Insulin was the first peptide hormone discovered. Frederick Banting and Charles Herbert Best, working in the laboratory of J.J.R. Macleod at the University of Toronto, were the first to isolate insulin from dog pancreas in 1921. Frederick Sanger sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced. The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is also the first protein to be chemically synthesised and produced by DNA recombinant technology. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
Introduction
Insulin
Insulin | Introduction
1921. 1921 January 1922 1921
the primary high energy molecule in human metabolism is
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Adenosine triphosphate (ATP)
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what is catabolism?
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It is the set of metabolic processes that breaks down large molecules.
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which hormones are related to it?
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Cortisol, glucagon, adrenaline, cytokines, orexin and melatonin.
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what is the emotional response due to the third one?
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Fear.
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how does the first hormone related to metabolism of glucose?
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Cortisol stimulates the synthesis of 'new' glucose from non-carbohydrate sources; this is known as gluconeogenesis..
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is process resisted by insulin?
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Yes.
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when was this substance which resists the process discovered?
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No such substance has been found as yet, and the existence of such a substance remains speculative.
Insulin resistance | Hormones
Between 1911 and 1912, E.L. Scott at the University of Chicago tried 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 1915, but World War I interrupted his work and he did not return to it.
Insulin | Discovery
While at the Diabetes Branch of NIH, under the mentorship of Jesse Roth, Philip Gorden, and C. Ronald Kahn, Flier discovered the existence of autoantibodies to the insulin receptor as a cause of severe insulin resistance. This discovery elucidated a rare cause of diabetes, advanced the field of membrane receptor biology and provided an important tool for research on insulin action.
Jeffrey Flier | Research contributions
Macleod's presentation at a meeting of the Association of American Physicians in Washington, D.C., on 3 May 1922 received a standing ovation, but Banting and Best refused to participate in protest. At that time, demonstrations of the method's efficiency drew huge public interest, because the effect on patients, especially children, who until then were bound to die, seemed almost miraculous. The pharmaceutical company Eli Lilly & Co. took over mass production, but without an exclusive license, as the patent was transferred to the British Medical Research Council to prevent exploitation.
John Macleod (physiologist) | Frederick Banting and the discovery of insulin
A series of experiments performed from the late 1800s to the early 1900s revealed that diabetes is caused by the absence of a substance normally produced by the pancreas. In 1869, Oskar Minkowski and Joseph von Mering found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor Frederick Banting and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity.
Pharmaceutical industry | Insulin
He demonstrated that Lilly's insulin process was contaminated, showing that, when injected into rats, the Lilly insulin caused initial hyperglycaemia and the Danish Novo insulin did not. Following his research published in 1947, Lilly upgraded its methods to eliminate the impurity. By then de Duve had joined Carl Cori and Gerty Cori at Washington University in St. Louis, where he worked with a fellow researcher Earl Wilbur Sutherland, Jr., who later won the Nobel Prize in Physiology or Medicine in 1971. Sutherland had been working on the puzzle of the insulin-impurity substance, which he had named hyperglycemic-glycogenolytic (HG) factor. He and de Duve soon discovered that the HG factor was synthesised not only by the pancreas but also by the gastric mucosa and certain other parts of the digestive tract.
Christian de Duve | Rediscovery of glucagon
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis. This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
Resistin | Discovery
The discovery and purification of insulin for clinical use between 1921–1922 by a group of researchers in Toronto—Frederick Banting, J.J.R. Macleod, Charles Best, and James Collip—paved the way for treatment. The patent for insulin was assigned to the University of Toronto in 1923 for a symbolic dollar to keep treatment accessible. In regard to "diabetes insipidus", treatment became available before the causes of the disease were clarified. The discovery of an antidiuretic substance extracted from the pituitary gland by researchers in Italy (A. Farini and B. Ceccaroni) and Germany (R. Von den Velden) in 1913 paved the way for treatment.
History of diabetes | Introduction
Initially, Macleod and Banting were particularly reluctant to patent their process for insulin on grounds of medical ethics. However, concerns remained that a private third-party would hijack and monopolize the research (as Eli Lilly and Company had hinted), and that safe distribution would be difficult to guarantee without capacity for quality control. To this end, Edward Calvin Kendall gave valuable advice. He had isolated thyroxin at the Mayo Clinic in 1914 and patented the process through an arrangement between himself, the brothers Mayo, and the University of Minnesota, transferring the patent to the public university. On April 12, Banting, Best, Collip, Macleod, and FitzGerald wrote jointly to the president of the University of Toronto to propose a similar arrangement with the aim of assigning a patent to the Board of Governors of the University.
Insulin | Patent
The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large scale purification of biological materials. Chemist George B. Walden of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy the life expectancy of diabetics was only a few months.
Pharmaceutical industry | Insulin
Attempts to extract insulin from ground-up pancreas cells were unsuccessful, likely because of the destruction of the insulin by the proteolysis enzyme of the pancreas. The challenge was to find a way to extract insulin from the pancreas prior to its destruction. Moses Barron published an article in 1920 which described experimental closure of the pancreatic duct by ligature; this further influenced Banting's thinking. The procedure caused deterioration of the cells of the pancreas that secrete trypsin which breaks down insulin, but it left the islets of Langerhans intact. Banting realized that this procedure would destroy the trypsin-secreting cells but not the insulin.
Frederick Banting | Isolation of insulin
Another measure of insulin resistance is the modified insulin suppression test developed by Gerald Reaven at Stanford University. The test correlates well with the euglycemic clamp, with less operator-dependent error. This test has been used to advance the large body of research relating to the metabolic syndrome. Patients initially receive 25 μg of octreotide (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of somatostatin (0.27 μg/m/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267 mg/m/min, respectively.
Insulin resistance | Modified insulin suppression test
This can be achieved through raising the response threshold (i.e., postponing the onset of sensitivity) by secreting placental growth factor to interfere with the interaction between insulin receptor substrate (IRS) and PI3K, which is the essence of the so-called "adjustable threshold hypothesis" of insulin resistance. Insulin resistance has been proposed to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.
Insulin resistance | Molecular mechanism
Once the trypsin-secreting cells had died, insulin could be extracted from the islets of Langerhans. Banting discussed this approach with J. J. R. Macleod, Professor of Physiology at the University of Toronto. Macleod provided experimental facilities and the assistance of one of his students, Charles Best. Banting and Best, with the assistance of biochemist James Collip, began the production of insulin by this means. As the experiments proceeded, the required quantities could no longer be obtained by performing surgery on living dogs. In November 1921, Banting hit upon the idea of obtaining insulin from the fetal pancreas. He removed the pancreases from fetal calves at a William Davies slaughterhouse and found the extracts to be just as potent as those extracted from the dog pancreases.
Frederick Banting | Isolation of insulin
Purified animal-sourced insulin was initially the only type of insulin available for experiments and diabetics. John Jacob Abel was the first to produce the crystallised form in 1926. Evidence of the protein nature was first given by Michael Somogyi, Edward A. Doisy, and Philip A. Shaffer in 1924. It was fully proven when Hans Jensen and Earl A. Evans Jr. isolated the amino acids phenylalanine and proline in 1935. The amino acid structure of insulin was first characterized in 1951 by Frederick Sanger, 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 mid-1960s.
Insulin | Structural analysis and synthesis
In a condition of insulin resistance insulin fails to block FoxO6, resulting in continued gluconeogenesis even upon feeding.
Hyperglycemia | Insulin resistance
In insulin resistant tissues, a threshold concentration of insulin is reached causing the cells to uptake glucose and therefore decreases blood glucose levels. Studies have shown that the high levels of insulin resulting from insulin resistance might enhance insulin resistance.
Hyperinsulinemia | Introduction
Following further concern regarding Eli Lilly's attempts to separately patent parts of the manufacturing process, Connaught's Assistant Director and Head of the Insulin Division Robert Defries established a patent pooling policy which would require producers to freely share any improvements to the manufacturing process without compromising affordability.
Insulin | Patent
Insulin was the first peptide hormone discovered. Frederick Banting and Charles Herbert Best, working in the laboratory of J.J.R. Macleod at the University of Toronto, were the first to isolate insulin from dog pancreas in 1921. Frederick Sanger sequenced the amino acid structure in 1951, which made insulin the first protein to be fully sequenced. The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is also the first protein to be chemically synthesised and produced by DNA recombinant technology. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
Insulin | Introduction
In the winter of 1922–23, his diabetes deteriorated badly after an attack of bronchitis and the end of his life seemed nigh. In early-1922, Banting, Best, Collip and Macleod in Toronto, Canada made the discovery and isolation of insulin. Supplies were initially in short supply and slow to reach the UK, but in May 1923, Harrison cabled Lawrence – "I've got insulin – it works – come back quick". By this point, Lawrence was weak and disabled by peripheral neuritis and with great difficulty; drove across the continent and reached King's College Hospital on 28 May 1923. Following some preliminary tests, he received his first insulin injection on 31 May.
Robert Daniel Lawrence | Diabetic patient
Progress accelerated through December 1921 as it was clarified that pancreatic extracts could be used without removing the external (digestive) secretion. As the group prepared for clinical trials, biochemist James B. Collip joined the team at Banting's request to help purify the extract for human injection. On January 23, 1922, Leonard Thompson was successfully treated with Collip's extract at Toronto General Hospital. Six more patients were treated by February 1922 and quickly experienced an improved standard of life. Other notable early recipients of insulin included Elizabeth Hughes, Constance Collier, James D. Havens, and Ted Ryder. In April 1922, the Toronto group jointly authored a paper summarizing all work thus far, and formally proposed to name the extract "insulin".
History of diabetes | Insulin
The test result was contrary to the dominant view at the time on proteins—proteins were considered as unlikely to have such highly specific physiological activity shown by a hormone such as insulin. In 1927, he was published in the journal Science for this work with a paper entitled "Chemistry in Relation to Biology and Medicine with Especial Reference to Insulin and Other Hormones". At the time, Abel's laboratory was no doubt the center of insulin research in the United States. A lot of young scientists came to his lab and worked under Abel to study the newly crystallized hormone. Abel himself gradually withdrew from the actual experimental work on insulin after the first four years, but he continued to guide the scientists in his lab to unravel more and more about the structure of insulin molecule.
John Jacob Abel | Crystallization of insulin
Even if the results were negative, it was the kind of experiment that ought to have been tried long ago, if only for completeness's sake. Banting, Macleod, and student assistant Charles Best began the first experiment on May 17, 1921. On June 14, Macleod left for Scotland and advised remotely through the summer, returning on September 21. During this time, Banting and Best obtained mixed but encouraging results. Since they began with the hypothesis (months later falsified through their own work) that it was necessary to avoid the external secretion in order to obtain the internal secretion, they first used degenerated pancreas, then used foetal pancreas obtained from slaughterhouses.
History of diabetes | Insulin
The discovery not only significantly precipitated progress on extracting active fractions but also offered the very first concrete information on the structure of insulin—sulfur is an integral part of insulin molecules. Continuing with his research on extracting insulin, on November 1925, Abel finally was able to witness one of the most beautiful sights of his life, "glistening crystals of insulin forming on the sides of a test tube". While at the California Institute of Technology, Abel completed an article in the proceedings of the National Academy of Sciences entitled "Crystalline Insulin" in 1926. Although Abel's work received great compliments from the media and the science community, some doubted the purity of his crystals as preliminary tests revealed that they were in fact proteins.
John Jacob Abel | Crystallization of insulin
Insulin was introduced by Banting and Best from the University of Toronto in 1921 as an injectable agent. German researchers first introduced the idea of inhalable insulin in 1924. Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation. In the 1980s Nektar Therapeutics developed technology to make insulin into small particles, technology then licensed to Pfizer. Alkermes developed a delivery device that they licensed to Eli Lilly and Company. Once concrete methods were developed, human tests began in the late 1990s. In January 2006, the U.S.
Inhalable insulin | History
Toward the end of January 1922, tensions mounted between the four "co-discoverers" of insulin and Collip briefly threatened to separately patent his purification process. John G. FitzGerald, director of the non-commercial public health institution Connaught Laboratories, therefore stepped in as peacemaker. The resulting agreement of 25 January 1922 established two key conditions: 1) that the collaborators would sign a contract agreeing not to take out a patent with a commercial pharmaceutical firm during an initial working period with Connaught; and 2) that no changes in research policy would be allowed unless first discussed among FitzGerald and the four collaborators. It helped contain disagreement and tied the research to Connaught's public mandate.
Insulin | Patent
The letter emphasized that:The patent would not be used for any other purpose than to prevent the taking out of a patent by other persons. When the details of the method of preparation are published anyone would be free to prepare the extract, but no one could secure a profitable monopoly.The assignment to the University of Toronto Board of Governors was completed on 15 January 1923, for the token payment of $1.00. The arrangement was congratulated in "The World's Work" in 1923 as "a step forward in medical ethics". It has also received much media attention in the 2010s regarding the issue of healthcare and drug affordability.
Insulin | Patent
Tabas discovered a calcium-IP3R-CaMKII pathway plays a key role in glucagon-mediated excessive hepatic glucose production, insulin resistance, fatty liver, and dyslipidemia in the setting of obesity and type 2 diabetes.
Ira Tabas | Molecular mechanism linking insulin resistance to enhanced atherosclerosis
Hagedorn and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in Toronto. In 1923 they formed Nordisk Insulinlaboratorium, and in 1926 with August Krogh he obtained a Danish Royal Charter as a non-profit foundation. In the 1930s he became interested in modifying the absorption rate of insulin. He was aware that contaminating proteins slowed the absorption of insulin into the bloodstream, but these caused irritation and side effects. Thus he searched for a protein that would not cause any irritation. He came upon protamine, a protein isolated from fish sperm. Hagedorn discovered that the addition of protamine to insulin caused the insulin to form microscopic clumps.
Hans Christian Hagedorn | Biography
Hans Christian Hagedorn (1888–1971) and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in Toronto, Canada. In 1923 they formed Nordisk Insulin laboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charter as a non-profit foundation. In 1936, Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or semen of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection. University of Toronto, Canada later licensed protamine zinc insulin (PZI), to several manufacturers.
NPH insulin | History
Animal glands were obtainable as a waste product of the meatpacking industry. Insulin was derived primarily from cows (Eli Lilly and Company) and pigs (Nordisk Insulinlaboratorium). The making of eight ounces of purified insulin could require as much as two tons of pig parts. Insulin from these sources is effective in humans as it is highly similar to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Initially, lower preparation purity resulted in allergic reactions to the presence of non-insulin substances. Purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods.
Insulin (medication) | Principles
In obese mice given the drug, the resulting resensitization to leptin levels produced decreased food intake, weight loss, and normalized responses to glucose and insulin. JD5037 is covered in the following US Patents issued to Jenrin Discovery: 8,088,809 (1/3/12) ), 7,666,889 (2/23/10), 7,482,470 (1/27/09). The synthesis of JD-5037 and related analogs along with structure activity relationships has been reported.
JD5037 | Introduction
Insulin was one of Hodgkin's most extraordinary research projects. It began in 1934 when she was offered a small sample of crystalline insulin by Robert Robinson. The hormone captured her imagination because of the intricate and wide-ranging effect it has in the body. However, at this stage X-ray crystallography had not been developed far enough to cope with the complexity of the insulin molecule. She and others spent many years improving the technique. It took 35 years after taking her first photograph of an insulin crystal for x-ray crystallography and computing techniques to be able to tackle larger and more complex molecules like insulin.
Dorothy Hodgkin | Insulin structure
Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin. Proinsulin is the final single chain protein structure secreted by cells before cleavage into mature insulin. Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967.
Proinsulin | Introduction
George B. Walden (February 18, 1895 - August 6, 1982) was a chemist who worked for Eli Lilly and Company on the mass production of insulin. He discovered isoelectric precipitation, which solved a major problem and led to the mass production of insulin. Insulin was first isolated and successfully tested by Frederick Banting, working in J.R.R. Macleod's laboratory at the University of Toronto in early 1922. A large number of patients suffering from diabetes were on the verge of dying. The supply of insulin was insufficient to treat all the patients. The team at the University of Toronto had inconsistent results in purifying insulin and eventually turned to Eli Lilly for help.
George B. Walden | Introduction
Heparin is a blood thinner (anticoagulant), originally discovered in 1916 by Jay McLean and William Henry Howell at Johns Hopkins University. However, the crude substance was toxic and could only be extracted in small quantities. As co-discoverer of insulin Charles Best returned from his postgraduate studies in Europe to continue as Connaught's Assistant Director, he began a program in 1928 to purify heparin for clinical use. This direction of development benefitted from Connaught's experience with insulin production and ongoing arrangements with Canadian meat processors to obtain research material. In 1933, Arthur Charles and David Scott published the first papers on increasing the yield of heparin by rotting source tissues.
Connaught Laboratories | Development of heparin: 1928-1930s
In 1919, at the Rockefeller Institute, Kleiner was one of the first to demonstrate the effect of extracts from the pancreas on animals, causing hypoglycemia. These were the early efforts which eventually helped lead to the discovery of insulin.
Israel Kleiner (biochemist) | Insulin
Bottlenecked by the time-consuming task of duct-tying dogs and waiting several weeks to extract insulin, Banting hit upon the idea of extracting insulin from the fetal calf pancreas, which had not yet developed digestive glands. By December, they had also succeeded in extracting insulin from the adult cow pancreas. Macleod discontinued all other research in his laboratory to concentrate on the purification of insulin. He invited biochemist James Collip to help with this task, and the team felt ready for a clinical test within a month.
Insulin | Extraction and purification
The limiting factor for the use of microorganisms like "E. coli" in biosynthesis of gene products like insulin is time, yet due to advancements in the synthesis of oligonucleotides and liquid chromatography, the production time needed for DNA fragments has greatly decreased. Recombinant human insulin was first approved for clinical trials in 1980. At this time the A and B chains of insulin were produced separately and then chemically joined. Joining of the two chains was often carried out through air oxidation with low efficiency. A 1978 study by Goedell et al. successfully accomplished correct joining of the A and B chains through S-sulfonated derivatives and an excess of the A chain, resulting in 50-80% correct joining.
Metagenics | Insulin Production
Other notable discoveries since the early development of insulin and metformin include: In 1980, U.S. biotech company Genentech developed biosynthetic human insulin. The insulin was isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing synthetic human insulin), which produce large quantities of insulin. The purified insulin is distributed to pharmacies for use by diabetes patients. Initially, this development was not regarded by the medical profession as a clinically meaningful development. However, by 1996, the advent of insulin analogues which had vastly improved absorption, distribution, metabolism, and excretion (ADME) characteristics which were clinically meaningful based on this early biotechnology development.
History of diabetes | Further developments
By early November, Connaught was producing about 1 litre of insulin per week. Nonetheless, large-scale manufacture of insulin at Connaught reached its limits, prompting the researchers to contract with Eli Lilly and Company to increase production and accept patents in Canada, the United States, and Great Britain. Banting objected initially to the taking out of patents and the charging of royalties for the manufacture of insulin; the Canadian patent was sold to the University of Toronto for a symbolic dollar. Following the discovery of the isoelectric point for insulin, Eli Lilly hoped to win an insulin production patent for itself but could not due to a similar and concurrent discovery by Michael Somogyi, Phillip Shaffer and E.
Connaught Laboratories | Improving production and affordability
However, the criteria advanced to prioritize the pair's early work alone (before the extract was purified) would itself run into challenges in the 1960s and 1970s as attention was drawn to successes in the same year (Nicolae Paulescu) or earlier (George Ludwig Zuelzer, Israel Kleiner). As tends to be true of any scientific line of inquiry, "the discovery of a preparation of insulin that could be used in treatment" was made possible through the joint effort of team members, and built on the insight of researchers who came before them. In 1954, American doctor Joseph H. Pratt, whose lifelong interest in diabetes and the pancreas went back well before the Toronto discovery, published a "reappraisal" of Macleod and Collip's contributions in refining Banting and Best's flawed experiments and crude extract.
History of diabetes | Nobel Prize Controversy
When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed. When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species. Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue.
Proinsulin | Immunogenicity
However, the scientists quickly realized that a step wise approach would be more practical; rather than immediately engineer a bacterium that synthesized insulin, they would engineer a bacterium that could synthesize somatostatin, a smaller hormone. Swanson resisted at first, since he believed that “If you are going to go for something, go for the real thing.” the "real thing" being insulin, in this case. He eventually agreed, albeit grudgingly.
Robert A. Swanson | Career at Genentech
Many hormones can induce insulin resistance including cortisol, growth hormone, and human placental lactogen. Cortisol counteracts insulin and can lead to increased hepatic gluconeogenesis, reduced peripheral utilization of glucose, and increased insulin resistance. It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane. Based on the significant improvement in insulin sensitivity in humans after bariatric surgery and rats with surgical removal of the duodenum, it has been proposed that some substance is produced in the mucosa of that initial portion of the small intestine that signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity.
Insulin resistance | Hormones
Researcher Frederick Banting famously refused to put his name on the patent after discovering insulin in 1923. The original patent for insulin was later sold by his collaborators for just $1 to the University of Toronto in an effort to make it as available as possible. Despite this, for various reasons, there remains no generic version of insulin available in the US. Insulin remains controlled by a small number of large pharmaceutical companies and sold at prices unaffordable to many who rely on it to live, particularly those without insurance. This lack of availability has led to fatalities, such as Alec Smith who passed away in 2018 due to lack of insulin.
Open Insulin Project | Motivation
Synthetic crystalline bovine insulin was achieved by Chinese researchers in 1965. The complete 3-dimensional structure of insulin was determined by X-ray crystallography in Dorothy Hodgkin's laboratory in 1969. The first genetically engineered, synthetic "human" insulin was produced using "E. coli" in 1978 by Arthur Riggs and Keiichi Itakura at the Beckman Research Institute of the City of Hope in collaboration with Herbert Boyer at Genentech. Genentech, founded by Swanson, Boyer and Eli Lilly and Company, went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name Humulin. The vast majority of insulin used worldwide is biosynthetic recombinant "human" insulin or its analogues.
Insulin | Structural analysis and synthesis
These clumps took longer to dissolve into the bloodstream. This complex of protamine and insulin is known as NPH (neutral protamine Hagedorn) insulin. It is one of the earliest example of engineering drug delivery.
Hans Christian Hagedorn | Biography
In 2001, Fawcett, Bennett, Hamel, Vajo and Duckworth showed that the effect of human insulin and its analogues on protein degradation vary significantly in different cell types and with different experimental conditions. The differences seen in the action of the insulin analogues cannot be attributed to binding differences only. Post-receptor mechanisms, including intracellular processing and degradation, must be also considered. Since then, recombinant DNA technology and the use of insulin analogues has become a major part of the treatment of diabetes.
Zoltan Vajo | Contributions
The introduction of insulin by Frederick Banting in 1922 allowed patients more flexibility in their eating.
Diabetic diet | History
However, Scott's thesis was not published in its original form until much later, in 1966. Instead, while departing for his new position in Kansas, Scott left his thesis with Carlson, who published a version in Scott's name in 1912 in the "American Journal of Physiology". In their subsequent work on insulin and diabetes, Frederick Banting and Charles Best expanded upon the themes in Scott's work and cited the 1912 paper. However, later controversy arose regarding Carlson's edits to Scott's thesis to produce the paper, which included a summary and conclusion paragraph described as "cautious" and insufficient to establish his priority in isolating insulin; in fact, writing in 1964, Scott himself denied authorship of the 1912 paper.
Ernest Lyman Scott | Role in the discovery of insulin
An article he read about the pancreas piqued Banting's interest in diabetes. Banting had to give a talk on the pancreas to one of his classes at the University of Western Ontario on November 1, 1920, and he was therefore reading reports that other scientists had written. Research by Naunyn, Minkowski, Opie, Sharpey-Schafer, and others suggested that diabetes resulted from a lack of a protein hormone secreted by the islets of Langerhans in the pancreas. Schafer had named this putative hormone "insulin". The hormone was thought to control the metabolism of sugar; its lack led to an increase of sugar in the blood which was then excreted in urine.
Frederick Banting | Isolation of insulin
Fetuin-A facilitates the binding of lipids to receptors, thereby inducing insulin resistance.
TLR4 | In insulin resistance
Macleod, a senior professor of physiology at the University of Toronto, to ask if he might mount a research project on the internal secretion of the pancreas. Banting lacked experience in physiological research and had superficial knowledge of the subject. Nonetheless, Macleod took some interest and accepted Banting's request to work in his lab. On account of what may have interested Macleod, Michael Bliss considers the following:Speculation is in order here and is permissible because we have some idea of Macleod's knowledge of the literature. Whether he and Banting were discussing grafting or extracting, what must have appealed to Macleod as "never having been tried before" was the idea of somebody experimenting with degenerated or atrophied pancreas.
History of diabetes | Insulin
Macleod, Professor of Physiology at the University of Toronto. Macleod was initially skeptical, since Banting had no background in research and was not familiar with the latest literature, but he agreed to provide lab space for Banting to test out his ideas. Macleod also arranged for two undergraduates to be Banting's lab assistants that summer, but Banting required only one lab assistant. Charles Best and Clark Noble flipped a coin; Best won the coin toss and took the first shift. This proved unfortunate for Noble, as Banting kept Best for the entire summer and eventually shared half his Nobel Prize money and credit for the discovery with Best.
Insulin | Extraction and purification
In 1869, while studying the structure of the pancreas under a microscope, Paul Langerhans, a medical student in Berlin, identified some previously unnoticed tissue clumps scattered throughout the bulk of the pancreas. The function of the "little heaps of cells", later known as the "islets of Langerhans", initially remained unknown, but Édouard Laguesse later suggested they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. In 1889, the physician Oskar Minkowski, in collaboration with Joseph von Mering, removed the pancreas from a healthy dog to test its assumed role in digestion.
Insulin | Discovery
Insulin which was extracted from animal sources was used as a medicine as early as 1922. These early insulin preparations required multiple daily injections due to the short duration of action and quick degradation of the insulin protein. For this reason, researchers began studying how to prolong the effects of injected insulin. In 1952, a team at Novo Terapeutisk led by K. Hallas-Møller discovered that crystals of various sizes would form when zinc was added to insulin suspensions. Larger insulin crystals take longer to dissolve into the bloodstream when injected into the body, and as such have a much longer duration of action than amorphous or small insulin crystals.
Ultralente insulin | History
Recently, another approach has been used by a pioneering group of Canadian researchers, using an easily grown safflower plant, for the production of much cheaper insulin.
Insulin | Structural analysis and synthesis
The researchers were hesitant to work with a commercial drug firm, particularly since they had the Connaught Laboratories' non-commercial facilities at hand. Nonetheless, as limits were reached at the scale to which Connaught could produce insulin, Clowes and Eli Lilly met with the researchers in 1922 to negotiate an agreement with the University of Toronto scientists to mass-produce insulin. The collaboration greatly accelerated the large-scale production of the extract. In 1923, Lilly began selling Iletin (Insulin, Lilly), their tradename for the first commercially available insulin product in the U.S for the treatment of diabetes. Numerous objections were registered by the Insulin Committee of the University of Toronto in regard to Lilly's use of the term "Iletin", although production continued under this name and the objection was later dropped "as a concession".
Eli Lilly and Company | Modernization:1900–1940
He was the second professor of internal medicine section of Kyushu University. In 1923, he firstly introduced the insulin suppression in diabetical regimen in Japan.
Takeya Hiroshi | Introduction
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that allows glucose to enter cells which also reduces blood glucose (blood sugar). Insulin is released by the pancreas in response to carbohydrates consumed in the diet. In states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. There are many causes of insulin resistance and the underlying process is still not completely understood. Risk factors for insulin resistance include obesity, sedentary lifestyle, family history of diabetes, various health conditions, and certain medications.
Insulin resistance | Introduction
Unlike many medicines, insulin cannot be taken orally at the present time. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (single amino acid components), whereupon all activity is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered in a pill. So far this is entirely experimental.
Insulin (medication) | Methods of administration
In October 1923, Banting and Macleod were awarded the Nobel Prize in Physiology based on a nomination by August Krogh for "the discovery of insulin "and" their exploration of its clinical and physiological characteristics". Banting and Macleod publicly shared the prize with Best and Collip, respectively.
History of diabetes | Insulin
Insulin may have originated more than a billion years ago. The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes. Apart from animals, insulin-like proteins are also known to exist in the Fungi and Protista kingdoms. Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish. Cone snails "Conus geographus" and "Conus tulipa", venomous sea snails that hunt small fish, use modified forms of insulin in their venom cocktails. The insulin toxin, closer in structure to fishes' than to snails' native insulin, slows down the prey fishes by lowering their blood glucose levels.
Insulin | Evolution and species distribution
Insulin was discovered in 1921, by Frederick G. Banting, Charles Herbert Best and John James Rickard Macleod at the University of Toronto. At a time when most child diabetics lived no more than months or a few years, insulin offered the hope of extending lives. Somogyi worked with Philip A. Shaffer and Edward Adelbert Doisy on insulin preparation and insulin's use in the treatment of diabetes. He developed a method for extracting insulin from the pancreases of dogs. In 1922 doctors treated the first diabetic American child, a baby boy, with Somogyi’s insulin. Somogyi also developed a quicker, less expensive method for screening for diabetes, using sodium carbonate, urine, and heat.
Michael Somogyi | Research
This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 diabetes, these phenotypes should be selected against. Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population. J.V. Neel postulates that originally in times of increased famine in ancient humans ancestors, that genes conferring a mechanism for increased glucose storage would be advantageous. In the modern environment today however this is not the case.
Insulin resistance | Adaptive explanations
Further experiments were successful and the three started to present their work at meetings. Macleod was a far better orator, and Banting came to believe that he wanted to take all the credit. Their discovery was first published in the February 1922 issue of "The Journal of Laboratory and Clinical Medicine". Macleod declined co-authorship because he considered it Banting's and Best's work. Despite their success, there remained the issue of how to get enough pancreas extract to continue the experiments. Together, the three researchers developed alcohol extraction, which proved to be far more efficient than other methods. This convinced Macleod to divert the whole laboratory to insulin research and to bring in the biochemist James Collip to help with purifying the extract.
John Macleod (physiologist) | Frederick Banting and the discovery of insulin
As a result, glucose accumulates in the blood. The human insulin protein is composed of 51 amino acids, and has a molecular mass of 5808 Da. It is a heterodimer of an A-chain and a B-chain, which are linked together by disulfide bonds. Insulin's structure varies slightly between species of animals. Insulin from animal sources differs somewhat in effectiveness (in carbohydrate metabolism effects) from human insulin because of these variations. Porcine insulin is especially close to the human version, and was widely used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies.
Insulin | Introduction
Somogyi showed that excessive insulin makes diabetes unstable and first published his findings in 1938. Compare with the dawn phenomenon, which is a morning rise in blood sugar in response to waning insulin and a growth hormone surge (that further antagonizes insulin).
Chronic Somogyi rebound | Introduction
By December 1921, he had also succeeded in extracting insulin from the adult pancreas. Pork and beef would remain the primary commercial sources of insulin until they were replaced by genetically-engineered bacteria in the late 20th century. In spring of 1922, Banting established a private practice in Toronto and began to treat diabetic patients. His first American patient was Elizabeth Hughes Gossett, daughter of U.S. Secretary of State Charles Evans Hughes.
Frederick Banting | Isolation of insulin
An increased expression level of this protein was found in the insulin-responsive tissue of obese, insulin-resistant individuals, and may contribute to the pathogenesis of insulin resistance. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported.
PTPRF | Introduction
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, incensed that Best was not mentioned, shared his prize with him, and Macleod immediately shared his with James Collip. The patent for insulin was sold to the University of Toronto for one dollar. Two other Nobel Prizes have been awarded for work on insulin. British molecular biologist Frederick Sanger, who determined the primary structure of insulin in 1955, was awarded the 1958 Nobel Prize in Chemistry.
Insulin | Nobel Prizes
He demonstrated the process at the Cantor Lecture of the Royal Society of Arts, and after an uninspiring start (the control sample initially worked just as well as the one using his process) his work turned out to be a success. After the discovery of Insulin in 1922 Morgan became interested in medicinal chemistry, and he applied to West Ham Municipal College, where he studied for his Master of Science part-time while still working for the Gas Light and Coke Company. He finished his degree in 1925, and published his first paper in the "Journal of the Chemical Society" in 1926.
Walter Thomas James Morgan | Academia
The method used by Paulescu to prepare his pancreatic extract was similar to a procedure described by the American researcher Israel S. Kleiner in an article published in 1919 in the "Journal of Biological Chemistry". Using his procedure, Kleiner had been able to demonstrate significant reductions in the concentration of blood and urinary glucose after intravenous injections of his extract. Paulescu then secured the patent rights for his method of manufacturing "pancreine" on 10 April 1922 (patent no. 6254) from the Romanian Ministry of Industry and Trade.
Nicolae Paulescu | Work on insulin
Insulin from cattles and pigs have been used since 1920's, and was the predominant form of insulin used for decades. The first synthetic human insulin was created using bacteria in 1978. In the United States, the manufacture of beef insulin was discontinued in 1998, and the manufacture of pork insulin was discontinued in 2006. Just normally.
Animal products in pharmaceuticals | Insulin
On 30 July 1921, Banting and Best successfully isolated an extract ("isleton") from the islets of a duct-tied dog and injected it into a diabetic dog, finding that the extract reduced its blood sugar by 40% in 1 hour. 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 moved Banting and Best into a better laboratory and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments was also a success, and Macleod helped publish their results privately in Toronto that November.
Insulin | Extraction and purification
Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan. Insulin from some species of fish may be also effective in humans. Non-human insulins have caused allergic reactions in some patients related to the extent of purification, formation of non-neutralising antibodies is rarely observed with recombinant human insulin (insulin human rDNA) but allergy may occur in some patients. This may be enhanced by the preservatives used in insulin preparations, or occur as a reaction to the preservative. Biosynthetic insulin (insulin human rDNA) has largely replaced animal insulin.
Insulin analog | Animal insulin
If treatment worked, he said, it was because patients were chosen for their good prognosis and were given special treatment: "insulin patients tend to be an elite group sharing common privileges and perils". Prior to publishing "The insulin myth" in "The Lancet", Bourne had tried to submit the article to the Journal of Mental Science; after a 12-month delay, the Journal informed Bourne they had rejected the article, telling him to "get more experience". In 1957, when insulin coma treatment use was declining, the "Lancet" published the results of a randomized, controlled trial where patients were either given insulin coma treatment or identical treatment but with unconsciousness produced by barbiturates.
Insulin shock therapy | Decline
The hormone glucagon was discovered by C.P. Kimball and John R. Murlin in 1923 as a hyperglycaemic (blood-sugar elevating) substance among the pancreatic extracts. The biological importance of glucagon was not known and the name itself was essentially forgotten. It was a still a mystery at the time de Duve joined Bouckaert at Leuven University to work on insulin. Since 1921, insulin was the first commercial hormonal drug originally produced by the Eli Lilly and Company, but their extraction methods introduced an impurity that caused mild hyperglycaemia, the very opposite of what was expected or desired. In May 1944 de Duve realised that cystallisation could remove the impurity.
Christian de Duve | Rediscovery of glucagon
One of them – a method of oxidizing proteins with performic acid, was adopted by the British chemist, Frederick Sanger, in his research to determine the molecular structure of insulin that won Sanger the Nobel prize in 1958.
Gerrit Friedrich Otto Toennies | Research
In 1945, Frederick Sanger described its use for determining the N-terminal amino acid in polypeptide chains, in particular insulin. Sanger's initial results suggested that insulin was a smaller molecule than previously estimated (molecular weight 12,000), and that it consisted of four chains (two ending in glycine and two ending in phenylalanine), with the chains cross-linked by disulfide bonds. Sanger continued work on insulin, using dinitrofluorobenzene in combination with other techniques, eventually resulted in the complete sequence of insulin (consisting of only two chains, with a molecular weight of 6,000). Following Sanger's initial report of the reagent, the dinitrofluorobenzene method was widely adopted for studying proteins, until it was superseded by other reagents for terminal analysis (e.g., dansyl chloride and later aminopeptidases and carboxypeptidases) and other general methods for sequence determination (e.g., Edman degradation).
1-Fluoro-2,4-dinitrobenzene | Uses
Hypoglycemia was first discovered by James Collip when he was working with Frederick Banting on purifying insulin in 1922. Collip was asked to develop an assay to measure the activity of insulin. He first injected insulin into a rabbit, and then measured the reduction in blood-glucose levels. Measuring blood glucose was a time-consuming step. Collip observed that if he injected rabbits with a too large a dose of insulin, the rabbits began convulsing, went into a coma, and then died. This observation simplified his assay. He defined one unit of insulin as the amount necessary to induce this convulsing hypoglycemic reaction in a rabbit.
Hypoglycemia | History
None were severely insulin-deficient and all were controlled with either diet or oral hypoglycemic agents.
MODY 4 | Introduction
Christian de Duve, the chairman of the Laboratory of Physiological Chemistry at the Catholic University of Louvain in Belgium, had been studying the mechanism of action of a pancreatic hormone insulin in liver cells. By 1949, he and his team had focused on the enzyme called glucose 6-phosphatase, which is the first crucial enzyme in sugar metabolism and the target of insulin. They already suspected that this enzyme played a key role in regulating blood sugar levels. However, even after a series of experiments, they failed to purify and isolate the enzyme from the cellular extracts. Therefore, they tried a more arduous procedure of cell fractionation, by which cellular components are separated based on their sizes using centrifugation.
Lysosome | Discovery
In 1928, Kathleen Culhane joined the League of Nations Health Organization Committee to compare the physiological activity of amorphous and crystalline insulin. The results she obtained were different from the other participants prompting the Committee to conclude her research was incorrect insisting that she remove them. Culhane did not, and her research was later proven to be more accurate.
Kathleen Culhane Lathbury | Career
Before the discovery of insulin, Joslin and Frederick Madison Allen promoted fasting and undernutrition to treat diabetic patients. Critics referred to this as "starvation dieting," and some patients starved to death.
Elliott P. Joslin | Controversy
Had Noble won the toss, his career might have taken a different path. MacLeod was overseeing the work of Banting, who had no experience of physiology, and his assistant Best. In December, when Banting and Best were having difficulties in refining the pancreatic extract and monitoring glucose levels, MacLeod assigned the biochemist James Collip to the team. In January 1922, while Collip was working on insulin purification, Best and Banting administered prematurely their pancreatic extracts to 14-year-old Leonard Thompson, who suffered a severe allergic reaction. Eventually, Collip succeeded in preparing insulin in a more pure, usable form. Banting, Best and Collip shared the patent for insulin, which they sold to the University of Toronto for one dollar.
Charles Best (medical scientist) | Co-discovery of insulin
HxA3 and HxB3 were first identified, named, shown to have biological activity in stimulating insulin secretion in cultured rat pancreatic islets of Langerhans in Canada in 1984 by CR Pace-Asciak and JM Martin. Shortly thereafter, Pace-Asciak identified, named, and showed to have insulin secretagogue activity HxA4 and HxB4.
Hepoxilin | History
Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four values are averaged to determine the steady-state plasma glucose level (SSPG). Subjects with an SSPG greater than 150 mg/dL are considered to be insulin-resistant.
Insulin resistance | Modified insulin suppression test
At the end of 1920, Macleod was approached by Frederick Grant Banting, a young Canadian physician who had the idea of curing diabetes using an extract from a pancreas whose functioning had been disrupted. Macleod was not enthusiastic, because (unlike Banting) he knew about unsuccessful experiments in this direction by other researchers. He thought it more likely that the nervous system had a crucial role in regulating blood glucose concentration. Even though Banting had virtually no experience of physiology, he managed to convince Macleod to lend him laboratory space during a vacation in Scotland that summer. In addition to the laboratory, Macleod provided experimental animals and his student Charles Herbert Best, who worked as a demonstrator.
John Macleod (physiologist) | Frederick Banting and the discovery of insulin
In October 1920, Canadian Frederick Banting concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion, thereby making it impossible to extract successfully. A surgeon by training, Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. 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 glycosuria." In the spring of 1921, Banting traveled to Toronto to explain his idea to J.J.R.
Insulin | Extraction and purification
among a group of genes that" are activated by lactose. Thus, the insulin-producing genes were also activated by lactose. The recombinant plasmids were inserted into "Escherichia coli" bacteria, which were "induced to produce 100,000 molecules of either chain A or chain B human insulin." The two protein chains were then combined to produce insulin molecules.
Biotechnology in pharmaceutical manufacturing | Human Insulin
In January 1922, after 14-year-old Leonard Thompson suffered a severe allergic reaction to an injection of insulin, Collip achieved the goal of preparing a pancreatic extract pure enough for him to recover and to use in clinical trials. Successful trials were soon completed and the future of insulin was assured. Banting, Best and Collip subsequently shared the patent for insulin, which they sold to the University of Toronto for one dollar. Regrettably, due to disagreements between Banting and MacLeod, there was ill-will generated within the team. The Nobel Prize for Medicine was awarded to Banting and MacLeod in 1923. Feeling that Best had been overlooked in the award, Banting shared his portion with Best.
James Collip | Success of insulin
Insulin is produced in the pancreas and the Brockmann body (in some fish), and released when any of several stimuli are detected. These stimuli include the rise in plasma concentrations of amino acids and glucose resulting from the digestion of food. Carbohydrates can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response.
Insulin | Synthesis
After maturation, these secretory vesicles hold insulin, C-peptide, and amylin until calcium triggers exocytosis of the granule contents. Through translational processing, insulin is encoded as a 110 amino acid precursor but is secreted as a 51 amino acid protein.
Beta cell | Insulin synthesis
Later in the 1960s, Grodsky's team first observed that the pancreas appears to release insulin in distinct phases. They went on to publish many studies in support of this theory, which informed the modern scientific understanding of the process of insulin secretion. In 1970, Grodsky's team conducted some of the earliest research on the release of insulin from pancreatic islets].
Gerold Grodsky | Career
The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Professor Wilhelm Falta and published in Vienna in 1931, and confirmed as contributory by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936, however, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion.
Insulin resistance | History
James Bertram Collip, (November 20, 1892 – June 19, 1965) was a Canadian biochemist who was part of the Toronto group which isolated insulin. He served as the Chair of the Department of Biochemistry at McGill University from 1928–1941 and Dean of Medicine at the University of Western Ontario from 1947–1961, where he was a charter member of The Kappa Alpha Society.
James Collip | Introduction
At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as PI3K/Akt/mTOR signaling pathway. Recent studies suggested that the pathway may operate as a bistable switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon. The pathway's sensitivity to insulin may be blunted by many factors such as free fatty acids, causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions. Pregnancy, for example, is a prominent change of metabolic conditions, under which the mother has to reduce her muscles' insulin sensitivity to spare more glucose for the brains (the mother's brain and the fetal brain).
Insulin resistance | Molecular mechanism
Insulin glargine is formulated at an acidic pH 4, where it is completely water-soluble. After subcutaneous injection of the acidic solute (which can cause discomfort and a stinging sensation), when a physiologic pH (approximately 7.4) is achieved the increase in pH causes the insulin to come out of solution resulting in the formation of higher order aggregates of insulin hexamers. The higher order aggregation slows the dissociation of the hexamers into insulin monomers, the functional and physiologically active unit of insulin. This gradual process ensures that small amounts of insulin glargine are released into the body continuously, giving an almost peakless profile.
Insulin glargine | Acceptance and repartition in the body