormone
composed of 51
amino acids and has a
molecular weight of 5808
Da. It is produced in the
islets of Langerhans in the
pancreas. The name comes from the
Latin insula for "island".
Insulin's structure varies slightly between
species of animal. Insulin from animal sources
differs somewhat in 'strength' (in
carbohydrate metabolism control
effects) in humans because of those variations. Porcine (
pig) insulin is especially close to the
human version.
Gene
The
proinsulin precursor of insulin is
encoded by the
INS gene.
Alleles
A variety of mutant
alleles with changes in
the coding region have been identified. There is a read-through
gene, INS-IGF2, which overlaps with this gene at the 5' region and
with the IGF2 gene at the 3' region.
Regulation
There are several
regulatory
sequences in the
promoter region of the
human insulin gene, to which
transcription factors bind.
In general, the
A-boxes bind to
Pdx1 factors,
E-boxes bind to
NeuroD,
C-boxes bind to
MafA and
cAMP
response elements to
CREB.
There are also
silencers that
inhibit transcription.
Protein structure
Within vertebrates, the similarity of insulins is extremely close.
Bovine insulin differs from human in only three
amino acid residues, and
porcine insulin in one. Even insulin from some species
of fish is similar enough to human to be clinically effective in
humans. Insulin in some invertebrates (eg, the
Caenorhabditis
elegans nematode) is quite close to
human insulin, has similar effects inside cells, and is produced
very similarly. Insulin has been strongly preserved over
evolutionary time, suggesting its centrality in animal metabolic
control. The C-peptide of
proinsulin
(discussed later), however, differs much more amongst species; it
is also a hormone, but a secondary one.
Insulin is produced and stored in the body as a hexamer (a unit of
six insulin molecules), while the active form is the monomer. The
hexamer is an inactive form with long-term stability which serves
as a way to keep the highly reactive insulin protected, yet readily
available. The hexamer-monomer conversion is one of the central
aspects of insulin formulations for injection. The hexamer is far
more stable than the monomer, which is desirable for practical
reasons, however the monomer is a much faster reacting drug because
diffusion rate is inversely related to particle size. A fast
reacting drug means that insulin injections do not have to precede
mealtimes by hours, which in turn gives diabetics more flexibility
in their daily schedule. Insulin can aggregate and form
fibrillar interdigitated
beta-sheets. This can cause injection
amyloidosis, and prevents the storage of insulin
for long periods.
Synthesis, physiological effects, and degradation
Synthesis
Insulin is produced in the
pancreas and
released when any of the several stimuli is detected. The stimuli
include ingested protein and glucose in the blood produced from
digested food.
Carbohydrate produces
glucose, although not all types of carbohydrate produce glucose and
thereby increase blood glucose levels. In target cells, they
initiate a
signal transduction,
which has the effect of increasing
glucose
uptake and storage. Finally, insulin is degraded, terminating the
response.
Insulin undergoes extensive
posttranslational modification along the production pathway.
Production and secretion are largely independent; prepared
insulin is stored awaiting secretion.
Both C-peptide and mature insulin are biologically
active.
Cell components and proteins in this image are not to
scale.
In mammals, insulin is synthesized in the
pancreas within the
beta
cells (β-cells) of the
islets
of Langerhans. One million to three million islets of
Langerhans (pancreatic islets) form the
endocrine part of the pancreas, which is primarily
an
exocrine gland. The
endocrine portion only accounts for 2% of the total mass of the
pancreas. Within the islets of Langerhans, beta cells constitute
60–80% of all the cells.
In beta cells, insulin is synthesized from the
proinsulin precursor molecule by the action of
proteolytic enzymes, known as
prohormone convertases (
PC1 and
PC2), as well as the exoprotease
carboxypeptidase E. These
modifications of proinsulin remove the center portion of the
molecule (ie,
C-peptide), from the C- and
N- terminal ends of proinsulin. The remaining polypeptides (51
amino acids in total), the B- and A- chains, are bound together by
disulfide bonds/disulphide bonds.
Confusingly, the primary sequence of proinsulin goes in the order
"B-C-A", since B and A chains were identified on the basis of mass,
and the C peptide was discovered after the others.
The endogenous production of insulin is regulated in several steps
along the synthesis pathway:
It has been shown that insulin and its related proteins, are also
produced inside the brain and that reduced levels of these proteins
are linked to Alzheimer's disease.
Release
Beta cells in the islets of Langerhans release insulin in two
phases. The first phase insulin release is rapidly triggered in
response to increased
blood glucose
levels. The second phase is a sustained, slow release of newly
formed vesicles that are triggered independently of sugar. The
description of first phase release is as follows:
- Glucose enters the beta cells through
the glucose transporter GLUT2
- Glucose goes into glycolysis and the
respiratory cycle where multiple high-energy ATP molecules are produced by
oxidation
- Dependent on ATP levels, and hence blood glucose levels, the
ATP-controlled potassium channels
(K+) close and the cell membrane depolarizes
- On depolarization, voltage
controlled calcium channels
(Ca2+) open and calcium flows into the cells
- An increased calcium level causes activation of phospholipase C, which cleaves the membrane
phospholipid phosphatidyl inositol
4,5-bisphosphate into inositol 1,4,5-triphosphate and
diacylglycerol.
- Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in
the membrane of endoplasmic
reticulum (ER). This allows the release of Ca2+ from
the ER via IP3 gated channels, and further raises the cell
concentration of calcium.
- Significantly increased amounts of calcium in the cells causes
release of previously synthesized insulin, which has been stored in
secretory vesicles
This is the main mechanism for release of insulin. In addition some
insulin release takes place generally with food intake, not just
glucose or
carbohydrate intake, and the
beta cells are also somewhat influenced by the
autonomic nervous system. The
signaling mechanisms controlling these linkages are not fully
understood.
Other substances known to stimulate insulin release include amino
acids from ingested proteins, acetylcholine, released from vagus
nerve endings (
parasympathetic nervous
system),
cholecystokinin ,
released by
enteroendocrine
cells of
intestinal
mucosa and
glucose-dependent
insulinotropic peptide (GIP). Three amino acids (alanine,
glycine and arginine) act similarly to glucose by altering the beta
cell's membrane potential. Acetylcholine triggers insulin release
through phospholipase C, while the last acts through the mechanism
of
adenylate cyclase.
The
sympathetic nervous
system (via Alpha
2-adrenergic stimulation as
demonstrated by the agonists
clonidine or
methyldopa) inhibit the release of
insulin. However, it is worth noting that circulating
adrenaline will activate
Beta
2-Receptors on the Beta cells in the pancreatic
Islets to promote insulin release. This is important since muscle
cannot benefit from the raised blood sugar resulting from
adrenergic stimulation (increased gluconeogenesis and
glycogenolysis from the low blood insulin: glucagon state) unless
insulin is present to allow for
GLUT-4
translocation in the tissue. Therefore, beginning with direct
innervation,
norepinephrine inhibits
insulin release via alpha
2-receptors, then subsequently,
circulating adrenaline from the
adrenal
medulla will stimulate beta
2-receptors thereby
promoting insulin release.
When the glucose level comes down to the usual physiologic value,
insulin release from the beta cells slows or stops. If blood
glucose levels drop lower than this, especially to dangerously low
levels, release of hyperglycemic hormones (most prominently
glucagon from Islet of Langerhans' alpha
cells) forces release of glucose into the blood from cellular
stores, primarily liver cell stores of glycogen. By increasing
blood glucose, the hyperglycemic hormones prevent or correct
life-threatening hypoglycemia. Release of insulin is strongly
inhibited by the
stress hormone
norepinephrine (noradrenaline), which
leads to increased blood glucose levels during stress.
Evidence of impaired first phase insulin release can be seen in the
glucose tolerance test,
demonstrated by a substantially elevated blood glucose level at 30
minutes, a marked drop by 60 minutes, and a steady climb back to
baseline levels over the following hourly time points.
Oscillations
Insulin release from pancreas
oscillates with a period of 3–6 minutes.
Even during digestion, generally one or two hours following a meal,
insulin release from pancreas is not continuous, but
oscillates with a period of 3–6 minutes, changing
from generating a blood insulin concentration more than ~800
pmol/l to less than
100 pmol/l. This is thought to avoid
downregulation of
insulin receptors in target cells and to
assist the liver in extracting insulin from the blood. This
oscillation is important to consider when administering
insulin-stimulating medication, since it is the oscillating blood
concentration of insulin release which should, ideally, be
achieved, not a constant high concentration. It is also important
to consider in that all methods of insulin replacement can never
hope to replicate this delivery mechanism precisely. This may be
achieved by delivering insulin rhythmically to the
portal vein or by
islet cell transplantation to the
liver. Future insulin pumps hope to address this characteristic.
(See also
Pulsatile
Insulin.)
Signal transduction
There are special transporter proteins in
cell membranes through which
glucose from the blood can enter a cell. These
transporters are, indirectly, under blood insulin's control in
certain body cell types (e.g., muscle cells). Low levels of
circulating insulin, or its absence, will prevent glucose from
entering those cells (e.g., in Type 1 diabetes). However, more
commonly there is a decrease in the sensitivity of cells to insulin
(e.g., the reduced insulin sensitivity characteristic of Type 2
diabetes), resulting in decreased glucose absorption. In either
case, there is 'cell starvation', weight loss, sometimes extreme.
In a few cases, there is a defect in the release of insulin from
the pancreas. Either way, the effect is, characteristically, the
same: elevated blood glucose levels.
Activation of
insulin receptors
leads to internal cellular mechanisms that directly affect glucose
uptake by regulating the number and operation of protein molecules
in the cell membrane that transport glucose into the cell. The
genes that specify the proteins that make up the insulin receptor
in cell membranes have been identified and the structure of the
interior, cell membrane section, and now, finally after more than a
decade, the extra-membrane structure of receptor (Australian
researchers announced the work 2Q 2006).
Two types of tissues are most strongly influenced by insulin, as
far as the stimulation of glucose uptake is concerned: muscle cells
(
myocytes) and fat cells (
adipocytes). The former are important because of
their central role in movement, breathing, circulation, etc, and
the latter because they accumulate excess
food energy against future needs. Together, they
account for about two-thirds of all cells in a typical human
body.
Physiological effects
The actions of insulin on the global human metabolism level
include:
The actions of insulin on cells include:
- Increased glycogen synthesis – insulin
forces storage of glucose in liver (and muscle) cells in the form
of glycogen; lowered levels of insulin cause liver cells to convert
glycogen to glucose and excrete it into the blood. This is the
clinical action of insulin which is directly useful in reducing
high blood glucose levels as in diabetes.
- Increased fatty acid synthesis –
insulin forces fat cells to take in blood lipids which are
converted to triglycerides; lack of
insulin causes the reverse.
- Increased esterification of fatty
acids – forces adipose tissue to make
fats (i.e., triglycerides) from fatty acid esters; lack of insulin
causes the reverse.
- Decreased proteolysis – decreasing
the breakdown of protein.
- Decreased lipolysis – forces reduction
in conversion of fat cell lipid stores into blood fatty acids; lack
of insulin causes the reverse.
- Decreased gluconeogenesis –
decreases production of glucose from non-sugar substrates,
primarily in the liver (remember, the vast majority of endogenous
insulin arriving at the liver never leaves the liver); lack of
insulin causes glucose production from assorted substrates in the
liver and elsewhere.
- Decreased autophagy - decreased level
of degradation of damaged organelles. Postprandial levels inhibit
autophagy completely.
- Increased amino acid uptake – forces cells to absorb
circulating amino acids; lack of insulin inhibits absorption.
- Increased potassium uptake – forces cells to absorb serum
potassium; lack of insulin inhibits absorption. Thus lowers
potassium levels in blood.
- Arterial muscle tone – forces arterial wall muscle to relax,
increasing blood flow, especially in micro arteries; lack of
insulin reduces flow by allowing these muscles to contract.
- Increase in the secretion of hydrochloric acid by Parietal
cells in the stomach.
Degradation
Once an insulin molecule has docked onto the receptor and effected
its action, it may be released back into the extracellular
environment, or it may be degraded by the cell. Degradation
normally involves
endocytosis of the
insulin-receptor complex followed by the action of
insulin degrading enzyme. Most
insulin molecules are degraded by
liver cells.
It has been estimated that an insulin molecule produced
endogenously by the pancreatic beta cells is degraded within
approximately one hour after its initial release into circulation
(insulin
half-life ~ 4–6
minutes).
Hypoglycemia
Although other cells can use other fuels for a while (most
prominently fatty acids),
neurons depend on
glucose as a source of energy in the non-starving human. They do
not require insulin to absorb glucose, unlike muscle and adipose
tissue, and they have very small internal stores of glycogen.
Glycogen stored in liver cells (unlike
glycogen stored in muscle cells) can be converted to glucose, and
released into the blood, when glucose from digestion is low or
absent, and the
glycerol backbone in
triglycerides can also be used to
produce blood glucose.
Sufficient lack of glucose and scarcity of these sources of glucose
can dramatically make itself manifest in the impaired functioning
of the
central nervous
system; dizziness, speech problems, and even loss of
consciousness, can occur. Low glucose is known as
hypoglycemia or, in cases producing
unconsciousness, "hypoglycemic coma" (sometimes termed "insulin
shock" from the most common causative agent). Endogenous causes of
insulin excess (such as an
insulinoma)
are very rare, and the overwhelming majority of insulin-excess
induced hypoglycemia cases are
iatrogenic and usually accidental. There have
been a few reported cases of murder, attempted murder, or suicide
using insulin overdoses, but most insulin shocks appear to be due
to errors in dosage of insulin (e.g., 20 units of insulin instead
of 2) or other unanticipated factors (didn't eat as much as
anticipated, or exercised more than expected, or unpredicted
kinetics of the subcutaneously injected insulin itself).
Possible causes of hypoglycemia include:
- External insulin (usually injected subcutaneously).
- Oral hypoglycemic agents (e.g., any of the sulfonylureas, or
similar drugs, which increase insulin release from beta cells in
response to a particular blood glucose level).
- Ingestion of low-carbohydrate sugar substitutes in people
without diabetes or with type 2 diabetes. Animal studies show these
can trigger insulin release, albeit in much smaller quantities than
sugar, according to a report in Discover magazine, August
2004, p 18. (This can never be a cause of hypoglycemia in patients
with type 1 diabetes since there is no endogenous insulin
production to stimulate.)
Diseases and syndromes
There are several conditions in which insulin disturbance is
pathologic:
- Diabetes mellitus – general
term referring to all states characterized by hyperglycemia.
- Type 1 –
autoimmune-mediated destruction of insulin producing beta cells in
the pancreas resulting in absolute insulin deficiency.
- Type 2 – multifactoral
syndrome with combined influence of genetic susceptibility and
influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting in
insulin resistance in cells
requiring insulin for glucose absorption. This form of diabetes is
strongly inherited.
- Other types of impaired glucose tolerance (see the diabetes article).
- Insulinoma - a tumor of pancreatic
beta cells producing excess of insulin or reactive hypoglycemia.
- Metabolic syndrome – a poorly
understood condition first called Syndrome
X by Gerald Reaven, Reaven's Syndrome after Reaven, CHAOS in
Australia (from the signs which seem to travel together), and
sometimes prediabetes. It is currently
not clear whether these signs have a single, treatable cause, or
are the result of body changes leading to type 2 diabetes. It is
characterized by elevated blood pressure, dyslipidemia
(disturbances in blood cholesterol forms and other blood lipids),
and increased waist circumference (at least in populations in much
of the developed world). The basic underlying cause may be the
insulin resistance of type 2 diabetes which is a diminished
capacity for insulin
response in some tissues (e.g., muscle, fat) to respond to
insulin. Commonly, morbidities such as essential hypertension, obesity,
Type 2 diabetes, and cardiovascular disease (CVD)
develop.
- Polycystic ovary
syndrome – a complex syndrome in women in the reproductive
years where there is anovulation and
androgen excess commonly displayed as
hirsutism. In many cases of PCOS insulin resistance is present.
As a medication
Biosynthetic "human" insulin is now manufactured for widespread
clinical use using genetic engineering techniques using
recombinant
DNA technology. More recently, researchers have succeeded in
introducing the gene for human insulin into plants and in producing
insulin in plants, specifically
safflower.
It is anticipated that this technique will reduce production
costs.
Several of these are slightly modified versions of human insulin
which, while having a clinical effect on blood glucose levels as
though they were exact copies, have been designed to have somewhat
different absorption or duration of action characteristics. They
are usually referred to as 'insulin analogues'. For instance, the
first available, insulin lispro, does not exhibit a delayed
absorption effect found in 'regular' insulin, and begins to have
effect in as little as 15 minutes. Using it therefore does not
require the pre-planning required for other insulins which begin to
take effect much later (up to many hours) after administration.
Another type is extended release insulin; the first of these was
'insulin glargine'. These have a steady effect for the entire time
they are active, without the peak and drop of effect in other
insulins; typically, they continue to have an insulin effect for an
extended period from 18 to 24 hours.
Unlike many medicines, insulin currently cannot be taken orally.
Like nearly all other proteins introduced into the
gastrointestinal tract, it is reduced
to fragments (even single amino acid components), whereupon all
'insulin activity' is lost. There has been some research into ways
to protect insulin from the digestive tract, so that it can be
administered orally or sublingually. While experimental, several
companies now have various formulations in human clinical trials,
which if successful, could see commercialization in several
years.
Insulin is usually taken as
subcutaneous injection by single-use
syringes with
needle, an
insulin
pump, or by repeated-use
insulin
pens with needles.
History
Discovery and characterization
In 1869
Paul Langerhans, a medical student
in Berlin
, was
studying the structure of the pancreas
under a microscope when he identified
some previously un-noticed tissue clumps scattered throughout the
bulk of the pancreas. The function of the "little heaps of
cells," later
known as the
Islets of Langerhans, was unknown,
but
Edouard Laguesse later
suggested that they might produce secretions that play a regulatory
role in digestion. Paul Langerhans' son, Archibald, also helped to
understand this regulatory role. The term
insulin origins
from
Insel, the German word for islet/island.
In 1889,
the 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. Several days after the dog's pancreas was
removed, Minkowski's animal keeper noticed a swarm of flies feeding
on the dog's urine. On testing the urine they found that there was
sugar in the dog's urine, establishing for the first time a
relationship between the pancreas and diabetes. In 1901, another
major step was taken by
Eugene Opie,
when he clearly established the link between the Islets of
Langerhans and diabetes:
Diabetes mellitus … is caused by
destruction of the islets of Langerhans and occurs only when these
bodies are in part or wholly destroyed. Before his work, the
link between the pancreas and diabetes was clear, but not the
specific role of the islets.
Over the next two decades, several attempts were made to isolate
whatever it was the islets produced as a potential treatment. In
1906
George Ludwig Zuelzer was
partially successful treating dogs with pancreatic extract but was
unable to continue his work. Between 1911 and 1912,
E.L. Scott at the
University of
Chicago
used aqueous pancreatic extracts and noted a
slight diminution of glycosuria but was unable to convince his
director of his work's value; it was shut down. Israel Kleiner demonstrated similar effects
at Rockefeller
University
in 1919, but his work was interrupted by World War I and he did not return to
it.
Nicolae Paulescu, a professor of physiology
at the University of Medicine and Pharmacy in
Bucharest
, was the first one to isolate insulin, which he
called at that time pancrein, and published in 1921 the work that
he had carried out in Bucharest. Use of his techniques
was patented in Romania
, though no
clinical use resulted.
In October 1920 Canadian
Frederick
Banting was reading one of Minkowski's papers and concluded
that it is the very digestive secretions that Minkowski had
originally studied that were breaking down the islet secretion(s),
thereby making it impossible to extract successfully. He jotted a
note to himself
Ligate pancreatic ducts of the dog.
Keep dogs alive till acini degenerate leaving islets.
Try to isolate internal secretion of these and relieve
glycosurea.
The idea was that the pancreas's internal secretion, which
supposedly regulates sugar in the bloodstream, might hold the key
to the treatment of diabetes. A surgeon by training, Banting knew
that certain arteries could be tied off that would lead to atrophy
of most of the pancreas while leaving the islets of Langerhans
intact. He theorized that a relatively pure extract could be made
from the islets once most of the rest of pancreas was gone.
In the
Spring of 1921 Banting traveled to Toronto
to explain
his idea to J.J.R.
Macleod who was Professor of
Physiology at the University of Toronto
, and asked Macleod if he could use his lab space to
test the idea. Macleod was initially skeptical, but
eventually agreed to let Banting use his lab space while he was on
vacation for the summer. He also supplied Banting with ten dogs to
experiment on, and two medical students,
Charles Best and Clark Noble, to use as lab
assistants, before leaving for Scotland. Since Banting only
required one lab assistant, Best and Noble flipped a coin to see
which would assist Banting for the first half of the summer. Best
won the coin toss, and took the first shift as Banting's assistant.
Loss of the coin toss may have proved unfortunate for Noble, given
that Banting decided to keep Best for the entire summer, and
eventually shared half his Nobel Prize money and a large part of
the credit for the discovery of insulin with the winner of the
toss. Had Noble won the toss, his career might have taken a
different path. Banting's method was to tie a ligature (string)
around the pancreatic duct, and, when examined several weeks later,
the pancreatic digestive cells had died and been absorbed by the
immune system, leaving thousands of islets. They then isolated an
extract from these islets, producing what they called
isletin (what we now know as insulin), and tested this
extract on the dogs. Banting and Best were then able to keep a
pancreatectomized dog named Alpha alive for the rest of the summer
by injecting her with the crude extract they had prepared. Removal
of the pancreas in test animals essentially mimics diabetes,
leading to elevated blood glucose levels. Alpha was able to remain
alive because the extracts, containing isletin, were able to lower
her blood glucose levels.
Banting and Best presented their results to Macleod on his return
to Toronto in the fall of 1921, but Macleod pointed out flaws with
the experimental design, and suggested the experiments be repeated
with more dogs and better equipment. He then supplied Banting and
Best with a better laboratory, and began paying Banting a salary
from his research grants. Several weeks later, it was clear the
second round of experiments was also a success; and Macleod helped
publish their results privately in Toronto that November. However,
they needed six weeks to extract the isletin, which forced
considerable delays. Banting suggested that they try to use fetal
calf pancreas, which had not yet developed digestive glands; he was
relieved to find that this method worked well. With the supply
problem solved, the next major effort was to purify the extract. In
December 1921, Macleod invited the
biochemist James
Collip to help with this task, and, within a month, the team
felt ready for a clinical test.
On January
11, 1922, Leonard
Thompson, a 14-year-old diabetic who lay dying at the Toronto General
Hospital
, was given the first injection of insulin.
However, the extract was so impure that Thompson suffered a severe
allergic reaction, and further
injections were canceled. Over the next 12 days, Collip worked day
and night to improve the ox-pancreas extract, and a second dose was
injected on the 23rd. This was completely successful, not only in
having no obvious side-effects, but in completely eliminating the
glycosuria sign of diabetes.
Children dying from diabetic keto-acidosis were kept in large
wards, often with 50 or more patients in a ward, mostly comatose.
Grieving family members were often in attendance, awaiting the
(until then, inevitable) death. In one of medicine's more dramatic
moments Banting, Best, and Collip went from bed to bed, injecting
an entire ward with the new purified extract. Before they had
reached the last dying child, the first few were awakening from
their coma, to the joyous exclamations of their families.
However, Banting and Best never worked well with Collip, regarding
him as something of an interloper, and Collip left the project soon
after.
Over the spring of 1922, Best managed to improve his techniques to
the point where large quantities of insulin could be extracted on
demand, but the preparation remained impure. The drug firm
Eli Lilly and Company had offered
assistance not long after the first publications in 1921, and they
took Lilly up on the offer in April. In November, Lilly made a
major breakthrough and were able to produce large quantities of
highly refined, 'pure' insulin. Insulin was offered for sale
shortly thereafter.
Purified animal-sourced insulin was the only type of insulin
available to diabetics until genetic breakthroughs occurred later
with medical research.
The amino-acid structure of insulin was
characterized in the 1950s and the first synthetic insulin was
produced simultaneously in the labs of Panayotis Katsoyannis at the University
of Pittsburgh
and Helmut Zahn at
RWTH
Aachen
University in the early 1960s.
The first genetically-engineered, synthetic "human" insulin was
produced in a laboratory in 1977 by
Herbert Boyer using
E. coli. Partnering with
Genentech founded by Boyer,
Eli Lilly went on in 1982 to sell the
first commercially available biosynthetic human insulin under the
brand name
Humulin. The vast majority of
insulin currently used worldwide is now biosynthetic recombinant
"human" insulin or its analogs.
Nobel prizes
The
Nobel Prize committee in 1923 credited
the practical extraction of insulin to a team at the University of
Toronto and awarded the Nobel Prize to two men; Frederick Banting and J.J.R. Macleod. They were awarded the
Nobel Prize in
Physiology or Medicine in 1923 for the discovery of insulin.
Banting, insulted that Best was not mentioned, shared his prize
with Best, and Macleod immediately shared his with
James Collip.
The patent for insulin was sold to the
University of
Toronto for one dollar.
Surprisingly, while
Paulescu's
pioneering work was being completely ignored by the Nobel prize
committee, Professor Ian Murray was particularly active in working
to correct the historical wrong against Paulescu.
Murray was a
professor of physiology at the Anderson College of Medicine in
Glasgow
, Scotland
, the head of the department of Metabolic Diseases
at a leading Glasgow hospital, vice-president of the British
Association of Diabetes, and a founding member of the International Diabetes
Federation. In an article for a 1971 issue of the
Journal of the History of Medicine and Allied Sciences, Murray
wrote:
"Insufficient recognition has been given to
Paulesco, the distinguished Roumanian scientist, who at the time
when the Toronto team were commencing their research had already
succeeded in extracting the antidiabetic hormone of the pancreas
and proving its efficacy in reducing the hyperglycaemia in diabetic
dogs."
Furthermore, Murray reported:
"In a recent private communication Professor
Tiselius, head of the Nobel Institute,
has expressed his personal opinion that Paulesco was equally worthy
of the award in 1923."
The
primary structure of insulin
was determined by British molecular biologist
Frederick Sanger. It was the first protein
to have its sequence be determined. He was awarded the 1958
Nobel Prize in Chemistry
for this work.
In 1969, after decades of work,
Dorothy Crowfoot Hodgkin determined
the spatial conformation of the molecule, the so-called
tertiary structure, by means of
X-ray diffraction studies. She had been
awarded a Nobel Prize in Chemistry in 1964 for the development of
crystallography.
Rosalyn Sussman Yalow received
the 1977 Nobel Prize in Medicine for the development of the
radioimmunoassay for insulin.
See also
- Insulin analog
- Anatomy and physiolology
- Forms of diabetes mellitus
- Treatment
- Other medical / diagnostic uses
References
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