title: Thalidomide

text: During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus. Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus. There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that peripheral neuritis developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter.


title: Thalidomide

text: While initially considered safe, the drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. The regulatory authorities in East Germany never approved thalidomide. One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time.


title: Thalidomide

text: In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of Diageo plc), marketed thalidomide throughout the UK, Australia and New Zealand, under the brand name Distaval, as a remedy for morning sickness. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country." Globally, more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names.


title: Thalidomide

text: In the US, representatives from Chemie Grünenthal approached Smith, Kline & French (SKF), now GlaxoSmithKline (GSK), with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice. And when administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep inducing", the researchers could still not achieve the hypnotic effect in animals that it had on humans. After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Grünenthal reached an agreement with William S Merrell Company in Cincinnati, Ohio (later Richardson-Merrell, now part of Sanofi), to market and distribute thalidomide throughout the US.


title: Thalidomide

text: The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September 1960. The official in charge of the FDA review, Frances Oldham Kelsey, did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times, and was refused each time. Nevertheless, a total of 17 children with thalidomide-induced malformations were born in the US. Oldham Kelsey was given a Presidential award for distinguished service from the federal government for not allowing thalidomide to be approved for sale in the U.S.


title: Thalidomide

text: In Canada, the history of thalidomide dates back to April 1961. There were many different forms sold, with the most common variant being called Talimol. Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. It was not until March 1962, that both drugs were banned from the Canadian market by the FDD and, soon afterward, physicians were warned to destroy their supplies.


title: Thalidomide

text: In 1964, Israeli physician Jacob Sheskin administered thalidomide to a patient critically ill with leprosy. The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomide's use, and results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed.


title: Thalidomide

text: Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965. Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue, with at least 100 cases identified in Brazil between 2005 and 2010. 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with poor access to healthcare, and these cases have occurred despite the controls.


title: Thalidomide

text: In 1998, the FDA approved the drug's use in the treatment of ENL. Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name "Thalomid", establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.


title: Thalidomide

text: In 2010, the World Health Organization (WHO) stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of clofazimine.


title: Thalidomide

text: Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive.


title: Thalidomide

text: Judah Folkman pioneered studies into the role of angiogenesis (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that solid tumors could not expand without it. In 1993 he surprised the scientific world by hypothesizing the same was true of blood cancers, and the next year he published work showing that a biomarker of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well. Meanwhile, a member of his lab, Robert D'Amato, who was looking for angiogenesis inhibitors, discovered in 1994 that thalidomide inhibited angiogenesis and was effective in suppressing tumor growth in rabbits. Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas. Folkman persuaded the patient's doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment. The results of that trial were published in the New England Journal of Medicine in 1999.


title: Thalidomide

text: After further work was done by Celgene and others, in 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.


title: Thalidomide

text: It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably results in an increase of the overall survival.


title: Thalidomide

text: In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as phocomelia, as a consequence of thalidomide use. The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment; thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. Thalidomide did not damage the fetus if taken after 42 days gestation.


title: Thalidomide

text: It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962.


title: Thalidomide

text: The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 Kefauver Harris Amendment (U.S.), 1965 Directive 65/65/EEC1 (E.U.), and the Medicines Act 1968 (UK). In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing. The FDA subsequently initiated the Drug Efficacy Study Implementation to reclassify drugs already on the market.


title: Thalidomide

text: In the 1960s, thalidomide was successfully marketed as a safer alternative to barbiturates. Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a teratogenic substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE.


title: Thalidomide

text: Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be a challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs.


title: Thalidomide

text: Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide.


title: Thalidomide

text: The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide, is now FDA approved. Additionally, apremilast was approved by the FDA in March 2014. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.


title: Thalidomide

text: Interest turned to pomalidomide, a derivative of thalidomide marketed by Celgene. It is a very active anti-angiogenic agent and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma. It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand name Imnovid.


title: Thalidomide

text: There is no conclusive evidence that thalidomide or lenalidomide is useful to bring about or maintain remission in Crohn's disease.


title: Thalidomide

text: Thalidomide was studied in a Phase II trial for Kaposi's sarcoma, a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the Kaposi's sarcoma-associated herpesvirus (KSHV).


title: Game Boy

text: The is an 8-bit fourth generation handheld game console developed and manufactured by Nintendo. It was first released in Japan on April 21, 1989, in North America later the same year, and in Europe in late 1990. It was designed by the same team that developed the Game & Watch series of handheld electronic games and several Nintendo Entertainment System (NES) games: Satoru Okada, Gunpei Yokoi, and Nintendo Research & Development 1.


title: Game Boy

text: It is Nintendo's second handheld game console and combines features from both the Game & Watch handheld and NES home system. The console features a dot-matrix screen with adjustable contrast dial, five game control buttons (a directional pad, two game buttons, and "START" and "SELECT"), a single speaker with adjustable volume dial and, like its rivals, uses cartridges as physical media for games. The color scheme is made from two tones of grey with accents of black, blue, and dark magenta. All the corners of the portrait-oriented rectangular unit are softly rounded, except for the bottom right, which is curved. At launch, it was sold either as a standalone unit, or bundled with one of several games, among them "Super Mario Land" and "Tetris". Several accessories were also developed, including a carrying pouch, a camera, and a printer.


title: Game Boy

text: The Game Boy received mixed reviews from critics and was deemed as technologically inferior to its fourth-generation competitors (Sega's Game Gear, Atari's Lynx, and NEC's TurboExpress). Its lack of a backlight, graphics, bulky design and price were met with criticism, but it also received praise for its battery life, library of games and durability in its construction. It quickly outsold the competition, selling one million units in the United States within a few weeks. An estimated 118.69 million units of the Game Boy and its successor, the Game Boy Color, have been sold worldwide, making it the third best-selling video game console of all time. It is one of the most recognizable devices from the 1990s, becoming a cultural icon in the years following its release. Several redesigns were released during the console's lifetime, including the Game Boy Pocket in 1996 and the Game Boy Light in 1998 (Japan only). Production of the Game Boy continued until 2003, well after the release of its second successor, the Game Boy Advance, in 2001.


title: Game Boy

text: The Game Boy was designed by Nintendo's chief engineer Gunpei Yokoi and its Nintendo R&D1 team. Following the popularity of the Nintendo Entertainment System, he held a meeting with Nintendo president Hiroshi Yamauchi, saying that he could do a handheld system with interchangeable games. The original internal code name for the Game Boy is "Dot Matrix Game", referring to its dot-matrix display in contrast to the preceding Game & Watch series (which Yokoi had created in 1980) that has segmented LCDs pre-printed with an overlay, limiting each model to only play one game. The initials DMG came to be featured on the final product's model number: "DMG-01". Satoru Okada and Yokoi led the development of the console, which led to disagreements. Yokoi felt that the console could be small, light, durable and successful and have a recognizable library of games. Shigesato Itoi visited Nintendo and conceived the name "Game Boy" for the console Yokoi was designing. The internal reaction to the Game Boy at Nintendo was initially very poor, earning it the derogatory nickname ""Dame"Game" from Nintendo employees, in which "dame" (だめ) means "hopeless" or "useless" (dame originating as a term used in the game Go, meaning "meaningless territory"). Henk Rogers brought the game Tetris to Nintendo of America and convinced its president Minoru Arakawa to port it for the new system so it can reach a wider audience. Arakawa agreed and as a result, the game was ultimately bundled with the Game Boy and the system was released in Japan in April 1989, North America in July, and in Europe in September the following year.


title: Game Boy

text: The Game Boy has four operation buttons labeled "A", "B", "SELECT", and "START", and a directional pad (d-pad). There is a volume control dial on the right side of the device and a similar dial on the left side to adjust the contrast. At the top of the Game Boy, a sliding on-off switch and the slot for the Game Boy cartridges are located. The on-off switch includes a physical lockout to prevent users from either inserting or removing a cartridge while the unit is switched on. Nintendo recommends users leave a cartridge in the slot to prevent dust and dirt from entering the system.


title: Game Boy

text: The Game Boy contains optional input or output connectors. On the left side of the system is an external 3.5 mm × 1.35 mm DC power supply jack that allows users to use an external rechargeable battery pack or AC adapter (sold separately) instead of four AA batteries. The Game Boy requires 6 V DC of at least 150 mA. A 3.5 mm stereo headphone jack is located on the bottom side of the unit which allows users to listen to the audio with the bundled headphones or external speakers.


title: Game Boy

text: The right side of the device offers a port that allows a user to connect to another Game Boy system via a link cable, provided both users are playing games that support connecting to each other (usually only the same copies of the game; the Pokémon games however, are a notable exception, as they can connect to each other between different generations). The port can also be used to connect a Game Boy Printer. The link cable was originally designed for players to play head-to-head two-player games such as in "Tetris". However, game developer Satoshi Tajiri later used the link cable technology as a method of communication and networking in the popular "Pokémon" video game series.


title: Game Boy

text: On March 20, 1995, Nintendo released several special edition Game Boy models with colored cases, advertising them in the "Play It Loud!" campaign, known in Japan as Play It Loud! units were manufactured in red, green, black, yellow, white, blue, and clear (transparent), or sometimes called X-Ray in the UK. Most common are the yellow, red, clear and black. Green is fairly scarce but blue and white are the rarest. Blue was a Europe and Japan-only release, white was a Japanese majority release with UK Toys R Us stores also getting it as an exclusive edition to them. The white remains the rarest of all the Play it Loud colors. A rare, limited edition Manchester United Game Boy is red, with the logos of the team emblazoned on it. It was released simultaneously with the Play it Loud! handhelds in the United Kingdom. The Play It Loud's screens also have a darker border than the normal Game Boy.


title: Game Boy

text: On July 21, 1996, Nintendo released the Game Boy Pocket for US$69.99: a smaller, lighter unit that required fewer batteries. It has space for two AAA batteries, which provide approximately 10 hours of gameplay. The unit is also fitted with a 3 volt, 2.35 mm x 0.75 mm DC jack which can be used to power the system. The Pocket has a smaller link port, which requires an adapter to link with the older Game Boy. The port design is used on all subsequent Game Boy models, excluding the Game Boy Micro. The screen was changed to a true black-and-white display, rather than the "pea soup" monochromatic display of the original Game Boy. Also, the Game Boy Pocket (GBP) has a larger screen than the Game Boy Color (GBC) that later superseded it. The GBP's screen has a diagonal, width, and height, compared to a diagonal for the GBC. Although like its predecessor, the Game Boy Pocket has no backlight to allow play in a darkened area, it did notably improve visibility and pixel response-time (mostly eliminating ghosting). The first version did not have a power LED. This was soon added due to public demand, along with new Game Boy Pocket units of different colors (released on April 28, 1997), some of them new to the Game Boy line. There were several limited-edition Game Boy Pockets, including a gold-metal model exclusive to Japan. The Game Boy Pocket was not a new software platform and played the same software as the original Game Boy model.


title: Game Boy

text: A clear 'skeleton' "Famitsu" Model-F edition appeared in 1997, which had only 5,000 units released, and a clear yellow edition.


title: Game Boy

text: The Game Boy Light was released on April 14, 1998, and only available in Japan. Like the Game Boy Pocket, the system was priced at ¥6,800. The Game Boy Light is slightly bigger than the Game Boy Pocket and features an electroluminescent backlight for low-light conditions. It uses two AA batteries, which give it approximately 12 gameplay hours with the light on and 20 with it off. It was available in two standard colors: gold and silver. It also received numerous special editions, including a clear 'skeleton' "Famitsu" 500 edition (Model-F02) with white buttons. This edition was also limited to 5000 units, like the first Model-F. Astro Boy edition with a clear case and a picture of Astro Boy on it, an Osamu Tezuka World edition with a clear red case and a picture of his characters, and a solid yellow Pokémon Center Tokyo version.


title: Game Boy

text: Though it was less technically advanced than the Lynx and other competitors, notably by not supporting color, the Game Boy's lower price along with longer battery life made it much more successful. In its first two weeks in Japan, from its release on April 21, 1989, the entire stock of 300,000 units was sold; a few months later on July 31, 1989, 40,000 units were sold on its first release day. More than 118.69 million units of the Game Boy and Game Boy Color combined have been sold worldwide, with 32.47 million units in Japan, 44.06 million in the Americas, and 42.16 million in other regions. By Japanese fiscal year 1997, before Game Boy Color's release in late 1998, 64.42 million units of the Game Boy had been sold worldwide. At a March 14, 1994, press conference in San Francisco, Nintendo vice president of marketing Peter Main answered queries about when Nintendo was coming out with a color handheld system by stating that sales of the Game Boy were strong enough that it had decided to hold off on developing a successor handheld for the near future.


title: Game Boy

text: In 1995, Nintendo of America announced that 46% of Game Boy players were female, which was higher than the percentage of female players for both the Nintendo Entertainment System (29%) and Super Nintendo Entertainment System (14%) combined. In 2009, the Game Boy was inducted into the National Toy Hall of Fame, 20 years after its introduction. As of June 6, 2011, Game Boy and Game Boy Color games are available on the Virtual Console service on the Nintendo 3DS's Nintendo eShop.


title: Game Boy

text: The console received mixed reviews from critics. In a 1997 year-end review, a team of four "Electronic Gaming Monthly" editors gave the Game Boy scores of 7.5, 7.0, 8.0, and 2.0. Sushi-X (who contributed the 2.0) panned the system due to its black-and-white display and motion blur, while his three co-reviewers praised its long battery life and strong games library, as well as the sleek, conveniently pocket-sized design of the new Game Boy Pocket model.


title: Vikings (TV series)

text: Vikings is a historical drama television series created and written by Michael Hirst for the History channel, a Canadian network. Filmed in Ireland, it premiered on March 3, 2013, in Canada. The series concluded on December 30, 2020, when the second half of the sixth season was released in its entirety on Amazon Prime Video in Ireland, ahead of its broadcast on History in Canada from January 1 to March 3, 2021. A sequel series, titled "", premiered on Netflix on February 25, 2022.


title: Vikings (TV series)

text: "Vikings" is inspired by the sagas of Ragnar Lodbrok, a Viking who is one of the best-known legendary Norse heroes and notorious as the scourge of Anglo-Saxon England and West Francia. The show portrays Ragnar as a farmer who rises to fame by raiding England and eventually becomes a Scandinavian king, with the support of his family and fellow warriors. In the later seasons, the series follows the fortunes of his sons and their adventures in England, Scandinavia, Kievan Rus', the Mediterranean and North America.


title: Vikings (TV series)

text: The series is inspired by the tales of the Norsemen of early medieval Scandinavia. It broadly follows the exploits of the legendary Viking chieftain Ragnar Lothbrok and his crew, family and descendants, as notably laid down in the 13th-century sagas "Ragnars saga Loðbrókar" and "Ragnarssona þáttr", as well as in Saxo Grammaticus' 12th-century work "Gesta Danorum". Norse legendary sagas were partially fictional tales based in the Norse oral tradition, written down about 200 to 400 years after the events they describe. Further inspiration is taken from historical sources of the period, such as records of the Viking raid on Lindisfarne depicted in the second episode, or Ahmad ibn Fadlan's 10th-century account of the Varangians. The series begins at the start of the Viking Age, marked by the Lindisfarne raid in 793.


title: Vikings (TV series)

text: An Irish-Canadian co-production, "Vikings" was developed and produced by Octagon Films and Take 5 Productions. Michael Hirst, Morgan O'Sullivan, John Weber, Sherry Marsh, Alan Gasmer, James Flynn and Sheila Hockin are credited as executive producers. The first season's budget was of US$40 million.


title: Vikings (TV series)

text: The series began filming in July 2012 at Ashford Studios in Ireland, which at the time was a newly built facility. This location was chosen for its scenery and tax advantages. On August 16, 2012, longship scenes were filmed at Luggala, as well as on the Poulaphouca Reservoir in the Wicklow Mountains. Seventy percent of the first season was filmed outdoors. Some additional background shots were done in western Norway.


title: Vikings (TV series)

text: Johan Renck, Ciarán Donnelly and Ken Girotti each directed three episodes. The production team included cinematographer John Bartley, costume designer Joan Bergin, production designer Tom Conroy, composer Trevor Morris and Irish choir Crux Vocal Ensemble, directed by Paul McGough.


title: Vikings (TV series)

text: On April 5, 2013, History renewed "Vikings" for a ten-episode second season. Jeff Woolnough and Kari Skogland joined Ken Girotti and Ciaran Donnelly as directors of the second season.


title: Vikings (TV series)

text: Two new series regulars were announced on June 11, 2013: Alexander Ludwig, portraying the teenage Björn; and Linus Roache, playing King Ecbert of Wessex. The second season undergoes a jump in time, aging the young Björn (Nathan O'Toole) into an older swordsman portrayed by Ludwig. The older Björn has not seen his father, Ragnar, for "a long period of time". Lagertha remarries to a powerful "jarl", a stepfather who provides harsh guidance to Björn. Edvin Endre and Anna Åström signed up for roles in the second season. Endre had the role of Erlendur, one of King Horik's sons.


title: Vikings (TV series)

text: Morgan O'Sullivan, Sheila Hockin, Sherry Marsh, Alan Gasmer, James Flynn, John Weber and Michael Hirst are credited as executive producers.


title: Vikings (TV series)

text: This season was produced by Steve Wakefield and Keith Thompson; Bill Goddard and Séamus McInerney acted as co-producers. The production team for this season included casting directors Frank and Nuala Moiselle; costume designer Joan Bergin; visual effects supervisors Julian Parry and Dominic Remane; stunt action designers Franklin Henson and Richard Ryan; composer Trevor Morris; production designer Mark Geraghty; editors Aaron Marshall for the first, third, fifth, seventh and ninth episodes and Tad Seaborn for the second, fourth, sixth, eighth and tenth episodes; and cinematographer PJ Dillon.


title: Vikings (TV series)

text: Norwegian music group Wardruna provided much of the background music to the series. Wardruna's founder Einar Kvitrafn Selvik also appeared as an actor in the show during the third season, portraying a shaman.


title: Vikings (TV series)

text: Michael Hirst announced plans for the fourth season before the third season had begun airing. The fourth season began production in Ireland around the Dublin and Wicklow areas in April 2015. Additional location photography featuring Ludwig took place in Canada.


title: Vikings (TV series)

text: Finnish actors Peter Franzén and Jasper Pääkkönen, as well as Canadian actress Dianne Doan, joined the cast of the fourth season. Franzén played Norwegian King Harald Finehair, a potential rival to Ragnar. Pääkkönen was cast as Halfdan the Black, Finehair's brother. Doan portrays Yidu, a Chinese character who has a major role in the first half of the fourth season.


title: Vikings (TV series)

text: Former Toronto Blue Jays player Josh Donaldson is a fan of the series and in January 2016, it was announced that he would have a guest appearance in the fourth season of the show as "Hoskuld".


title: Vikings (TV series)

text: At the same time that the series was renewed for a fifth season, it was announced that Irish actor Jonathan Rhys Meyers would be joining the cast, as Heahmund, a "warrior bishop". "Vikings"’ creator Michael Hirst, explained: "I was looking at the history books, and I came across these warrior bishops. The antecedents of the Knights Templar: these are people who were absolutely religious, yet they put on armor and they fought. Don't let their priestly status fool you, either. 'They were crazy! They believed totally in Christianity and the message, and yet, on the battlefield, they were totally berserk.'"


title: Vikings (TV series)

text: WWE wrestler Adam Copeland was cast in a recurring role for the fifth season as Kjetill Flatnose, a violent and bold warrior. He is chosen by Floki to lead an expedition to Iceland to set up a colony. Irish actor Darren Cahill plays the role of Æthelred of Wessex in the fifth season. Nigerian actor Stanley Aguzie told local media he had landed a small role in the fifth season. The fifth season also features Irish actor, musician and real-life police detective, Kieran O'Reilly, who plays the role of "White Hair". In April 2017 it was announced that Danish actor Erik Madsen would join the cast for the fifth season, as King Hemmig. He spent several months of 2016 on the set of "The Last Kingdom", portraying a Viking. Season 5 involved location shooting in Iceland as well as Morocco, the latter standing in for Sicily and Egypt.


title: Vikings (TV series)

text: Russian actor Danila Kozlovsky joined the series for the sixth season, as Oleg of Novgorod, the 10th century Varangian (east European Vikings) ruler of the Rus people. Katheryn Winnick, who portrays Lagertha in the series, directed an episode of the season. Music for the series was contributed by Scandinavian artists with strong Nordic folk influences, including Wardruna and Danheim.


title: Vikings (TV series)

text: "Vikings" premiered on March 3, 2013, in Canada and the United States. "Vikings" was renewed for a fourth season in March 2015 with an extended order of 20 episodes, which premiered on February 18, 2016. On March 17, 2016, History renewed "Vikings" for a fifth season of 20 episodes, which premiered on November 29, 2017. On September 12, 2017, ahead of its fifth-season premiere, the series was renewed for a sixth season of 20 episodes. On January 4, 2019, it was announced that the sixth season would be the series' last. The sixth season premiered on December 4, 2019. The second part of the sixth and final season was released in its entirety on December 30, 2020, on Amazon Prime Video in Ireland, the United States, the United Kingdom, Germany, and Austria; and aired in Canada on History from January 1, 2021.


title: Vikings (TV series)

text: In the UK, "Vikings" premiered on May 24, 2013, where it was exclusively available on the streaming video-on-demand service LoveFilm. The second season premiered on March 24, 2015. The third season began airing on February 20, 2015, on Amazon Prime Video.


title: Vikings (TV series)

text: In Australia, the series premiered on August 8, 2013, on SBS One. It was later moved to FX, which debuted the second season on February 4, 2015. Season three of Vikings began broadcasting in Australia on SBS One on March 19, 2015. Season four of Vikings began broadcasting in Australia on SBS One on February 24, 2016.


title: Vikings (TV series)

text: The nudity and sex scenes are regularly edited out for American audiences. For example, the sex scene between Lagertha and Astrid in the fourth-season episode "The Outsider" only showed them kissing. The scene continued for airings in other countries and on home video releases.


title: Vikings (TV series)

text: The first episode received favorable reviews, with an average rating of 71% according to "Metacritic". Alan Sepinwall of "HitFix" praised the casting, notably of Fimmel as Ragnar, and observed that "Vikings" "isn't complicated. It ... relies on the inherent appeal of the era and these characters to drive the story". Nancy DeWolf Smith of "The Wall Street Journal" noted the "natural and authentic" setting and costumes, and appreciated that "Vikings" was (unlike, for example, "Spartacus") not a celebration of sex and violence, but "a study of character, stamina, power and ... of social, emotional and even intellectual awakening". Hank Stuever, writing for "The Washington Post", said that the "compelling and robust new drama series ... delivers all the expected gore and blood spatter", but that it successfully adapted the skills of cable television drama, with the care taken in acting, writing and sense of scope reminiscent of "Rome", "Sons of Anarchy" and "Game of Thrones". He also suggested that the way the series emphasized "a core pride and nobility in this tribe of thugs" reflected "just another iteration of Tony Soprano". Neil Genzlinger, in "The New York Times", praised the "arresting" cinematography and the actors' performances, notably Fimmel's, and favorably contrasted "Vikings" to "Game of Thrones" and "Spartacus" for the absence of gratuitous nudity.


title: Vikings (TV series)

text: In "TIME", James Poniewozik noted that the relatively simple generational conflict underlying "Vikings" "doesn't nearly have the narrative ambition of a "Game of Thrones" or the political subtleties of a "Rome"", nor these series' skill with dialogue, but that it held up pretty well compared to the "tabloid history" of "The Tudors" and "The Borgias". He concluded that "Vikings' larger story arc is really more about historical forces" than about its not very complex characters. Clark Collis of "Entertainment Weekly" appreciated the performances, but considered "Vikings" to be "kind of a mess", lacking the intrigue of "The Tudors" and "Game of Thrones". Brian Lowry criticized the series in "Variety" as an "unrelenting cheese-fest" and as a "more simpleminded version of "Game of Thrones"", but considered that it had "a level of atmosphere and momentum that makes it work as a mild diversion". In the "San Francisco Chronicle", David Wiegand was disappointed by the series' "glacial pace" and lack of action as well as the "flabby direction and a gassy script", while appreciating the performances and characters.


title: Vikings (TV series)

text: The second season received a Metacritic rating of 77%, and a Rotten Tomatoes rating of 92% based on twelve professional critic reviews.


title: Vikings (TV series)

text: According to Nielsen, the series premiere drew six million viewers in the US, topping all broadcast networks among viewers aged 18 to 49. An earlier claim of over eighteen million viewers was later retracted by the channel with an apology.


title: Vikings (TV series)

text: Lars Walker, in the magazine "The American Spectator", criticised its portrayal of early Viking Age government (represented by Earl Haraldson) as autocratic rather than essentially democratic. Joel Robert Thompson criticised depiction of the Scandinavians' supposed ignorance of the existence of Britain and Ireland and of the death penalty rather than outlawry ("skoggangr") as their most serious punishment.


title: Vikings (TV series)

text: Monty Dobson, a historian at Central Michigan University, criticised the depiction of Viking clothing but went on to say that fictional shows like "Vikings" could still be a useful teaching tool. The Norwegian newspaper "Aftenposten" reported that the series incorrectly depicted the temple at Uppsala as a stave church in the mountains, whereas the historical temple was situated on flat land and stave churches were characteristic of later Christian architecture. The temple in the series has similarities with reconstructions of the Uppåkra hof.


title: Vikings (TV series)

text: Many characters are based on (or inspired by) real people from history or legend and the events portrayed are broadly drawn from history. The history of more than a century has been condensed; people who could never have met are shown as of similar age, with the history amended for dramatic effect. Season one leads up to the attack on Lindisfarne Abbey of 793 (before the real Rollo was born). In season three the same characters at roughly the same ages participate in the Siege of Paris of 845. By this time, Ecbert was dead and King Æthelwulf was already on the throne. Rollo is shown having his followers killed and fighting his fellow Vikings, whereas in history they were granted what became Normandy and continued to co-operate with their Norse kinsmen.


title: Vikings (TV series)

text: Little is known about Viking religious practice and its depiction is largely fictitious. When Katheryn Winnick was asked why she licked the seer's hand she answered: "It wasn't originally in the script and we just wanted to come up with something unique and different". The showrunner Michael Hirst said, "I especially had to take liberties with "Vikings" because no one knows for sure what happened in the Dark Ages ... we want people to watch it. A historical account of the Vikings would reach hundreds, occasionally thousands, of people. Here we've got to reach millions".


title: Vikings (TV series)

text: The depiction of Christianity in the show is also somewhat controversial. In the fourth episode of the second season, the bishop of Wessex is shown inflicting crucifixion as punishment for apostasy, while it had been outlawed more than four centuries earlier by Emperor Constantine the Great, and it would have been blasphemous for the Christian population.


title: Vikings (TV series)

text: Zenescope partnered with the History Channel to create a free "Vikings" comic book based on the series. It was first distributed at Comic-Con 2013 and by comiXology in February 2014. The comic was written by Michael Hirst, features interior artwork by Dennis Calero ("X-Men Noir"), and is set before the events of season one. In addition to featuring Ragnar and Rollo battling alongside their father, the comic depicts the brothers' first encounter with Lagertha.


title: Vikings (TV series)

text: On January 4, 2019, alongside the announcement that the series would end after its sixth season, it was announced that Hirst and MGM Television were developing a spin-off series with writer Jeb Stuart. On November 19, 2019, it was announced that this, titled "", would take place a century after the end of the original series and would be released on Netflix. The 24-episode series was made by MGM Television, and filmed primarily in Ireland, working from the same Ashford Studios in County Wicklow. The series focuses "on the adventures of Leif Erikson, Freydis, Harald Hardrada and the Norman king William the Conqueror".


title: Insulin

text: Insulin (, from Latin "insula", 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the "INS" gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.


title: Insulin

text: Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose, and inhibit secretion of insulin when glucose levels are low. Insulin enhances glucose uptake and metabolism in the cells, thereby reducing blood sugar level. Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high. Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver. The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis.


title: Insulin

text: Decreased or absent insulin activity results in diabetes mellitus, a condition of high blood sugar level (hyperglycaemia). There are two types of the disease. In diabetes mellitus type 1, the beta cells are destroyed by an autoimmune reaction so that insulin can no longer be synthesized or be secreted into the blood. In diabetes mellitus type 2, the destruction of beta cells is less pronounced than in type 1, and is not due to an autoimmune process. Instead, there is an accumulation of amyloid in the pancreatic islets, which likely disrupts their anatomy and physiology. The pathogenesis of type 2 diabetes is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, and peripheral tissue insulin resistance are known to be involved. Type 2 diabetes is characterized by increased glucagon secretion which is unaffected by, and unresponsive to the concentration of blood glucose. But insulin is still secreted into the blood in response to the blood glucose. As a result, glucose accumulates in the blood.


title: Insulin

text: 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 non-human 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.


title: Insulin

text: 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.


title: Insulin

text: 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.


title: Insulin

text: 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.


title: Insulin

text: Insulin is produced exclusively in the beta cells of the pancreatic islets in mammals, and the Brockmann body in some fish. Human insulin is produced from the "INS" gene, located on chromosome 11. Rodents have two functional insulin genes; one is the homolog of most mammalian genes ("Ins2"), and the other is a retroposed copy that includes promoter sequence but that is missing an intron ("Ins1"). Transcription of the insulin gene increases in response to elevated blood glucose. This is primarily controlled by transcription factors that bind enhancer sequences in the ~400 base pairs before the gene's transcription start site.


title: Insulin

text: During a low-glucose state, PDX1 (pancreatic and duodenal homeobox protein 1) is located in the nuclear periphery as a result of interaction with HDAC1 and 2, which results in downregulation of insulin secretion. An increase in blood glucose levels causes phosphorylation of PDX1, which leads it to undergo nuclear translocation and bind the A3 element within the insulin promoter. Upon translocation it interacts with coactivators HAT p300 and SETD7. PDX1 affects the histone modifications through acetylation and deacetylation as well as methylation. It is also said to suppress glucagon.


title: Insulin

text: NeuroD1, also known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes involved in exocytosis. It is localized in the cytosol, but in response to high glucose it becomes glycosylated by OGT and/or phosphorylated by ERK, which causes translocation to the nucleus. In the nucleus β2 heterodimerizes with E47, binds to the E1 element of the insulin promoter and recruits co-activator p300 which acetylates β2. It is able to interact with other transcription factors as well in activation of the insulin gene.


title: Insulin

text: MafA is degraded by proteasomes upon low blood glucose levels. Increased levels of glucose make an unknown protein glycosylated. This protein works as a transcription factor for MafA in an unknown manner and MafA is transported out of the cell. MafA is then translocated back into the nucleus where it binds the C1 element of the insulin promoter.


title: Insulin

text: These transcription factors work synergistically and in a complex arrangement. Increased blood glucose can after a while destroy the binding capacities of these proteins, and therefore reduce the amount of insulin secreted, causing diabetes. The decreased binding activities can be mediated by glucose induced oxidative stress and antioxidants are said to prevent the decreased insulin secretion in glucotoxic pancreatic β cells. Stress signalling molecules and reactive oxygen species inhibits the insulin gene by interfering with the cofactors binding the transcription factors and the transcription factors itself.


title: Insulin

text: Several regulatory sequences in the promoter region of the human insulin gene bind to transcription factors. 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.


title: Insulin

text: Insulin is synthesized as an inactive precursor molecule, a 110 amino acid-long protein called "preproinsulin". Preproinsulin is translated directly into the rough endoplasmic reticulum (RER), where its signal peptide is removed by signal peptidase to form "proinsulin". As the proinsulin folds, opposite ends of the protein, called the "A-chain" and the "B-chain", are fused together with three disulfide bonds. Folded proinsulin then transits through the Golgi apparatus and is packaged into specialized secretory vesicles. In the granule, proinsulin is cleaved by proprotein convertase 1/3 and proprotein convertase 2, removing the middle part of the protein, called the "C-peptide". Finally, carboxypeptidase E removes two pairs of amino acids from the protein's ends, resulting in active insulin – the insulin A- and B- chains, now connected with two disulfide bonds.


title: Insulin

text: The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the cell into the circulation.


title: Insulin

text: Insulin and its related proteins have been shown to be produced inside the brain, and reduced levels of these proteins are linked to Alzheimer's disease.


title: Insulin

text: Insulin release is stimulated also by beta-2 receptor stimulation and inhibited by alpha-1 receptor stimulation. In addition, cortisol, glucagon and growth hormone antagonize the actions of insulin during times of stress. Insulin also inhibits fatty acid release by hormone sensitive lipase in adipose tissue.


title: Insulin

text: Contrary to an initial belief that hormones would be generally small chemical molecules, as the first peptide hormone known of its structure, insulin was found to be quite large. A single protein (monomer) of human insulin is composed of 51 amino acids, and has a molecular mass of 5808 Da. The molecular formula of human insulin is CHNOS. It is a combination of two peptide chains (dimer) named an A-chain and a B-chain, which are linked together by two disulfide bonds. The A-chain is composed of 21 amino acids, while the B-chain consists of 30 residues. The linking (interchain) disulfide bonds are formed at cysteine residues between the positions A7-B7 and A20-B19. There is an additional (intrachain) disulfide bond within the A-chain between cysteine residues at positions A6 and A11. The A-chain exhibits two α-helical regions at A1-A8 and A12-A19 which are antiparallel; while the B chain has a central α -helix (covering residues B9-B19) flanked by the disulfide bond on either sides and two β-sheets (covering B7-B10 and B20-B23).


title: Insulin

text: The amino acid sequence of insulin is strongly conserved and varies only slightly between species. 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 is quite similar in sequence to human insulin, and has similar physiological effects. The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history. The C-peptide of proinsulin, however, differs much more among species; it is also a hormone, but a secondary one.


title: Insulin

text: 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 about 36000 Da in size. The six molecules are linked together as three dimeric units to form symmetrical molecule. An important feature is the presence of zinc atoms (Zn) on the axis of symmetry, which are surrounded by three water molecules and three histidine residues at position B10.


title: Insulin

text: 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 insulin injections do not have to precede mealtimes by hours, which in turn gives people with diabetes more flexibility in their daily schedules. Insulin can aggregate and form fibrillar interdigitated beta-sheets. This can cause injection amyloidosis, and prevents the storage of insulin for long periods.


title: Insulin

text: Beta cells in the islets of Langerhans release insulin in two phases. The first-phase release is rapidly triggered in response to increased blood glucose levels, and lasts about 10 minutes. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar, peaking in 2 to 3 hours. The two phases of the insulin release suggest that insulin granules are present in diverse stated populations or "pools". During the first phase of insulin exocytosis, most of the granules predispose for exocytosis are released after the calcium internalization. This pool is known as Readily Releasable Pool (RRP). The RRP granules represent 0.3-0.7% of the total insulin-containing granule population, and they are found immediately adjacent to the plasma membrane. During the second phase of exocytosis, insulin granules require mobilization of granules to the plasma membrane and a previous preparation to undergo their release. Thus, the second phase of insulin release is governed by the rate at which granules get ready for release. This pool is known as a Reserve Pool (RP). The RP is released slower than the RRP (RRP: 18 granules/min; RP: 6 granules/min). Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes. First-phase release and insulin sensitivity are independent predictors of diabetes.


title: Insulin

text: This is the primary mechanism for release of insulin. Other substances known to stimulate insulin release include the amino acids arginine and leucine, parasympathetic release of acetylcholine (acting via the phospholipase C pathway), sulfonylurea, cholecystokinin (CCK, also via phospholipase C), and the gastrointestinally derived incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).


title: Insulin

text: Release of insulin is strongly inhibited by norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress. It appears that release of catecholamines by the sympathetic nervous system has conflicting influences on insulin release by beta cells, because insulin release is inhibited by α-adrenergic receptors and stimulated by β-adrenergic receptors. The net effect of norepinephrine from sympathetic nerves and epinephrine from adrenal glands on insulin release is inhibition due to dominance of the α-adrenergic receptors.


title: Insulin

text: When the glucose level comes down to the usual physiologic value, insulin release from the β-cells slows or stops. If the blood glucose level drops 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 the liver glycogen stores, supplemented by gluconeogenesis if the glycogen stores become depleted. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia.


title: Insulin

text: 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 after the ingestion of a glucose load (75 or 100 g of glucose), followed by a slow drop over the next 100 minutes, to remain above 120 mg/100 mL after two hours after the start of the test. In a normal person the blood glucose level is corrected (and may even be slightly over-corrected) by the end of the test. An insulin spike is a 'first response' to blood glucose increase, this response is individual and dose specific although it was always previously assumed to be food type specific only.


title: Insulin

text: Even during digestion, in general, one or two hours following a meal, insulin release from the pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood insulin concentration more than about 800 p mol/l to less than 100 pmol/L (in rats). 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. This may be achieved by delivering insulin rhythmically to the portal vein, by light activated delivery, or by islet cell transplantation to the liver.


title: Insulin

text: The blood insulin level can be measured in international units, such as µIU/mL or in molar concentration, such as pmol/L, where 1 µIU/mL equals 6.945 pmol/L. A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).


title: Insulin

text: The effects of insulin are initiated by its binding to a receptor, the insulin receptor (IR), present in the cell membrane. The receptor molecule contains an α- and β subunits. Two molecules are joined to form what is known as a homodimer. Insulin binds to the α-subunits of the homodimer, which faces the extracellular side of the cells. The β subunits have tyrosine kinase enzyme activity which is triggered by the insulin binding. This activity provokes the autophosphorylation of the β subunits and subsequently the phosphorylation of proteins inside the cell known as insulin receptor substrates (IRS). The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin.


title: Insulin

text: The cascade that leads to the insertion of GLUT4 glucose transporters into the cell membranes of muscle and fat cells, and to the synthesis of glycogen in liver and muscle tissue, as well as the conversion of glucose into triglycerides in liver, adipose, and lactating mammary gland tissue, operates via the activation, by IRS-1, of phosphoinositol 3 kinase (PI3K). This enzyme converts a phospholipid in the cell membrane by the name of phosphatidylinositol 4,5-bisphosphate (PIP2), into phosphatidylinositol 3,4,5-triphosphate (PIP3), which, in turn, activates protein kinase B (PKB). Activated PKB facilitates the fusion of GLUT4 containing endosomes with the cell membrane, resulting in an increase in GLUT4 transporters in the plasma membrane. PKB also phosphorylates glycogen synthase kinase (GSK), thereby inactivating this enzyme. This means that its substrate, glycogen synthase (GS), cannot be phosphorylated, and remains dephosphorylated, and therefore active. The active enzyme, glycogen synthase (GS), catalyzes the rate limiting step in the synthesis of glycogen from glucose. Similar dephosphorylations affect the enzymes controlling the rate of glycolysis leading to the synthesis of fats via malonyl-CoA in the tissues that can generate triglycerides, and also the enzymes that control the rate of gluconeogenesis in the liver. The overall effect of these final enzyme dephosphorylations is that, in the tissues that can carry out these reactions, glycogen and fat synthesis from glucose are stimulated, and glucose production by the liver through glycogenolysis and gluconeogenesis are inhibited. The breakdown of triglycerides by adipose tissue into free fatty acids and glycerol is also inhibited.


title: Insulin

text: After the intracellular signal that resulted from the binding of insulin to its receptor has been produced, termination of signaling is then needed. As mentioned below in the section on degradation, endocytosis and degradation of the receptor bound to insulin is a main mechanism to end signaling. In addition, the signaling pathway is also terminated by dephosphorylation of the tyrosine residues in the various signaling pathways by tyrosine phosphatases. Serine/Threonine kinases are also known to reduce the activity of insulin.


title: Insulin

text: The structure of the insulin–insulin receptor complex has been determined using the techniques of X-ray crystallography.


title: Insulin

text: Insulin also influences other body functions, such as vascular compliance and cognition. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular. Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the co-ordination of a wide variety of homeostatic or regulatory processes in the human body. Insulin also has stimulatory effects on gonadotropin-releasing hormone from the hypothalamus, thus favoring fertility.


title: Insulin

text: 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. The two primary sites for insulin clearance are the liver and the kidney. It is broken down by the enzyme, protein-disulfide reductase (glutathione), which breaks the disulphide bonds between the A and B chains. The liver clears most insulin during first-pass transit, whereas the kidney clears most of the insulin in systemic circulation. Degradation normally involves endocytosis of the insulin-receptor complex, followed by the action of insulin-degrading enzyme. An insulin molecule produced endogenously by the beta cells is estimated to be degraded within about one hour after its initial release into circulation (insulin half-life ~ 4–6 minutes).


title: Insulin

text: Insulin is a major regulator of endocannabinoid (EC) metabolism and insulin treatment has been shown to reduce intracellular ECs, the 2-arachidonoylglycerol (2-AG) and anandamide (AEA), which correspond with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression is disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. Findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation, whereby obese insulin-resistant individuals exhibit increased concentrations of ECs. This dysregulation contributes to excessive visceral fat accumulation and reduced adiponectin release from abdominal adipose tissue, and further to the onset of several cardiometabolic risk factors that are associated with obesity and type 2 diabetes.


title: Insulin

text: Hypoglycemia, also known as "low blood sugar", is when blood sugar decreases to below normal levels. This may result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures or death. A feeling of hunger, sweating, shakiness and weakness may also be present. Symptoms typically come on quickly.


title: Insulin

text: The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin and sulfonylureas. Risk is greater in diabetics who have eaten less than usual, exercised more than usual or have consumed alcohol. Other causes of hypoglycemia include kidney failure, certain tumors, such as insulinoma, liver disease, hypothyroidism, starvation, inborn error of metabolism, severe infections, reactive hypoglycemia and a number of drugs including alcohol. Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.


title: Insulin

text: Biosynthetic human insulin (insulin human rDNA, INN) for clinical use is manufactured by recombinant DNA technology. Biosynthetic human insulin has increased purity when compared with extractive animal insulin, enhanced purity reducing antibody formation. Researchers have succeeded in introducing the gene for human insulin into plants as another method of producing insulin ("biopharming") in safflower. This technique is anticipated to reduce production costs.


title: Insulin

text: Several analogs of human insulin are available. These insulin analogs are closely related to the human insulin structure, and were developed for specific aspects of glycemic control in terms of fast action (prandial insulins) and long action (basal insulins). The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), Humalog (insulin lispro), it is more rapidly absorbed after subcutaneous injection than regular insulin, with an effect 15 minutes after injection. Other rapid-acting analogues are NovoRapid and Apidra, with similar profiles. All are rapidly absorbed due to amino acid sequences that will reduce formation of dimers and hexamers (monomeric insulins are more rapidly absorbed). Fast acting insulins do not require the injection-to-meal interval previously recommended for human insulin and animal insulins. The other type is long acting insulin; the first of these was Lantus (insulin glargine). These have a steady effect for an extended period from 18 to 24 hours. Likewise, another protracted insulin analogue (Levemir) is based on a fatty acid acylation approach. A myristic acid molecule is attached to this analogue, which associates the insulin molecule to the abundant serum albumin, which in turn extends the effect and reduces the risk of hypoglycemia. Both protracted analogues need to be taken only once daily, and are used for type 1 diabetics as the basal insulin. A combination of a rapid acting and a protracted insulin is also available, making it more likely for patients to achieve an insulin profile that mimics that of the body's own insulin release. Insulin is also used in many cell lines, such as CHO-s, HEK 293 or Sf9, for the manufacturing of monoclonal antibodies, virus vaccines, and gene therapy products.


title: Insulin

text: Insulin is usually taken as subcutaneous injections by single-use syringes with needles, via an insulin pump, or by repeated-use insulin pens with disposable needles. Inhaled insulin is also available in the U.S. market.


title: Insulin

text: Unlike many medicines, insulin cannot be taken by mouth because, like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments, 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 orally or sublingually.


title: Insulin

text: Insulin, and all other medications, are supplied free of charge to people with diabetes by the National Health Service in the countries of the United Kingdom.


title: Insulin

text: 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.


title: Insulin

text: 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. On testing the urine, they found sugar, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by the American physician and scientist Eugene Lindsay Opie, when he isolated the role of the pancreas to the islets of Langerhans: "Diabetes mellitus when the result of a lesion of the pancreas is caused by destruction of the islands of Langerhans and occurs only when these bodies are in part or wholly destroyed".


title: Insulin

text: Over the next two decades researchers made several attempts to isolate the islets' secretions. In 1906 George Ludwig Zuelzer achieved partial success in treating dogs with pancreatic extract, but he was unable to continue his work. 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.


title: Insulin

text: In 1916, Nicolae Paulescu developed an aqueous pancreatic extract which, when injected into a diabetic dog, had a normalizing effect on blood sugar levels. He had to interrupt his experiments because of World War I, and in 1921 he wrote four papers about his work carried out in Bucharest and his tests on a diabetic dog. Later that year, he published "Research on the Role of the Pancreas in Food Assimilation".


title: Insulin

text: The name "insulin" was coined by Edward Albert Sharpey-Schafer in 1916 for a hypothetical molecule produced by pancreatic islets of Langerhans (Latin "insula" for islet or island) that controls glucose metabolism. Unbeknown to Sharpey-Schafer, Jean de Meyer had introduced the very similar word "insuline" in 1909 for the same molecule.


title: Insulin

text: 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 dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these + relieve glycosurea[sic]."


title: Insulin

text: In the spring of 1921, Banting traveled to Toronto to explain his idea to J.J.R. 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. 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.


title: Insulin

text: 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. 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.


title: Insulin

text: 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 had a severe allergic reaction, and further injections were cancelled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract. A second dose was injected on January 23, eliminating the glycosuria that was typical of diabetes without causing any obvious side-effects. The first American patient was Elizabeth Hughes, the daughter of U.S. Secretary of State Charles Evans Hughes. The first patient treated in the U.S. was future woodcut artist James D. Havens; Dr. John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens.


title: Insulin

text: 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's head chemist, George B. Walden discovered isoelectric precipitation and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public.


title: Insulin

text: 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.


title: Insulin

text: 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. The letter emphasized that: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.


title: Insulin

text: 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.


title: Insulin

text: 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.


title: Insulin

text: 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. 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.


title: Insulin

text: Dr. Hans E. Weber discovered preproinsulin while working as a research fellow at the University of California Los Angeles in 1974. In 1973–1974, Weber learned the techniques of how to isolate, purify, and translate messenger RNA. To further investigate insulin, he obtained pancreatic tissues from a slaughterhouse in Los Angeles and then later from animal stock at UCLA. He isolated and purified total messenger RNA from pancreatic islet cells which was then translated in oocytes from "Xenopus laevis" and precipitated using anti-insulin antibodies. When total translated protein was run on an SDS-polyacrylamide gel electrophoresis and sucrose gradient, peaks corresponding to insulin and proinsulin were isolated. However, to the surprise of Dr. Weber a third peak was isolated corresponding to a molecule larger than proinsulin. After reproducing the experiment several times, he consistently noted this large peak prior to proinsulin that he determined must be a larger precursor molecule upstream of proinsulin. In May 1975, at the American Diabetes Association meeting in New York, Weber gave an oral presentation of his work where he was the first to name this precursor molecule "preproinsulin". Following this oral presentation, Weber was invited to dinner to discuss his paper and findings by Dr. Donald Steiner, a researcher who contributed to the characterization of proinsulin. A year later in April 1976, this molecule was further characterized and sequenced by Steiner, referencing the work and discovery of Hans Weber. Preproinsulin became an important molecule to study the process of transcription and translation.


title: Insulin

text: 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. 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.


title: Insulin

text: Recombinant insulin is produced either in yeast (usually "Saccharomyces cerevisiae") or "E. coli". In yeast, insulin may be engineered as a single-chain protein with a KexII endoprotease (a yeast homolog of PCI/PCII) site that separates the insulin A chain from a C-terminally truncated insulin B chain. A chemically synthesized C-terminal tail is then grafted onto insulin by reverse proteolysis using the inexpensive protease trypsin; typically the lysine on the C-terminal tail is protected with a chemical protecting group to prevent proteolysis. The ease of modular synthesis and the relative safety of modifications in that region accounts for common insulin analogs with C-terminal modifications (e.g. lispro, aspart, glulisine). The Genentech synthesis and completely chemical synthesis such as that by Bruce Merrifield are not preferred because the efficiency of recombining the two insulin chains is low, primarily due to competition with the precipitation of insulin B chain.


title: Insulin

text: 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.


title: Insulin

text: 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. Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for insulin.


title: Insulin

text: Several Nobel Prizes also have an indirect connection with insulin. George Minot, co-recipient of the 1934 Nobel Prize for the development of the first effective treatment for pernicious anemia, had diabetes mellitus. Dr. William Castle observed that the 1921 discovery of insulin, arriving in time to keep Minot alive, was therefore also responsible for the discovery of a cure for pernicious anemia. Dorothy Hodgkin was awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography, the technique she used for deciphering the complete molecular structure of insulin in 1969.


title: Insulin

text: The work published by Banting, Best, Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients. Although Paulescu discovered the principles of the treatment, his saline extract could not be used on humans; he was not mentioned in the 1923 Nobel Prize. Professor Ian Murray was particularly active in working to correct "the historical wrong" against Nicolae 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. Murray wrote:


title: Insulin

text: In a private communication, Professor Arne Tiselius, former head of the Nobel Institute, expressed his personal opinion that Paulescu was equally worthy of the award in 1923.


title: Citric acid cycle

text: The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism and may have originated abiogenically. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.


title: Citric acid cycle

text: The name of this metabolic pathway is derived from the citric acid (a tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD to NADH, releasing carbon dioxide. The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP.


title: Citric acid cycle

text: In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. In prokaryotic cells, such as bacteria, which lack mitochondria, the citric acid cycle reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the cell's surface (plasma membrane) rather than the inner membrane of the mitochondrion. The overall yield of energy-containing compounds from the citric acid cycle is three NADH, one FADH, and one GTP.


title: Citric acid cycle

text: Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of Albert Szent-Györgyi, who received the Nobel Prize in Physiology or Medicine in 1937 specifically for his discoveries pertaining to fumaric acid, a key component of the cycle. He made this discovery by studying pigeon breast muscle. Because this tissue maintains its oxidative capacity well after breaking down in the Latapie mill and releasing in aqueous solutions, breast muscle of the pigeon was very well qualified for the study of oxidative reactions. The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebs and William Arthur Johnson while at the University of Sheffield, for which the former received the Nobel Prize for Physiology or Medicine in 1953, and for whom the cycle is sometimes named the "Krebs cycle".


title: Citric acid cycle

text: The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize acetate (a two carbon molecule), in the form of acetyl-CoA, into two molecules each of carbon dioxide and water. Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The reactions of the cycle also convert three equivalents of nicotinamide adenine dinucleotide (NAD) into three equivalents of reduced NAD (NADH), one equivalent of flavin adenine dinucleotide (FAD) into one equivalent of FADH, and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (P) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH generated by the citric acid cycle are, in turn, used by the oxidative phosphorylation pathway to generate energy-rich ATP.


title: Citric acid cycle

text: One of the primary sources of acetyl-CoA is from the breakdown of sugars by glycolysis which yield pyruvate that in turn is decarboxylated by the pyruvate dehydrogenase complex generating acetyl-CoA according to the following reaction scheme:


title: Citric acid cycle

text: The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids. Below is a schematic outline of the cycle:


title: Citric acid cycle

text: There are ten basic steps in the citric acid cycle, as outlined below. The cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 0 in the table.


title: Citric acid cycle

text: Two carbon atoms are oxidized to CO, the energy from these reactions is transferred to other metabolic processes through GTP (or ATP), and as electrons in NADH and QH. The NADH generated in the citric acid cycle may later be oxidized (donate its electrons) to drive ATP synthesis in a type of process called oxidative phosphorylation. FADH is covalently attached to succinate dehydrogenase, an enzyme which functions both in the CAC and the mitochondrial electron transport chain in oxidative phosphorylation. FADH, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.


title: Citric acid cycle

text: Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP. Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase). Several of the enzymes in the cycle may be loosely associated in a multienzyme protein complex within the mitochondrial matrix.


title: Citric acid cycle

text: The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).


title: Citric acid cycle

text: Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two FADH, and four CO.


title: Citric acid cycle

text: The above reactions are balanced if P represents the HPO ion, ADP and GDP the ADP and GDP ions, respectively, and ATP and GTP the ATP and GTP ions, respectively.


title: Citric acid cycle

text: The total number of ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 32 and 38.


title: Citric acid cycle

text: The theoretical maximum yield of ATP through oxidation of one molecule of glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is 38 (assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH). In eukaryotes, two equivalents of NADH and four equivalents of ATP are generated in glycolysis, which takes place in the cytoplasm. Transport of two of these equivalents of NADH into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and FADH to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH, further reducing the total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.


title: Citric acid cycle

text: While the citric acid cycle is in general highly conserved, there is significant variability in the enzymes found in different taxa (note that the diagrams on this page are specific to the mammalian pathway variant).


title: Citric acid cycle

text: Some differences exist between eukaryotes and prokaryotes. The conversion of D-"threo"-isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD-dependent EC 1.1.1.41, while prokaryotes employ the NADP-dependent EC 1.1.1.42. Similarly, the conversion of ("S")-malate to oxaloacetate is catalyzed in eukaryotes by the NAD-dependent EC 1.1.1.37, while most prokaryotes utilize a quinone-dependent enzyme, EC 1.1.5.4.


title: Citric acid cycle

text: A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utilize EC 6.2.1.5, succinate–CoA ligase (ADP-forming) (despite its name, the enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (GDP-forming) (EC 6.2.1.4) also operates. The level of utilization of each isoform is tissue dependent. In some acetate-producing bacteria, such as "Acetobacter aceti", an entirely different enzyme catalyzes this conversion – EC 2.8.3.18, succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms. Some bacteria, such as "Helicobacter pylori", employ yet another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase (EC 2.8.3.5).


title: Citric acid cycle

text: Some variability also exists at the previous step – the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD-dependent 2-oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin-dependent 2-oxoglutarate synthase (EC 1.2.7.3).


title: Citric acid cycle

text: Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via succinate semialdehyde, using EC 4.1.1.71, 2-oxoglutarate decarboxylase, and EC 1.2.1.79, succinate-semialdehyde dehydrogenase.


title: Citric acid cycle

text: In cancer, there are substantial metabolic derangements that occur to ensure the proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate tumorigenesis, dubbed oncometabolites. Among the best characterized oncometabolites is 2-hydroxyglutarate which is produced through a heterozygous gain-of-function mutation (specifically a neomorphic one) in isocitrate dehydrogenase (IDH) (which under normal circumstances catalyzes the oxidation of isocitrate to oxalosuccinate, which then spontaneously decarboxylates to alpha-ketoglutarate, as discussed above; in this case an additional reduction step occurs after the formation of alpha-ketoglutarate via NADPH to yield 2-hydroxyglutarate), and hence IDH is considered an oncogene. Under physiological conditions, 2-hydroxyglutarate is a minor product of several metabolic pathways as an error but readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes (L2HGDH and D2HGDH) but does not have a known physiologic role in mammalian cells; of note, in cancer, 2-hydroxyglutarate is likely a terminal metabolite as isotope labelling experiments of colorectal cancer cell lines show that its conversion back to alpha-ketoglutarate is too low to measure. In cancer, 2-hydroxyglutarate serves as a competitive inhibitor for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent dioxygenases. This mutation results in several important changes to the metabolism of the cell. For one thing, because there is an extra NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of alpha-ketoglutarate available to the cell. In particular, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. It is produced largely via the pentose phosphate pathway in the cytoplasm. The depletion of NADPH results in increased oxidative stress within the cell as it is a required cofactor in the production of GSH, and this oxidative stress can result in DNA damage. There are also changes on the genetic and epigenetic level through the function of histone lysine demethylases (KDMs) and ten-eleven translocation (TET) enzymes; ordinarily TETs hydroxylate 5-methylcytosines to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote epithelial-mesenchymal transition (EMT) and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group. Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of hypoxia-inducible factor alpha, which is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). This results in a pseudohypoxic phenotype in the cancer cell that promotes angiogenesis, metabolic reprogramming, cell growth, and migration.


title: Citric acid cycle

text: Allosteric regulation by metabolites. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of metabolic energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-coA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase. When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α-ketoglutarate dehydrogenase; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.