document_title: Peloponnesian War

question_text: who did the spartans ask for help during the second war

text: Peloponnesian War

text: Prelude

text: As the preeminent Athenian historian, Thucydides, wrote in his influential History of the Peloponnesian War, "The growth of the power of Athens, and the alarm which this inspired in Lacedaemon, made war inevitable."[5] Indeed, the nearly fifty years of Greek history that preceded the outbreak of the Peloponnesian War had been marked by the development of Athens as a major power in the Mediterranean world. Its empire began as a small group of city-states, called the Delian League—from the island of Delos, on which they kept their treasury—that came together to ensure that the Greco-Persian Wars were truly over. After defeating the Persian invasion of Greece in the year 480 BC, Athens led the coalition of Greek city-states that continued the Greco-Persian Wars with attacks on Persian territories in the Aegean and Ionia. What then ensued was a period, referred to as the Pentecontaetia (the name given by Thucydides), in which Athens increasingly became in fact an empire,[6] carrying out an aggressive war against Persia and increasingly dominating other city-states. Athens proceeded to bring under its control all of Greece except for Sparta and its allies, ushering in a period which is known to history as the Athenian Empire. By the middle of the century, the Persians had been driven from the Aegean and forced to cede control of a vast range of territories to Athens. At the same time, Athens greatly increased its own power; a number of its formerly independent allies were reduced, over the course of the century, to the status of tribute-paying subject states of the Delian League. This tribute was used to support a powerful fleet and, after the middle of the century, to fund massive public works programs in Athens, causing resentment.[7]

text: Friction between Athens and the Peloponnesian states, including Sparta, began early in the Pentecontaetia; in the wake of the departure of the Persians from Greece, Sparta attempted to prevent the reconstruction of the walls of Athens (without the walls, Athens would have been defenseless against a land attack and subject to Spartan control), but was rebuffed.[8] According to Thucydides, although the Spartans took no action at this time, they "secretly felt aggrieved".[9] Conflict between the states flared up again in 465 BC, when a helot revolt broke out in Sparta. The Spartans summoned forces from all of their allies, including Athens, to help them suppress the revolt. Athens sent out a sizable contingent (4,000 hoplites), but upon its arrival, this force was dismissed by the Spartans, while those of all the other allies were permitted to remain. According to Thucydides, the Spartans acted in this way out of fear that the Athenians would switch sides and support the helots; the offended Athenians repudiated their alliance with Sparta.[10] When the rebellious helots were finally forced to surrender and permitted to evacuate the state, the Athenians settled them at the strategic city of Naupactus on the Corinthian Gulf.[11]

text: In 459 BC, Athens took advantage of a war between its neighbors Megara and Corinth, both Spartan allies, to conclude an alliance with Megara, giving the Athenians a critical foothold on the Isthmus of Corinth. A fifteen-year conflict, commonly known as the First Peloponnesian War, ensued, in which Athens fought intermittently against Sparta, Corinth, Aegina, and a number of other states. For a time during this conflict, Athens controlled not only Megara but also Boeotia; at its end, however, in the face of a massive Spartan invasion of Attica, the Athenians ceded the lands they had won on the Greek mainland, and Athens and Sparta recognized each other's right to control their respective alliance systems.[12] The war was officially ended by the Thirty Years' Peace, signed in the winter of 446/5 BC.[13]

text: Breakdown of the peace

text: The Thirty Years' Peace was first tested in 440 BC, when Athens' powerful ally Samos rebelled from its alliance with Athens. The rebels quickly secured the support of a Persian satrap, and Athens found itself facing the prospect of revolts throughout the empire. The Spartans, whose intervention would have been the trigger for a massive war to determine the fate of the empire, called a congress of their allies to discuss the possibility of war with Athens. Sparta's powerful ally Corinth was notably opposed to intervention, and the congress voted against war with Athens. The Athenians crushed the revolt, and peace was maintained.[14]

text: The more immediate events that led to war involved Athens and Corinth. After suffering a defeat at the hands of their colony of Corcyra, a sea power that was not allied to either Sparta or Athens, Corinth began to build an allied naval force. Alarmed, Corcyra sought an alliance with Athens, which after debate and input from both Corcyra and Corinth, decided to swear a defensive alliance with Corcyra. At the Battle of Sybota, a small contingent of Athenian ships played a critical role in preventing a Corinthian fleet from capturing Corcyra. In order to uphold the Thirty Years' Peace, however, the Athenians were instructed not to intervene in the battle unless it was clear that Corinth was going to press onward to invade Corcyra. However, the Athenian warships participated in the battle nevertheless, and the arrival of additional Athenian warships was enough to dissuade the Corinthians from exploiting their victory, thus sparing much of the routed Corcyraean and Athenian fleet.[15]

text: Following this, Athens instructed Potidaea (Chalcidice peninsula), a tributary ally of Athens but a colony of Corinth, to tear down its walls, send hostages to Athens, dismiss the Corinthian magistrates from office, and refuse the magistrates that the city would send in the future.[16] The Corinthians, outraged by these actions, encouraged Potidaea to revolt and assured them that they would ally with them should they revolt from Athens. Meanwhile, the Corinthians were unofficially aiding Potidaea by sneaking contingents of men into the besieged city to help defend it. This was a direct violation of the Thirty Years' Peace, which had (among other things) stipulated that the Delian League and the Peloponnesian League would respect each other's autonomy and internal affairs.

text: A further source of provocation was an Athenian decree, issued in 433/2 BC, imposing stringent trade sanctions on Megarian citizens (once more a Spartan ally after the conclusion of the First Peloponnesian War). It was alleged that the Megarians had desecrated the Hiera Orgas. These sanctions, known as the Megarian decree, were largely ignored by Thucydides, but some modern economic historians have noted that forbidding Megara to trade with the prosperous Athenian empire would have been disastrous for the Megarans, and have accordingly considered the decree to be a contributing factor in bringing about the war.[17] Historians that attribute responsibility for the war to Athens cite this event as the main cause for blame.[18]

text: At the request of the Corinthians, the Spartans summoned members of the Peloponnesian League to Sparta in 432 BC, especially those who had grievances with Athens to make their complaints to the Spartan assembly. This debate was attended by members of the league and an uninvited delegation from Athens, which also asked to speak, and became the scene of a debate between the Athenians and the Corinthians. Thucydides reports that the Corinthians condemned Sparta's inactivity up to that point, warning the Spartans that if they continued to remain passive while the Athenians were energetically active, they would soon find themselves outflanked and without allies.[19] The Athenians, in response, reminded the Spartans of their record of military success and opposition to Persia, and warned them of the dangers of confronting such a powerful state, ultimately encouraging Sparta to seek arbitration as provided by the Thirty Years' Peace.[20] Undeterred, a majority of the Spartan assembly voted to declare that the Athenians had broken the peace, essentially declaring war.[21]

text: The "Archidamian War"

text: Sparta and its allies, with the exception of Corinth, were almost exclusively land-based powers, able to summon large land armies which were very nearly unbeatable (thanks to the legendary Spartan forces). The Athenian Empire, although based in the peninsula of Attica, spread out across the islands of the Aegean Sea; Athens drew its immense wealth from tribute paid from these islands. Athens maintained its empire through naval power. Thus, the two powers were relatively unable to fight decisive battles.

text: The Spartan strategy during the first war, known as the Archidamian War (431–421 BC) after Sparta's king Archidamus II, was to invade the land surrounding Athens. While this invasion deprived Athenians of the productive land around their city, Athens itself was able to maintain access to the sea, and did not suffer much. Many of the citizens of Attica abandoned their farms and moved inside the Long Walls, which connected Athens to its port of Piraeus. At the end of the first year of the war, Pericles gave his famous Funeral Oration (431 BC).

text: The Spartans also occupied Attica for periods of only three weeks at a time; in the tradition of earlier hoplite warfare the soldiers were expected to go home to participate in the harvest. Moreover, Spartan slaves, known as helots, needed to be kept under control, and could not be left unsupervised for long periods of time. The longest Spartan invasion, in 430 BC, lasted just forty days.

text: The Athenian strategy was initially guided by the strategos, or general, Pericles, who advised the Athenians to avoid open battle with the far more numerous and better trained Spartan hoplites, relying instead on the fleet. The Athenian fleet, the most dominant in Greece, went on the offensive, winning a victory at Naupactus. In 430 BC an outbreak of a plague hit Athens. The plague ravaged the densely packed city, and in the long run, was a significant cause of its final defeat. The plague wiped out over 30,000 citizens, sailors and soldiers, including Pericles and his sons. Roughly one-third to two-thirds of the Athenian population died. Athenian manpower was correspondingly drastically reduced and even foreign mercenaries refused to hire themselves out to a city riddled with plague. The fear of plague was so widespread that the Spartan invasion of Attica was abandoned, their troops being unwilling to risk contact with the diseased enemy.

text: After the death of Pericles, the Athenians turned somewhat against his conservative, defensive strategy and to the more aggressive strategy of bringing the war to Sparta and its allies. Rising to particular importance in Athenian democracy at this time was Cleon, a leader of the hawkish elements of the Athenian democracy. Led militarily by a clever new general Demosthenes (not to be confused with the later Athenian orator Demosthenes), the Athenians managed some successes as they continued their naval raids on the Peloponnese. Athens stretched their military activities into Boeotia and Aetolia, quelled the Mytilenean revolt and began fortifying posts around the Peloponnese. One of these posts was near Pylos on a tiny island called Sphacteria, where the course of the first war turned in Athens's favour. The post off Pylos struck Sparta where it was weakest: its dependence on the helots, who tended the fields while its citizens trained to become soldiers. The helots made the Spartan system possible, but now the post off Pylos began attracting helot runaways. In addition, the fear of a general revolt of helots emboldened by the nearby Athenian presence drove the Spartans to action. Demosthenes, however, outmanoeuvred the Spartans in the Battle of Pylos in 425 BC and trapped a group of Spartan soldiers on Sphacteria as he waited for them to surrender. Weeks later, though, Demosthenes proved unable to finish off the Spartans. After boasting that he could put an end to the affair in the Assembly, the inexperienced Cleon won a great victory at the Battle of Sphacteria. The Athenians captured 300 Spartan hoplites. The hostages gave the Athenians a bargaining chip.

text: After these battles, the Spartan general Brasidas raised an army of allies and helots and marched the length of Greece to the Athenian colony of Amphipolis in Thrace, which controlled several nearby silver mines; their product supplied much of the Athenian war fund. Thucydides was dispatched with a force which arrived too late to stop Brasidas capturing Amphipolis; Thucydides was exiled for this, and, as a result, had the conversations with both sides of the war which inspired him to record its history. Both Brasidas and Cleon were killed in Athenian efforts to retake Amphipolis (see Battle of Amphipolis). The Spartans and Athenians agreed to exchange the hostages for the towns captured by Brasidas, and signed a truce.

text: Peace of Nicias

text: With the death of Cleon and Brasidas, zealous war hawks for both nations, the Peace of Nicias was able to last for some six years. However, it was a time of constant skirmishing in and around the Peloponnese. While the Spartans refrained from action themselves, some of their allies began to talk of revolt. They were supported in this by Argos, a powerful state within the Peloponnese that had remained independent of Lacedaemon. With the support of the Athenians, the Argives succeeded in forging a coalition of democratic states within the Peloponnese, including the powerful states of Mantinea and Elis. Early Spartan attempts to break up the coalition failed, and the leadership of the Spartan king Agis was called into question. Emboldened, the Argives and their allies, with the support of a small Athenian force under Alcibiades, moved to seize the city of Tegea, near Sparta.

text: The Battle of Mantinea was the largest land battle fought within Greece during the Peloponnesian War. The Lacedaemonians, with their neighbors the Tegeans, faced the combined armies of Argos, Athens, Mantinea, and Arcadia. In the battle, the allied coalition scored early successes, but failed to capitalize on them, which allowed the Spartan elite forces to defeat the forces opposite them. The result was a complete victory for the Spartans, which rescued their city from the brink of strategic defeat. The democratic alliance was broken up, and most of its members were reincorporated into the Peloponnesian League. With its victory at Mantinea, Sparta pulled itself back from the brink of utter defeat, and re-established its hegemony throughout the Peloponnese.

text: Sicilian Expedition

text: In the 17th year of the war, word came to Athens that one of their distant allies in Sicily was under attack from Syracuse. The people of Syracuse were ethnically Dorian (as were the Spartans), while the Athenians, and their ally in Sicilia, were Ionian. The Athenians felt obliged to assist their ally.

text: The Athenians did not act solely from altruism: rallied on by Alcibiades, the leader of the expedition, they held visions of conquering all of Sicily. Syracuse, the principal city of Sicily, was not much smaller than Athens, and conquering all of Sicily would have brought Athens an immense amount of resources. In the final stages of the preparations for departure, the hermai (religious statues) of Athens were mutilated by unknown persons, and Alcibiades was charged with religious crimes. Alcibiades demanded that he be put on trial at once, so that he might defend himself before the expedition. The Athenians however allowed Alcibiades to go on the expedition without being tried (many believed in order to better plot against him). After arriving in Sicily, Alcibiades was recalled to Athens for trial. Fearing that he would be unjustly condemned, Alcibiades defected to Sparta and Nicias was placed in charge of the mission. After his defection, Alcibiades claimed to the Spartans that the Athenians planned to use Sicily as a springboard for the conquest of all of Italy and Carthage, and to use the resources and soldiers from these new conquests to conquer the Peloponnese.

text: The Athenian force consisted of over 100 ships and some 5,000 infantry and light-armored troops. Cavalry was limited to about 30 horses, which proved to be no match for the large and highly trained Syracusan cavalry. Upon landing in Sicily, several cities immediately joined the Athenian cause. Instead of attacking at once, Nicias procrastinated and the campaigning season of 415 BC ended with Syracuse scarcely damaged. With winter approaching, the Athenians were then forced to withdraw into their quarters, and they spent the winter gathering allies and preparing to destroy Syracuse. The delay allowed the Syracusans to send for help from Sparta, who sent their general Gylippus to Sicily with reinforcements. Upon arriving, he raised up a force from several Sicilian cities, and went to the relief of Syracuse. He took command of the Syracusan troops, and in a series of battles defeated the Athenian forces, and prevented them from invading the city.

text: Nicias then sent word to Athens asking for reinforcements. Demosthenes was chosen and led another fleet to Sicily, joining his forces with those of Nicias. More battles ensued and again, the Syracusans and their allies defeated the Athenians. Demosthenes argued for a retreat to Athens, but Nicias at first refused. After additional setbacks, Nicias seemed to agree to a retreat until a bad omen, in the form of a lunar eclipse, delayed any withdrawal. The delay was costly and forced the Athenians into a major sea battle in the Great Harbor of Syracuse. The Athenians were thoroughly defeated. Nicias and Demosthenes marched their remaining forces inland in search of friendly allies. The Syracusan cavalry rode them down mercilessly, eventually killing or enslaving all who were left of the mighty Athenian fleet.

text: The Second War

text: The Lacedaemonians were not content with simply sending aid to Sicily; they also resolved to take the war to the Athenians. On the advice of Alcibiades, they fortified Decelea, near Athens, and prevented the Athenians from making use of their land year round. The fortification of Decelea prevented the shipment of supplies overland to Athens, and forced all supplies to be brought in by sea at increased expense. Perhaps worst of all, the nearby silver mines were totally disrupted, with as many as 20,000 Athenian slaves freed by the Spartan hoplites at Decelea. With the treasury and emergency reserve fund of 1,000 talents dwindling away, the Athenians were forced to demand even more tribute from her subject allies, further increasing tensions and the threat of further rebellion within the Empire.

text: The Corinthians, the Spartans, and others in the Peloponnesian League sent more reinforcements to Syracuse, in the hopes of driving off the Athenians; but instead of withdrawing, the Athenians sent another hundred ships and another 5,000 troops to Sicily. Under Gylippus, the Syracusans and their allies were able to decisively defeat the Athenians on land; and Gylippus encouraged the Syracusans to build a navy, which was able to defeat the Athenian fleet when they attempted to withdraw. The Athenian army, attempting to withdraw overland to other, more friendly Sicilian cities, was divided and defeated; the entire Athenian fleet was destroyed, and virtually the entire Athenian army was sold off into slavery.

text: Following the defeat of the Athenians in Sicily, it was widely believed that the end of the Athenian Empire was at hand. Her treasury was nearly empty, her docks were depleted, and the flower of her youth was dead or imprisoned in a foreign land. They overestimated the strength of their own empire and the beginning of the end was indeed imminent.

text: Athens recovers

text: Following the destruction of the Sicilian Expedition, Lacedaemon encouraged the revolt of Athens's tributary allies, and indeed, much of Ionia rose in revolt against Athens. The Syracusans sent their fleet to the Peloponnesians, and the Persians decided to support the Spartans with money and ships. Revolt and faction threatened in Athens itself.

text: The Athenians managed to survive for several reasons. First, their foes were lacking in initiative. Corinth and Syracuse were slow to bring their fleets into the Aegean, and Sparta's other allies were also slow to furnish troops or ships. The Ionian states that rebelled expected protection, and many rejoined the Athenian side. The Persians were slow to furnish promised funds and ships, frustrating battle plans.

text: At the start of the war, the Athenians had prudently put aside some money and 100 ships that were to be used only as a last resort.

text: These ships were then released, and served as the core of the Athenians' fleet throughout the rest of the war. An oligarchical revolution occurred in Athens, in which a group of 400 seized power. A peace with Sparta might have been possible, but the Athenian fleet, now based on the island of Samos, refused to accept the change. In 411 BC this fleet engaged the Spartans at the Battle of Syme. The fleet appointed Alcibiades their leader, and continued the war in Athens's name. Their opposition led to the reinstitution of a democratic government in Athens within two years.

text: Alcibiades, while condemned as a traitor, still carried weight in Athens. He prevented the Athenian fleet from attacking Athens; instead, he helped restore democracy by more subtle pressure. He also persuaded the Athenian fleet to attack the Spartans at the battle of Cyzicus in 410. In the battle, the Athenians obliterated the Spartan fleet, and succeeded in re-establishing the financial basis of the Athenian Empire.

text: Between 410 and 406, Athens won a continuous string of victories, and eventually recovered large portions of its empire. All of this was due, in no small part, to Alcibiades.

text: Lysander triumphs, Athens surrenders

text: Faction triumphed in Athens following a minor Spartan victory by their skillful general Lysander at the naval battle of Notium in 406 BC. Alcibiades was not re-elected general by the Athenians and he exiled himself from the city. He would never again lead Athenians in battle. Athens was then victorious at the naval battle of Arginusae. The Spartan fleet under Callicratidas lost 70 ships and the Athenians lost 25 ships. But, due to bad weather, the Athenians were unable to rescue their stranded crews or to finish off the Spartan fleet. Despite their victory, these failures caused outrage in Athens and led to a controversial trial. The trial resulted in the execution of six of Athens’s top naval commanders. Athens’s naval supremacy would now be challenged without several of its most able military leaders and a demoralized navy.

text: Unlike some of his predecessors the new Spartan general, Lysander, was not a member of the Spartan royal families and was also formidable in naval strategy; he was an artful diplomat, who had even cultivated good personal relationships with the Persian prince Cyrus, the son of Darius II. Seizing its opportunity, the Spartan fleet sailed at once to the Hellespont, the source of Athens' grain. Threatened with starvation, the Athenian fleet had no choice but to follow. Through cunning strategy, Lysander totally defeated the Athenian fleet, in 405 BC, at the Battle of Aegospotami, destroying 168 ships and capturing some three or four thousand Athenian sailors. Only 12 Athenian ships escaped, and several of these sailed to Cyprus, carrying the "strategos" (General) Conon, who was anxious not to face the judgment of the Assembly.

text: Facing starvation and disease from the prolonged siege, Athens surrendered in 404 BC, and its allies soon surrendered as well. The democrats at Samos, loyal to the bitter last, held on slightly longer, and were allowed to flee with their lives. The surrender stripped Athens of its walls, its fleet, and all of its overseas possessions. Corinth and Thebes demanded that Athens should be destroyed and all its citizens should be enslaved. However, the Spartans announced their refusal to destroy a city that had done a good service at a time of greatest danger to Greece, and took Athens into their own system. Athens was "to have the same friends and enemies" as Sparta.[22]

text: Aftermath

text: The overall effect of the war in Greece proper was to substitute a Spartan empire for an Athenian one. After the battle of Aegospotami, Sparta took over the Athenian empire and kept all of its tribute revenues for itself; Sparta's allies, who had made greater sacrifices for the war effort than had Sparta, got nothing.[1]

text: For a short period of time, Athens was ruled by the "Thirty Tyrants", and democracy was suspended. This was a reactionary regime set up by Sparta. In 403 BC, the oligarchs were overthrown and a democracy was restored by Thrasybulus.

text: Although the power of Athens was broken, it made something of a recovery as a result of the Corinthian War and continued to play an active role in Greek politics. Sparta was later humbled by Thebes at the Battle of Leuctra in 371 BC, but the rivalry between Athens and Sparta was brought to an end a few decades later when Philip II of Macedon conquered all of Greece except Sparta.


document_title: Insulin

question_text: where is insulin stored in the human body

question_tokens: where is insulin stored in the human body

root

text: Insulin

text: Evolution and species distribution[edit]

text: Insulin may have originated more than a billion years ago.[15] The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.[16] Apart from animals, insulin-like proteins are also known to exist in the Fungi and Protista kingdoms.[15]

tag: p

text: Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish.[17] 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.[18][19]

text: Gene[edit]

text: The preproinsulin precursor of insulin is encoded by the INS gene.[20][21]

text: Alleles[edit]

text: A variety of mutant alleles with changes in the coding region have been identified. A read-through gene, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.[20]

text: Regulation[edit]

text: In the pancreatic β cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis. Insulin is mainly regulated through the transcription factors PDX1, NeuroD1, and MafA.[22][23][24][25]

text: PDX1 (Pancreatic and duodenal homeobox protein 1) is in the nuclear periphery upon low blood glucose levels[26] interacting with corepressors HDAC1 and 2 which is downregulating the insulin secretion.[27] An increase in blood glucose levels causes phosphorylation of PDX1 and it translocates centrally and binds the A3 element within the insulin promoter.[28] Upon translocation it interacts with coactivators HAT p300 and acetyltransferase set 7/9. PDX1 affects the histone modifications through acetylation and deacetylation as well as methylation. It is also said to suppress glucagon.[29]

text: NeuroD1, also known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes involved in exocytosis.[30] 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.[30]

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.[31][32]

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 it self.[33]

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.

text:
Regulatory sequences and their transcription factors for the insulin gene.[34]

Regulatory sequence
binding transcription factors

ILPR
Par1

A5
Pdx1

negative regulatory element (NRE)[35]
glucocorticoid receptor, Oct1

Z (overlapping NRE and C2)
ISF

C2
Pax4, MafA(?)

E2
USF1/USF2

A3
Pdx1

CREB RE
–

CREB RE
CREB, CREM

A2
–

CAAT enhancer binding (CEB) (partly overlapping A2 and C1)
–

C1
–

E1
E2A, NeuroD1, HEB

A1
Pdx1

G1
–

tag: table

text: Protein structure[edit]

text: Within vertebrates, the amino acid sequence of insulin is strongly conserved. 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 (discussed later), however, differs much more among species; it is also a hormone, but a secondary one.

text: The primary structure of bovine insulin was first determined by Frederick Sanger in 1951.[36] After that, this polypeptide was synthesized independently by several groups.[37][38][39] The 3-dimensional structure of insulin was determined by X-ray crystallography in Dorothy Hodgkin's laboratory in 1969 (PDB file 1ins).[40]

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 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.[41] Insulin can aggregate and form fibrillar interdigitated beta-sheets. This can cause injection amyloidosis, and prevents the storage of insulin for long periods.[42]

text: Synthesis, physiological effects, and degradation[edit]

text: Synthesis[edit]

text: Insulin is produced in the pancreas and the Brockmann body (in some fish), and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food.[43] Carbohydrates can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response.

text: In mammals, insulin is synthesized in the pancreas within the beta cells. One million to three million pancreatic islets form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the pancreatic islets, beta cells constitute 65–80% of all the cells.

text: Insulin consists of two polypeptide chains, the A- and B- chains, linked together by disulfide bonds. It is however first synthesized as a single polypeptide called preproinsulin in beta cells. Preproinsulin contains a 24-residue signal peptide which directs the nascent polypeptide chain to the rough endoplasmic reticulum (RER).  The signal peptide is cleaved as the polypeptide is translocated into lumen of the RER, forming proinsulin.[44] In the RER the proinsulin folds into the correct conformation and 3 disulfide bonds are formed.  About 5–10 min after its assembly in the endoplasmic reticulum, proinsulin is transported to the trans-Golgi network (TGN) where immature granules are formed. Transport to the TGN may take about 30 min.

text: Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E.[45]  The endopeptidases cleave at 2 positions, releasing a fragment called the C-peptide, and leaving 2 peptide chains, the B- and A- chains, linked by 2 disulfide bonds.  The cleavage sites are each located after a pair of basic residues (lysine-64 and arginine-65, and arginine-31 and −32). After cleavage of the C-peptide, these 2 pairs of basic residues are removed by the carboxypeptidase.[46]  The C-peptide is the central portion of proinsulin, and the primary sequence of proinsulin goes in the order "B-C-A"  (the B and A chains were identified on the basis of mass and the C-peptide was discovered later).

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.[47]

text: The endogenous production of insulin is regulated in several steps along the synthesis pathway:

text:
At transcription from the insulin gene
In mRNA stability
At the mRNA translation
In the posttranslational modifications

tag: ul

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.[48][49][50]

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.[6]

text: Release[edit]

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. Reduced first-phase insulin release may be the earliest detectable beta cell defect predicting onset of type 2 diabetes.[51] First-phase release and insulin sensitivity are independent predictors of diabetes.[52]

text: The description of first phase release is as follows:

text:
Glucose enters the β-cells through the glucose transporters, GLUT2. These glucose transporters have a relatively low affinity for glucose, ensuring that the rate of glucose entry into the β-cells is proportional to the extracellular glucose concentration (within the physiological range). At low blood sugar levels very little glucose enters the β-cells; at high blood glucose concentrations large quantities of glucose enter these cells.[53]
The glucose that enters the β-cell is phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase (hexokinase IV) which is not inhibited by G-6-P in the way that the hexokinases in other tissues (hexokinase I – III) are affected by this product. This means that the intracellular G-6-P concentration remains proportional to the blood sugar concentration.[8][53]
Glucose-6-phosphate enters glycolytic pathway and then, via the pyruvate dehydrogenase reaction, into the Krebs cycle, where multiple, high-energy ATP molecules are produced by the oxidation of acetyl CoA (the Krebs cycle substrate), leading to a rise in the ATP:ADP ratio within the cell.[54]
An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/Kir6.2 potassium channel (see sulfonylurea receptor). This prevents potassium ions (K+) from leaving the cell by facilitated diffusion, leading to a buildup of intracellular potassium ions. As a result, the inside of the cell becomes less negative with respect to the outside, leading to the depolarization of the cell surface membrane.
Upon depolarization, voltage-gated calcium ion (Ca2+) channels open, allowing calcium ions to move into the cell by facilitated diffusion.
The cytosolic calcium ion concentration can also be increased by calcium release from intracellular stores via activation of ryanodine receptors.[55]
The calcium ion concentration in the cytosol of the beta cells can also, or additionally, be increased through the activation of phospholipase C resulting from the binding of an extracellular ligand (hormone or neurotransmitter) to a G protein-coupled membrane receptor. Phospholipase C cleaves the membrane phospholipid, phosphatidyl inositol 4,5-bisphosphate, into inositol 1,4,5-trisphosphate and diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the plasma membrane of the endoplasmic reticulum (ER). This allows the release of Ca2+ ions from the ER via IP3-gated channels, which raises the cytosolic concentration of calcium ions independently of the effects of a high blood glucose concentration. Parasympathetic stimulation of the pancreatic islets operates via this pathway to increase insulin secretion into the blood.[56]
The significantly increased amount of calcium ions in the cells' cytoplasm causes the release into the blood of previously synthesized insulin, which has been stored in intracellular secretory vesicles.

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),[57] and the gastrointestinally derived incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).

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 α2-adrenergic receptors[58] and stimulated by β2-adrenergic receptors.[59] 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.[60]

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.

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.

text: Oscillations[edit]

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.[61] This is thought to avoid downregulation of insulin receptors in target cells, and to assist the liver in extracting insulin from the blood.[61] 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.[61] This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver.[61]

text: Blood insulin level[edit]

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.[62] A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).[63]

text: Signal transduction[edit]

text: The effects of insulin are initiated by its binding to a receptor 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.[64]

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.[65] PKB also phosphorylates glycogen synthase kinase (GSK), thereby inactivating this enzyme.[66] 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.[67] The breakdown of triglycerides by adipose tissue into free fatty acids and glycerol is also inhibited.[67]

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.[47]  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.

text: The structure of the insulin–insulin receptor complex has been determined using the techniques of X-ray crystallography.[68]

text: Physiological effects[edit]

text: The actions of insulin on the global human metabolism level include:

text:
Increase of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells)[69]
Increase of DNA replication and protein synthesis via control of amino acid uptake
Modification of the activity of numerous enzymes.

text: The actions of insulin (indirect and direct) on cells include:

text:
Stimulates the uptake of glucose –  Insulin decreases blood glucose concentration by inducing intake of glucose by the cells. This is possible because Insulin causes the insertion of the GLUT4 transporter in the cell membranes of muscle and fat tissues which allows glucose to enter the cell.[64]
Increased fat synthesis – insulin forces fat cells to take in blood glucose, which is converted into triglycerides; decrease of insulin causes the reverse.[69]
Increased esterification of fatty acids – forces adipose tissue to make neutral fats (i.e., triglycerides) from fatty acids; decrease of insulin causes the reverse.[69]
Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids and glycerol; decrease  of insulin causes the reverse.[69]
Induce glycogen synthesis – When glucose levels are high, insulin induces the formation of glycogen by the activation of the hexokinase enzyme, which adds a phosphate group in glucose, thus resulting in a molecule that cannot exit the cell. At the same time, insulin inhibits the enzyme glucose-6-phosphatase, which removes the phosphate group. These two enzymes are key for the formation of glycogen. Also, insulin activates the enzymes phosphofructokinase and glycogen synthase which are responsible for glycogen synthesis.[70]
Decreased gluconeogenesis and glycogenolysis – decreases production of glucose from noncarbohydrate substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); increase of insulin causes glucose production by the liver from assorted substrates.[69]
Decreased proteolysis – decreasing the breakdown of protein[69]
Decreased autophagy – decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.[71]
Increased amino acid uptake – forces cells to absorb circulating amino acids; decrease of insulin inhibits absorption.[69]
Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; decrease of insulin reduces flow by allowing these muscles to contract.[citation needed]
Increase in the secretion of hydrochloric acid by parietal cells in the stomach.[citation needed]
Increased potassium uptake – forces cells synthesizing glycogen (a very spongy, "wet" substance, that increases the content of intracellular water, and its accompanying K+ ions)[72] to absorb potassium from the extracellular fluids; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood plasma.  This possibly occurs via insulin-induced translocation of the Na+/K+-ATPase to the surface of skeletal muscle cells.[73][74]
Decreased renal sodium excretion.[75]

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.[76] 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.[77] Insulin also has stimulatory effects on gonadotropin-releasing hormone from the hypothalamus, thus favoring fertility.[78]

text: Degradation[edit]

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. 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).[79][80]

text: Regulator of endocannabinoid metabolism[edit]

text: Insulin is a major regulator of endocannabinoid (EC) metabolism and insulin treatment has been shown to reduce intracellular ECs, the 2-arachidonylglycerol (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.[81][82] 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.[83]

text: Hypoglycemia[edit]

text: Hypoglycemia, also known as "low blood sugar", is when blood sugar decreases to below normal levels.[84] This may result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures or death.[84] A feeling of hunger, sweating, shakiness and weakness may also be present.[84] Symptoms typically come on quickly.[84]

text: The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin and sulfonylureas.[85][86] Risk is greater in diabetics who have eaten less than usual, exercised more than usual or have drunk alcohol.[84] 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.[84][86] Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.[87]

text: Diseases and syndromes[edit]

text: This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2018) (Learn how and when to remove this template message)

text: There are several conditions in which insulin disturbance is pathologic:

text:
Diabetes mellitus – general term referring to all states characterized by hyperglycemia
Type 1 – autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency
Type 2 – either inadequate insulin production by the β-cells or insulin resistance or both because of reasons not completely understood.
there is correlation with diet, with sedentary lifestyle, with obesity, with age and with metabolic syndrome. Causality has been demonstrated in multiple model organisms including mice and monkeys; Importantly, non-obese people do get Type 2 diabetes due to diet, sedentary lifestyle and unknown risk factors.
it is likely that there is genetic susceptibility to develop Type 2 diabetes under certain environmental conditions
Other types of impaired glucose tolerance (see the Diabetes)
Insulinoma – a tumor of beta cells producing excess insulin or reactive hypoglycemia.
Metabolic syndrome – a poorly understood condition first called Syndrome X by Gerald Reaven. It is currently not clear whether the syndrome has a single, treatable cause, or is the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance that precedes type 2 diabetes, which is a diminished capacity for insulin response in some tissues (e.g., muscle, fat). It is common for morbidities such as essential hypertension, obesity, type 2 diabetes, and cardiovascular disease (CVD) to develop.
Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where anovulation and androgen excess are commonly displayed as hirsutism. In many cases of PCOS, insulin resistance is present.

text: Medical uses[edit]

text: Biosynthetic human insulin (insulin human rDNA, INN) for clinical use is manufactured by recombinant DNA technology.[10] 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.[88] This technique is anticipated to reduce production costs.

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).[89] The first biosynthetic insulin analog was developed for clinical use at mealtime (prandial insulin), Humalog (insulin lispro),[citation needed] 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.

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 now.

text: Synthetic insulin can trigger adverse effects, so some people with diabetes rely on animal-source insulin.[90]

text: Unlike many medicines, insulin currently cannot be taken orally 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.[91][92]

text: History of study[edit]

text: Discovery[edit]

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.[93] 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.[94] Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term "insulin" originates from insula, the Latin word for islet/island.

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".[95][96][97]

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.[98]

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".[99][100]

text: Extraction and purification[edit]

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 certain arteries could be tied off that would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. He jotted a note to himself: "Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosuria."[101]

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 keep Best for the entire summer and eventually shared half his Nobel Prize money and credit for the discovery with Best.[102] 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.[103][101]

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.[101]

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.[104] However, the extract was so impure that Thompson suffered a severe allergic reaction, and further injections were canceled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract. A second dose was injected on January 23, completely 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.[105]  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.[106]

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.

text: Synthesis[edit]

text: Purified animal-sourced insulin was initially the only type of insulin available to diabetics. The amino acid structure of insulin was characterized in the early 1950s by Frederick Sanger,[107] and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the early 1960s.[108][109] Synthetic crystalline bovine insulin was achieved by Chinese researchers in 1965.[110]

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.[11][12] 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.[12] The vast majority of insulin currently used worldwide is now biosynthetic recombinant "human" insulin or its analogues.[13]

text: Recombinant insulin is produced either in yeast (usually Saccharomyces cerevisiae) or E. coli.[111] 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.

text: Nobel Prizes[edit]

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.[112] They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin. Banting, insulted that Best was not mentioned, shared his prize with him, and Macleod immediately shared his with James Collip. The patent for insulin was sold to the University of Toronto for one half-dollar.

text: Two other Nobel Prizes have been awarded for work on insulin. British molecular biologist Frederick Sanger determined the primary structure of insulin in 1955, making it the first protein to be sequenced.[107] Sanger was awarded the 1958 Nobel Prize in Chemistry for this work. Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for 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.[113] Dorothy Hodgkin was awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography. In 1969, after decades of work, Hodgkin determined the spatial conformation of insulin, the so-called tertiary structure, by means of X-ray diffraction studies.

text: Controversy[edit]

text: The work published by Banting, Best, Collip and Macleod represented the preparation of purified insulin extract suitable for use on human patients.[114] 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:

text: Insufficient recognition has been given to Paulescu, the distinguished Romanian scientist, who at the time when the Toronto team were commencing their research had already succeeded in extracting the antidiabetic hormone of the pancreas and proving its efficacy in reducing the hyperglycaemia in diabetic dogs.[115]

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.[116]


document_title: Welfare state in the United Kingdom

question_text: when did the welfare state began in britain

text: Welfare state in the United Kingdom

text: History[edit]

text: In 1984 historian Derek Fraser told the British story in a nutshell. The welfare state, he said:[3]

text: The welfare state in the modern sense was anticipated by the Royal Commission into the Operation of the Poor Laws 1832 which found that the old poor law (a part of the English Poor laws) was subject to widespread abuse and promoted squalor, idleness and criminality in its recipients, compared to those who received private charity. Accordingly, the qualifications for receiving aid were tightened up, forcing many recipients to either turn to private charity or accept employment.

text: Opinions began to be changed late in the century by reports drawn up by men such as Seebohm Rowntree and Charles Booth into the levels of poverty in Britain. These reports indicated that in the massive industrial cities, between one-quarter and one-third of the population were living below the poverty line.

text: Liberal reforms[edit]

text: The Liberal Party launched the welfare state in Britain with a series of major Liberal welfare reforms in 1906–1914.[4] The reforms were greatly extended over the next forty years.[4]

text: The minimum wage was introduced in Great Britain in 1909 for certain low-wage industries and expanded to numerous industries, including farm labour, by 1920. However, by the 1920s, a new perspective was offered by reformers to emphasise the usefulness of family allowance targeted at low-income families was the alternative to relieving poverty without distorting the labour market.[5][6] The trade unions and the Labour Party adopted this view. In 1945, family allowances were introduced; minimum wages faded from view.

text: The experience of almost total state control during the Second World War had encouraged the belief that the state might be able to solve problems in wide areas of national life.[7]

text: The Liberal government of 1906–1914 implemented welfare policies concerning three main groups in society: the old, the young and working people.[4]

text:
In 1906 local authorities were allowed to provide free school meals.[8]
The Children and Young Persons Act 1908 introduced a set of regulations that became known as the Children's Charter. This imposed severe punishments for neglecting or treating children cruelly. It was made illegal to sell cigarettes to children or send them out begging. Separate juvenile courts were set up, which sent children convicted of a crime to borstals (a forerunner to modern youth detention centres), instead of prison.[9]

text: In 1908 pensions were introduced for the over 70s.[10]

text:
In 1909 Labour Exchanges were set up to help unemployed people find work.[11]
The National Insurance Act 1911 was passed, ensuring free medical treatment, and sick pay of 10 shillings a week for 26 weeks.[4] An estimated 13 million workers came to be compulsorily covered under this scheme.[12]

text: Beveridge Report and Labour[edit]

text: The aftermath of the First World War boosted demands for social reform, and led to a permanent increase in the role of the state in British society. The end of the war also brought a slump, particularly in northern industrial towns, that deepened into the Great Depression by the 1930s.[7]

text: During the war, the government became much more involved in people's lives via governmental organisation of the rationing of foodstuffs, clothing and fuel and extra milk and meals being given to expectant mothers and children.[7] The wartime coalition government also committed itself to full employment through Keynesian policies, free universal secondary education, and the introduction of family allowances.[13] Many people welcomed this government intervention and wanted it to go further.[7]

text: The Beveridge Report of 1942, (which identified five "Giant Evils" in society: squalor, ignorance, want, idleness and disease) essentially recommended a national, compulsory, flat rate insurance scheme which would combine health care, unemployment and retirement benefits. Beveridge himself was careful to emphasise that unemployment benefits should be held to a subsistence level, and after six months would be conditional on work or training, so as not to encourage abuse of the system.[14] That was however predicated on the concept of the "maintenance of employment" which meant ‘it should be possible to make unemployment of any individual for more than 26 weeks continuously a rare thing in normal times’ [14] and recognised that the imposition of a training condition would be impractical if the unemployed were numbered by the million.[14] After its victory in the 1945 general election, the Labour Party pledged to eradicate the Giant Evils, and undertook policy measures to provide for the people of the United Kingdom "from the cradle to the grave."

text: Included among the laws passed were the National Assistance Act 1948, National Insurance Act 1946, and National Insurance (Industrial Injuries) Act 1946.

text: Impact[edit]

text: This policy resulted in increased expenditure and a widening of what was considered to be the state's responsibility. In addition to the central services of education, health, unemployment and sickness allowances, the welfare state also included the idea of increasing redistributive taxation, increasing regulation of industry, food, and housing (better safety regulations, weights and measures controls, etc.)

text: The foundation of the National Health Service (NHS) did not involve building new hospitals, but nationalisation of existing municipal provision and charitable foundations. The aim was not to substantially increase provision but to standardise care across the country; indeed William Beveridge believed that the overall cost of medical care would decrease, as people became healthier and so needed less treatment.

text: However, instead of falling, the cost of the NHS has risen by 4% annually on average due to an ageing population,[15] leading to a reduction in provision. Charges for dentures, and spectacles were introduced in 1951 by the same Labour government that had founded the NHS three years earlier, and prescription charges by the successive Conservative Government were introduced in 1952.[16] In 1988, free eye tests for all were abolished, although they are now free for the over-60s.[17]

text: Policies differ in different countries of the United Kingdom, but the provision of a welfare state is still a basic principle of government policy in the United Kingdom today. The principle of health care "free at the point of use" became a central idea of the welfare state, which later Conservative governments, although critical of some aspects of the welfare state, did not reverse.

text: Expenditure[edit]

text: In the financial year 2014/15, state pensions were overwhelmingly the largest governmental welfare expense, costing £86,500,000,000 followed by housing benefit, which accounted for over £20,000,000,000[18] Expenditure in 2015–16 on benefits included: £2,300,000,000 paid to unemployed people and £27,100,000,000 to people on low incomes, and £27,600,000,000 for personal tax credits.[19][20]

text: UK Government welfare expenditure 2011–12 (percent)

text:
UK Government welfare expenditure 2014–15[18]

Benefit
Expenditure (£bn)

State pension
86.5

Tax credits (Working tax credits and Child tax credits)
29.7

Housing Benefit
23.5

Disability Living Allowance
15.4

Incapacity benefits
14.1

Child benefit
11.6

Pension Credit
6.6

Attendance Allowance
5.4

Jobseeker's allowance
3.1

Income Support
2.6

Maternity and paternity pay
2.4

Carer's allowance
2.3

Winter fuel payments
2.1

War pensions
0.8

Universal credit
0.1

Other
5.9

TOTAL
pounds 213.9

text: Criticisms[edit]

text: Critics of the welfare state claim that, in addition to the vast expense, by relieving citizens of personal responsibility for their own welfare the government has inadvertently promoted irresponsible and immature attitudes, with the result that squalor, ignorance, and idleness are common.[21][22] In 1980, T. E. Utley, wrote that the welfare state was "an arrangement under which we all largely cease to be responsible for our own behaviour and in return become responsible for everyone else's. The temptations which this way of doing things offers to synthetic anger, fraudulent penitence, all other forms of hypocrisy and the sheer evasion of duty are infinitely too strong for fallen man".[23]

text: In 2010, the Conservative-Lib Dem coalition government led by David Cameron has argued for a reduction of welfare spending in the United Kingdom as part of their programme of austerity.[24] Government ministers have argued that a growing culture of welfare dependency is perpetuating welfare spending, and claim that a cultural change is required to reduce the welfare bill.[25] Public opinion in the UK appears to support a reduction in welfare spending, however commentators have suggested that negative public perceptions are founded on exaggerated assumptions about the proportion of spending on unemployment benefit and the level of benefit fraud.[26][27]

text: Figures from the Department for Work and Pensions show that benefit fraud is thought to have cost taxpayers £1,200,000,000 during 2012–13, up 9% on the year before.[28] This is lower than the £1,500,000,000 of benefit underpayment due to error.[29]

text: There are also widespread complaints from church groups and others that the UK welfare state does insufficient work to prevent hunger.[30]

text: Historical statistics on welfare trends[edit]

text: Benefit rates as a percentage of industrial earnings[edit]

text:
Benefit rates as a per cent of industrial earnings of male manual workers aged 21 and over (1948–71)[31]

Year (month)
Single pension
Supplementary Benefit for single person
Family Allowance for four children

1948 (October)
18.9
17.5
10.9

1961 (April)
19.1
17.8
9.3

1962 (April)
18.4
17.1
8.9

1963 (May)
20.8
19.5
8.6

1964 (April)
19.2
18.1
8.0

1964 (October)
18.7
17.6
7.7

1965 (April)
21.2
20.1
7.4

1965 (October)
20.4
19.4
7.1

1966 (April)
19.8
18.8
6.9

1966 (October)
19.7
20.0
6.9

1967 (April)
19.4
19.7
6.8

1967 (October)
21.0
20.1
7.7

1968 (April)
20.2
19.3
11.9

1968 (October)
19.6
19.8
12.6

1969 (April)
18.8
19.3
12.1

1969 (November)
20.0
19.2
11.7

1970 (April)
19.0
18.3
11.3

1970 (November)
17.6
18.3
10.2

1971 (March) (est.)
17.3
18.0
10.0

text: Note on source, as quoted in the text: "based on statistics of weekly earnings, Employment and Productivity Gazette."

text: Changes in National Assistance/Supplementary Benefit[edit]

text:
Changes in National Assistance/Supplementary Benefit scale (1963–1969) (a)[31]

Date of change
Real value single pensioner
Real value married man with three children (b)
Real take home pay for average worker

May 1963
100
100
100

March 1965
111
112
106

November 1966
117
110
106

October 1967
122
115
108

November 1969
122
115
110

text:
(a) As quoted in the text: "the scale is calculated using the average discretionary addition (adjusted to spread winter fuel costs throughout the year) for retirement pensioners. It does not include any allowance for rent. The price index used for the single pensioner is that in the Employment and Productivity Gazette."
(b) As quoted in the text: "it is assumed that the children are aged four, six, and eleven."

text: Increases in National Insurance benefits[edit]

text:
Increases in National Insurance benefits (1963–69):[31]

Date of increase
Real take home pay for average worker (a)
Real value of single pension (b)
Real value of unemployment benefit
(man with wife and three children) (c)

March/May 1963
100
100
100

January/March 1965
106
111
110

October 1967
108
114
113

November 1969
110
114
116

text:
(a) As quoted by text: "Based on average earnings for adult male manual workers in manufacturing, allowing for income tax and national insurance contributions.
(b) As quoted by text: "Calculated on the special price index for single pensioner households published by the Employment and Productivity Gazette adjusted for housing expenditure using the housing component of the retail price index. Since a disproportionate number of pensioners have controlled tenancies, this may overstate the increase in prices."
(c) This column is deflated by use of the Retail Price Index

text: Social security benefits as a percentage of average earnings[edit]

text:
Social security benefits as a percentage of average earnings for last increases of various governments, 1951–79[32]

Government
Sickness/unemployment benefit a
a plus earnings related supplement
Retirement pensions c
Supplementary allowance/benefits d
Family allowance/child benefit e

Labour (1951)
25.7
25.7
30.4
30.4
8.0

Conservative (1963)
33.8
33.8
33.0
31.6
5.3

Labour (1969)
32.4
52.3
32.4
31.4
3.8

Conservative (1973)
29.1
46.2
30.5
28.5
3.0

Labour (1978)
30.5
44.4
37.4
30.2
3.7

text:
a,b Man plus dependent wife.
c Man plus dependent wife on his insurance.
d Married couple.
e For one child.

text: Social policy benefits and earnings under the Labour Government 1963–69[edit]

text:
Social policy benefits and earnings under Labour 1963–69:[33]

Year
Unemployment, sickness, and retirement benefits (single)
Retirement pension (married)
National assistance/supplementary benefit (married couple)
Adult male manual workers (weekly earnings)
Adult male administrative, technical, and clerical employees (weekly earnings)

1963
100
100
100
100
100

1969
148
149
150
154
148

text: Supplementary benefits rates as a proportion of income[edit]

text:
Supplementary benefit rates as a proportion of gross and net income at average earnings, married couple:[34]

Year
End of year (a)

As % of gross average earnings

Ordinary rate
Long term rate

1973
28.5
31.4

1974
28.1
33.6

1975
29.8
36.2

1976
30.8
37.1

1977
32.3
38.9

1978
30.6
37.8

As % of net income (b) at average earnings

Ordinary rate
Long term rate

1973
37.9
41.8

1974
38.8
46.5

1975
42.4
51.5

1976
43.9
52.9

1977
44.1
53.1

1978
41.6
51.4

text:
Supplementary benefit: long term scale rate as proportion of ordinary rate (%)

Date of introduction
Single
Married couple

1973
14.0
10.3

1974
23.8
19.8

1975 (April)
25.0
20.4

1975 (November)
25.7
21.4

1976
23.6
20.3

1977
23.4
20.4

1978
28.0
23.5

text: Households dependent on Supplementary Benefit[edit]

text:
Numbers in households dependent on supplementary benefit or with estimated incomes below SB level, 1974 and 1976 (thousands)

Year
Pensioners
Under pensionable age family head or single parent

(as % of total)
Unemployed
Normally in full-time work
Sick or disabled
Others

1974
2,680
(52%)
450
360
480
1,170

1976
2,800
(44%)
1,080
890
280
1,300

text: Changes in real terms in social security benefits[edit]

text:
Changes in real terms in social security benefits, 1964–79 (in 1981 prices, 1951= 100):[32]

Year
Supplementary benefits (a)
Sickness/unemployment benefit (b)
Retirement pensions (c)
Family allowance/child benefit (d)

1964
146
176
149
85

1965
166
199
168
85

1966
165
199
168
82

1967
173
318
173
80

1968
173
318
173
77

1969
172
329
172
72

1970
173
329
172
69

1971
178
354
177
80

1972
187
356
183
75

1973
186
342
191
68

1974
191
345
216
78

1975
187
327
215
69

1976
189
323
219
72

1977
190
326
221
69

1978
189
321
228
82

1979
190
308
232
102

text:
(a) Refers to married couple.
(b) Refers to man plus dependent wife.
(c) Refers to man plus wife on his insurance. After 1971 refers to recipients under 80 years old.
(d) Includes family allowance and tax allowance combined for second child up to 1977, when these were unified into the child benefit.

text: Percentage change in social security benefits, prices and earnings[edit]

text:
Percentage change in social security benefits, prices, and earnings since previous updating (1974–1978):[34]

Date
Unemployment and sickness benefit (a)
Retirement pension (b)
Prices (c)
Average earnings (d)

July 1974
17.0
29.0
13.5
12.9

April 1975
14.0
16.0
17.7
17.4

November 1975
13.3
14.7
11.7
10.7

November 1976
16.2
15.0
15.0
12.8

November 1977
14.0
14.4
13.0
9.6

November 1978
7.1
11.4
8.1
14.6

Total increase October 1973–1978
114.3
151.6
109.6
107.9

text:
(a) Single person.
(b) Single pensioner under age 80.
(c) General index of retail prices.
(d) Average gross weekly earnings of full-time adult male manual workers. For November 1978, October 1977 to October 1978 increase used.

text: Unemployment and sickness benefits as a percentage of income[edit]

text:
Unemployment or sickness benefits as percentage of net income (a) at average earnings (b):[34]

Year
Single person
Married couple
Married couple with two children

Excl. ERS
Inc. ERS (c)
Excl. ERS
Inc. ERS (c)
Excl. ERS
Inc. ERS (c)

1965
27.0
27.0
41.2
41.2
49.3
49.3

1970
25.0
53.3
38.4
65.2
48.3
72.7

1973
24.8
48.4
38.7
61.5
49.5
70.6

1974
25.6
48.6
39.5
61.6
50.2
70.3

1975
24.5
45.9
38.0
58.4
48.3
67.0

1976
24.9
46.7
38.3
59.1
48.4
67.3

1977
25.8
47.9
39.1
59.9
49.7
68.8

1978
25.4
45.1
38.8
57.4
49.6
66.9

text:
(a) After allowing for income tax and national insurance contributions.
(b) Average earnings of adult male manual workers.
(c) Earnings Related Supplement calculated using average earnings in October of the relevant tax year.

text: The real value of social security benefits, 1948–75 (£s, 1981 prices)[edit]

text: Unemployment benefit[35]

text: July 1948: 19.64

text: April 1961: 26.88

text: September 1971: 34.96

text: November 1975: 36.47

text: Retirement pension[35]

text: July 1948: 19.64

text: April 1961: 26.88

text: September 1971: 34.96

text: November 1975: 42.96

text: Supplementary benefit[35]

text: July 1948: 17.93

text: April 1961: 25.31

text: September 1971: 33.39

text: November 1975: 35.10

text: Child support: one child[35]

text: July 1948: 4.87

text: April 1961: 4.36

text: September 1971: 4.27

text: November 1975: 3.67

text: Child support: three children[35]

text: July 1948: 17.60

text: April 1961: 16.62

text: September 1971: 15.36

text: November 1975: 13.81


document_title: Impractical Jokers

question_text: where are the guys from impractical jokers from

text: Impractical Jokers

text: Development[edit]

text: Joseph "Joe" Gatto, James "Murr" Murray, Brian "Q" Quinn, and Salvatore "Sal" Vulcano, four high school friends who attended Monsignor Farrell High School, from Staten Island, New York, formed the live improv and sketch comedy troupe, The Tenderloins in 1999. After a long and successful history, including winning the $100,000 grand prize in NBC's "It’s Your Show" competition, the group went into television. In 2008, they filmed a pilot episode for a scripted sitcom for Spike TV, but the show did not go to series. TruTV announced the series Impractical Jokers, originally slated to be named Mission: Uncomfortable, on April 12, 2011, eight months before the show's debut. Murray explained how the hidden camera format made sense based on the jokesters skills. "We needed to find the right format... thing is, we've been doing this for years, but when it's on camera, the embarrassment is amplified."[5] Q and Sal have said when they gave their pilot episode to TruTV, it was recorded on their iPhones. At the time they pitched the idea to TruTV, Murray was VP of Development for NorthSouth Productions, the company that has produced the series since its inception.

text: Episodes[edit]

text:
Season
Episodes
Originally aired

First aired
Last aired

1
16
December 15, 2011 (2011-12-15)
May 4, 2012 (2012-05-04)

2
28
September 6, 2012 (2012-09-06)
December 12, 2013 (2013-12-12)

3
31
January 2, 2014 (2014-01-02)
October 30, 2014 (2014-10-30)

4
26
January 29, 2015 (2015-01-29)
October 22, 2015 (2015-10-22)

5
26
February 11, 2016 (2016-02-11)
November 3, 2016 (2016-11-03)

6
26[6]
February 9, 2017 (2017-02-09)
November 2, 2017 (2017-11-02)

Specials
18
February 2, 2012 (2012-02-02)
TBA

text: Before every challenge, the Jokers explain where they are, what the challenge is, and what will happen if they fail. Often (but not always) there is an ear piece placed on the cast member(s) performing the prank while the others have a mic in a covert location. There are also hidden cameras near the area to capture the action. The location in which the challenge takes place is usually a public area in or around New York City such as a city park, or store. The criteria of each challenge are the same for each of the jokers competing in the round. If the joker cannot complete their task, they get a Thumbs-Down. At the end of the episode, the joker or jokers with the most thumbs down is punished, and the punishments are usually more embarrassing, humiliating, disgusting, painful or scary than any of the challenges. Punishments cannot be refused, or the joker is off the show.

text: Statistics[edit]

text:
Impractical Jokers statistics

Joker
Punishments
Thumbs down
Thumbs up
Challenges

Joe
34 (22.9%)
131 (35.1%)
244 (66.2%)
370 (89.5%)

Murr
47 (32.3%)
161 (48.1%)
220 (59.7%)
373 (90.6%)

Q
36 (25.0%)
130 (35.7%)
240 (65.8%)
368 (89.4%)

Sal
52 (36.1%)
156 (42.2%)
225 (60.3%)
370 (89.5%)

text:
Some statistics have been rounded.
Some challenges involved double-thumbs down; punishment percentage rates based on total episodes that involve punishments (145 out of 148) challenge percentage rates based on total challenges attempted (413 as of September 28, 2017)

text: In some instances, a joker can bet that another joker can't complete a (usually difficult) task. If the task is complete, the challenge will end (even if not all jokers participated), and the joker who loses the bet loses the entire episode, regardless of the loser board. This has only happened on three occasions in the show's run.

text: Cast[edit]

text: Main[edit]

text: Brian "Q" Quinn (born March 14, 1976) is an American improvisational comedian from the New York City borough of Staten Island. He attended Monsignor Farrell High School where he was involved in numerous activities including drama and sports.[7] Following his graduation, he attended Brooklyn College and later went on to join the New York City Fire Department.[8] He is also the third host of the podcast Tell 'Em Steve-Dave! on SModcast.com.

text: James "Murr" Murray (born May 1, 1976) is an American improvisational comedian from the New York City borough of Staten Island. He attended Monsignor Farrell High School there and was also a part of a community theatre.[7] He continued his education at Georgetown University where he received a BA in English.[9] He currently continues to work at NorthSouth Productions where he is the Senior Vice President of Development.[10]

text: Salvatore "Sal" Vulcano (born November 6, 1976) is an American improvisational and stand-up comedian from the New York City borough of Staten Island. He attended Monsignor Farrell High School in Staten Island where he took part in various sports such as hockey, basketball and football. He received degree in Finance from St. John's University.

text: Joseph "Joe" Gatto Jr. (born June 5, 1976) is an American improvisational comedian from the New York City borough of Staten Island. While in Staten Island, he went to Monsignor Farrell High School.[7] After graduation, he studied at LIU Post where he received a degree in Accounting.[11] He founded the Tenderloins comedy troupe in 2000 and worked at the baby retail store, Giggle, until January 2011.[12]

text: Guest appearances[edit]

text:
Daniel Ribacoff Season 2
Imagine Dragons Season 2
Joey Fatone Season 3, 5,6
Tommy Dreamer Season 3, 6
Soren Thompson Season 4
Danica McKellar Season 4,6
Ulambayaryn Byambajav Season 4
Alex Brightman Season 5
Howie Mandel Season 4
Rosie O'Donnell Season 2
James Buckley Season 5
Travis Pastrana Season 5
Gary Busey Season 6
Bully Ray Season 6
Velvet Sky Season 6
Jesse Bravo Season 6
Matthew Lewis Season 6
Victoria Justice Season 6
Noah Syndergaard Season 6
Kayla Harrison Season 6
Casey Jost Season 5,6

text: Reception[edit]

text: Impractical Jokers has been very well received by some critics with Linda Stasi of the New York Post calling it "possibly the funniest, most ridiculous show I’ve seen in years."[13]

text: While it has been compared to earlier hit prank shows such as Candid Camera and Jackass, critics have offered praise for its unique twist on the genre, wherein the stars' reactions to the pranks are often equally as humorous as those of the innocent bystanders. Neil Genzlinger of The New York Times stated that "the gag pays off twice: once in the reaction of the unsuspecting passer-by, once in the discomfort of the fellow doing the asking." He later wrote that the cast-members' occasional integrity [kept] these four clowns a little bit lovable."[14] Dean Robbins of The Daily Page echoed this sentiment, stating that "the friends are jovial rather than Jackass-obnoxious, even rejecting some dares as too offensive."[15]

text: The series has been generally well received, garnering 1.5 million viewers during its December 15, 2011, premiere.[16]

text: The review of the show by Variety's Brian Lowry was less positive, ending with this statement: "Nobody will ever confuse Impractical Jokers with high art, certainly, but as low-brow, micro-cost comedy in the context of TruTV's programming resources, it's actually quite practical—and occasionally funny."[17]

text: Impractical Jokers: Inside Jokes[edit]

text: Impractical Jokers: Inside Jokes is a spin-off of Impractical Jokers in which episodes that have already aired are shown again with pop-up facts throughout, including behind-the-scenes stories and facts directly from the Jokers. The first episode of Impractical Jokers: Inside Jokes aired on July 14, 2016, following the mid season British special"[18][19]

text: Impractical Jokers: After Party[edit]

text: Impractical Jokers: After Party is a spin-off of Impractical Jokers, hosted by Joey Fatone, in which the Jokers and surprise guests go through a deep dive of challenges, special play-by-play punishment analysis from the latest episode, and bonus content from the latest episode or the whole show. The first episode of the series aired on August 3, 2017 after the episode "The Q-Pay" had aired.

text: International versions[edit]

text:
A UK version of Impractical Jokers began airing in winter 2012 on BBC Three. It starred comedians Paul McCaffrey, Joel Dommett, Marek Larwood and Roisin Conaty.[20] The pilot was filmed and placed online as part of "The Comedy Kitchen" in 2012. The first series included six episodes, which aired from November 15 - December 20, 2012. The second series also included six episodes, and aired from February 24 - April 2, 2014. It is produced by Yalli Productions.[21] It was cancelled after Series 2 in April 2014 mainly due to its unpopularity. However, more recently, Comedy Central and Channel 5 picked up the rights to co-produce a third season of Impractical Jokers UK with Yalli Productions, starring Late Night Gimp Fight.[22]
 A Dutch version was broadcast on Veronica in 2013, called "De Fukkers". In 2015 a new version started at RTL 5 with the name "Foute Vrienden", like the Flemish version.[23]
 A Belgian (Flemish) version broadcast on 2BE in fall 2012, with the title "Foute Vrienden". James Murray was spotted in episode 5 of the first season.[24] The second season, which started in March 2014, includes 10 episodes.
 A Brazilian version is currently being broadcast on SBT with the title "Amigos da Onça". The series premiere aired January 7, 2013[25] and ended August 13, 2013. James Murray was spotted in episode 3 of the second season.
 A Lebanese version broadcast on Al Jadeed in autumn / fall 2013.
 A Mexican version broadcast on TBS Latin America started in May 20, 2015 with the title "Impractical Jokers".
 A Greek version broadcast on Ant1 in February 2014 with the title "Wanted".
 A French-Canadian version broadcast on V in February 24, 2014 with the title "Les Jokers".
 A Swedish version broadcast on TV6 in April 2014 with the title "Radiostyrd".
 A Spanish version broadcast on Neox in 2014 with the title "Sinvergüenzas".
 An Egyptian version was released in 2015 with the title "Al Mohayesoun".[26]

text: International broadcasts[edit]

text:
On April 18, 2014, during the first ever live recording of their "What Say You?" Podcast at the Prince Charles Cinema in London, Q and Sal stated that, when the BBC bought the rights to create a UK version of the show, they also bought the rights to air the US version of the show in the UK. This was meant to be aired after the 1st season of the UK show, but the BBC never aired it. However it finally came to air on August 22, 2014. The US version now airs on Comedy Central UK and Channel 5.
 It is presently airing on RTÉ2 in Ireland
 The series currently airs on Comedy Central India (India, Pakistan, Bangladesh, Sri Lanka, Nepal, Bhutan and Maldives), WB Channel (India, Sri Lanka, Nepal, Bhutan and Maldives) and WB Channel Pakistan (Pakistan, Bangladesh, Afghanistan, Iran and Tajikistan)
 The series currently airs in Canada on ACTION, CMT and OLN.[27]
 It is currently being shown in Australia on the Nine Network.
 It is currently being shown in New Zealand on Comedy Central New Zealand.
 The series currently airs in France and Belgium on MTV France with the title "Les Jokers".
 The series currently airs in Italy on DMAX with the title "Cattivissimi amici".
 The series currently airs in Spain on Neox and Comedy Central Spain with the title "Agárralos como Puedas".
 The series currently airs in Brazil on TBS with the title "Tirando a Maior Onda".
 The series currently airs in Bulgaria on BTV with the title "Шегаджии".[28]
 The series currently airs in Germany on ProSieben Maxx.[29]
 The original series currently airs in Poland on TTV.
 The original series currently airs in Russia on MTV Russia with the title "Нереальные подставы" (Unreal Trolling).[30]
 The show aired on +TVI with the original title.
 In Malaysia, Impractical Jokers is shown in Warner TV.
 The original series currently airs in the Netherlands on RTL 5.
 The series currently airs in Vietnam on Warner TV.