This is a working overview of Dual agonist, written for readers who want more than a one-paragraph summary but less than a textbook.
This page was last updated on 2026-05-30 and is reviewed periodically as new material appears.
At the receptor level, the compound binds both GIP and GLP-1 receptors and triggers downstream signalling that raises cyclic AMP in target cells. GLP-1 receptor activation is associated with glucose-dependent insulin release, slower gastric emptying, and reduced appetite signalling. GIP receptor activation contributes effects that are less completely characterised, and how much each receptor adds to the overall clinical response is still an open question. The two pathways appear to interact in a complementary rather than a purely additive way.
An extended fatty diacid moiety promotes binding to serum albumin, which slows renal clearance and extends the circulating half-life to roughly five days. That property supports once-weekly administration and largely explains the dosing interval described in clinical reports. Published data come mainly from large randomised programmes that evaluated glycaemic control and body weight over periods of many months. Long-term outcomes beyond those trial windows, including what happens after treatment stops, remain an active area of investigation.
Tirzepatide is a synthetic peptide built from thirty-nine amino acids. Its sequence is derived from native glucose-dependent insulinotropic polypeptide, or GIP, with several non-natural residues and a fatty diacid side chain attached through a linker. The molecule behaves as a dual agonist at two incretin receptors, GIP and GLP-1, instead of targeting a single receptor. This dual engagement separates it from earlier single-receptor incretin compounds and underpins most of its reported pharmacological activity.
Tirzepatide is a synthetic peptide of 39 amino acids engineered from the native glucose-dependent insulinotropic polypeptide sequence. Its structure incorporates several non-natural residues and a C-terminal segment derived from glucagon-like peptide-1, together with a C20 fatty diacid moiety attached through a linker. The lipophilic side chain promotes binding to serum albumin, which slows renal clearance after administration. The compound is classified as a dual incretin receptor agonist and is supplied as a lyophilized powder for reconstitution or as a preformulated solution, depending on the presentation.
The peptide activates two G protein-coupled receptors, GIPR and GLP-1R. Binding triggers adenylyl cyclase activity and raises intracellular cyclic AMP in pancreatic beta cells, which potentiates insulin release when glucose is elevated. Signaling in the central nervous system is associated with reduced appetite and lower energy intake, while effects on gastric emptying and glucagon secretion are also reported. Because activity at both receptors is retained, the pharmacological profile is often described as incretin-based rather than selective for a single receptor.
After subcutaneous injection, absorption is gradual, and peak plasma levels are generally reached within one to three days. Albumin binding extends the apparent half-life to roughly five days, which supports a weekly administration schedule. Metabolism proceeds mainly through proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid chain, rather than through cytochrome P450 pathways. Eliminated fragments are largely recycled through general protein turnover, and excretion of intact drug in urine is minimal. These properties distinguish the molecule from short-acting incretin mimetics.
| Property | Value | Notes |
|---|---|---|
| Molecular formula | C225H348N48O68 | Free base form |
| Molecular mass | Approximately 4813 Da | Calculated from the sequence |
| Amino acid residues | 39 | GIP-derived backbone |
| Receptor targets | GIP and GLP-1 | Dual agonist |
| Circulating half-life | About 5 days | Supports weekly administration |
质量控制环节关注外观、含量、纯度、有关物质、水分与微生物限度等项目。检测结果需要有对照品和系统适用性数据支持，单次测定不足以判定批次的稳定性。实验室之间方法转移时，色谱柱品牌与梯度差异常导致保留时间漂移，因此方法验证十分必要。
固体状态的 tirzepatide 通常以冻干粉形式保存，推荐在低温、避光、干燥条件下存放，常见区间为 2 至 8 摄氏度，长期保存可考虑更低温度并避免反复冻融。冻融循环会导致肽链聚集或析出，从而影响后续定量结果。容器密封性与湿度控制同样是稳定性研究中反复强调的因素。
溶解操作一般使用注射用水或适宜的水性缓冲液，必要时加入少量助溶剂以改善溶解速度，但应避免剧烈涡旋振荡，因为剪切力可能促进聚集。配制后的溶液在冷藏条件下的稳定时间通常短于固体形态，具体时限取决于浓度、缓冲体系与容器材质。是否加入防腐成分，则取决于用途是否为多次取样。
Tirzepatide activates both the glucose-dependent insulinotropic polypeptide receptor and the glucagon-like peptide-1 receptor, making it a dual agonist rather than a selective agent. Engagement of the GLP-1 receptor is linked to glucose-dependent insulin release, slower gastric emptying, and reduced appetite signalling. The relative contribution of the GIP arm remains an active research question; proposed roles include improved insulin sensitivity and altered adipose tissue handling. Receptor occupancy studies suggest the molecule interacts with both targets at circulating concentrations achieved during therapy.
Development began in the 2010s, when researchers modified a GIP-based scaffold to add GLP-1 activity and then attached the fatty diacid to lengthen its half-life. Clinical evaluation proceeded through large phase 3 programmes in type 2 diabetes and in obesity, and regulators in the United States cleared the compound for type 2 diabetes in 2022 and for chronic weight management in 2023. Several cardiovascular and metabolic outcome studies are still reporting, so the picture of long-term benefit and risk is incomplete. Approvals in other regions followed on different timelines.
Clinical research programs have evaluated tirzepatide in adults with type 2 diabetes and in adults with obesity or excess weight. Trials generally reported reductions in glycated hemoglobin and body weight across treatment periods of several months. Since these studies enrolled defined populations under controlled conditions, the findings describe group averages rather than individual outcomes. Open questions include the durability of effects after treatment stops, variation among subgroups, and the long-term consequences of sustained dual receptor stimulation. Published trial summaries should be consulted for exact measurements rather than secondary accounts.
Tirzepatide is a synthetic peptide built from 39 amino acid residues. Its backbone derives from the native glucose-dependent insulinotropic polypeptide sequence, altered at several positions to resist enzymatic cleavage. A fatty diacid group attached through a linker extends plasma residence time by promoting reversible binding to serum albumin. The molecule carries a net negative charge near physiological pH and has a reported molecular weight close to 4813 daltons. These features separate it from shorter incretin analogs and account for its prolonged dosing interval.
Pharmacologically, tirzepatide activates two distinct G protein-coupled receptors: the glucose-dependent insulinotropic polypeptide receptor and the glucagon-like peptide-1 receptor. Binding at each target triggers cyclic AMP accumulation and downstream signaling in pancreatic beta cells, adipose tissue and the central nervous system. Because the two pathways overlap only partially, the combined effect on insulin secretion, glucagon suppression and appetite signaling differs from that of selective single-receptor compounds. Affinity is not equal across the two targets, and the clinical meaning of that imbalance remains an area of active study.
=== Subunits === CHS exists as a homodimeric protein with each monomer approximately 42-45 kDa in size. Each monomer possesses a β-keto synthase (KS) activity that catalyzes the sequential head to tail incorporation of two-carbon acetate units into a growing polyketide chain. CHS contains a five layer αβαβα core, a location of the active site and dimerization interface that is highly similar to thiolase-fold containing enzymes. The dimerization interface contains both hydrophobic and hydrophilic residues and is generally flat except for a pair of N-terminal helices that lay entwined across the top. Although the helices are not involved in reaction, they may contain intracellular localization signals as in yeast thiolase. They may also undergo a conformational change to participate in the formation of transient multi-protein complexes with other enzymes in the various pathways diverging from the general phenylpropanoid biosynthetic pathway.
The sans-culottes (French: [sɑ̃kylɔt]; lit. 'without breeches') were the common people of the lower classes in late 18th-century France, a great many of whom became radical and militant partisans of the French Revolution in response to their poor quality of life under the Ancien Régime. The name sans-culottes refers to their clothing, and through that to their lower-class status: culottes were the fashionable silk knee-breeches of the 18th-century nobility and bourgeoisie, and the working class sans-culottes wore pantaloons, or long trousers, instead. The sans-culottes, most of them urban labourers, served as the driving popular force behind the revolution. The word sans-culotte, which is opposed to "aristocrat", seems to have been used for the first time on 28 February 1791 by Jean-Bernard Gauthier de Murnan in a derogatory sense, speaking about a "sans-culottes army". The word came into vogue during the demonstration of 20 June 1792. They were judged by the other revolutionaries as "radicals" because they advocated a direct democracy, that is to say, without intermediaries such as members of parliament. Though ill-clad and ill-equipped, with little or no support from the middle and upper classes, they made up the bulk of the Revolutionary army and were responsible for many executions during the early years of the French Revolutionary Wars. According to Peter Stephen Du Ponceau, secretary and interpreter to Baron de Steuben, Steuben first used the expression sans culottes in 1778: "The Baron loved to speak of that dinner, and of his sans culottes as he called us.
Evidence of the use of dye in pottery are found in most cases on the upper part of ceramic basins, on the inside surface, the areas in which the reduced dye-solution was exposed to air, and underwent oxidation that turned it purple. In the Late Bronze Age Hala Sultan Tekke on Cyprus was a major exporter of purple-dyed textiles with the dye coming from the mucus gland of the murex sea snail. The production of Murex purple for the Byzantine court came to an abrupt end with the sack of Constantinople in 1204, the critical episode of the Fourth Crusade. David Jacoby concludes that "no Byzantine emperor nor any Latin ruler in former Byzantine territories could muster the financial resources required for the pursuit of murex purple production. On the other hand, murex fishing and dyeing with genuine purple are attested for Egypt in the tenth to 13th centuries." By contrast, Jacoby finds that there are no mentions of purple fishing or dyeing, nor trade in the colorant in any Western source, even in the Frankish Levant. The European West turned instead to kermes dye provided by the insect Kermes vermilio, known as grana, or crimson. In 1909, Harvard anthropologist Zelia Nuttall compiled an intensive comparative study on the historical production of the purple dye produced from the carnivorous murex snail, source of the royal purple dye valued higher than gold in the ancient Near East and ancient Mexico.
Sources: en.wikipedia.org
The Scud missiles targeting Israel were relatively ineffective, as firing at extreme range resulted in a dramatic reduction in accuracy and payload. Two Israeli civilians died as a direct result of the missile attacks. Between 11 and 74 died from incorrect use of gas masks, heart attacks, and incorrect use of the anti-chemical weapons drug atropine. Approximately 230 Israelis were injured. Extensive property damage was also caused, and, according to the Israel Ministry of Foreign Affairs, "Damage to general property consisted of 1,302 houses, 6,142 apartments, 23 public buildings, 200 shops and 50 cars." It was feared that Iraq would fire missiles filled with nerve agents such as sarin. As a result, Israel's government issued gas masks to its citizens. When the first Iraqi missiles hit Israel, some people injected themselves with an antidote for nerve gas. It has been suggested that the sturdy construction techniques used in Israeli cities, coupled with the fact that Scuds were only launched at night, played an important role in limiting the number of casualties from Scud attacks.
=== BK channels === The second type of potassium channel that tertiapin blocks is the calcium activated large conductance potassium channel (BK). The block of BK cells is voltage-, concentration- and use-dependent, meaning the blockage changes with different stimulation voltages and frequencies, different concentrations and with the duration of application of tertiapin. The IC50 for BK channels is 5.8 nM. The BK channels have a role in the onset of the afterhyperpolarization, thereby shortening the action potential and enhancing the speed of repolarization. Total blockage by tertiapin prolongs the duration of the action potential and inhibits the afterhyperpolarization amplitude, leading to an increase of the neuronal excitability. Tertiapin inhibits the BK channels only after a minimal stimulation of 15 minutes, in contrast with less than a minute for the GIRK channels. For this reason it is thought that the mode of action of tertiapin is different for each channel type.
The shortage of manpower proved to be decisive as well. During the war, the Slovak National Council brought its demands to the young Austrian Emperor, Franz Joseph I, who seemed to take a note of it and promised support for the Slovaks against the revolutionary radical Hungarians. However the moment the revolution was over, Slovak demands were forgotten. These demands included an autonomous land within the Austrian Empire called "Slovenský kraj" which would be eventually led by a Serbian prince. This act of ignorance from the Emperor convinced the Slovak and the Czech elite who proclaimed the concept of Austroslavism as dead. Disgusted by the Emperor's policy, in 1849, Ľudovít Štúr, the person who codified the first largely used Slovak language, wrote a book he would name Slavdom and the World of the Future. This book served as a manifesto where he noted that Austroslavism was not the way to go anymore. He also wrote a sentence that often serves as a quote until this day: "Every nation has its time under God's sun, and the linden [a symbol of the Slavs] is blossoming, while the oak [a symbol of the Teutons] bloomed long ago." He expressed confidence in the Russian Empire however, as it was the only country of Slavs that was not dominated by anybody else, yet it was one of the most powerful nations in the world. He often symbolized Slavs as being a tree, with "minor" Slavic nations being branches while the trunk of the tree was Russian.
Sources: en.wikipedia.org
In February of 2025 the first case of CRISPR gene editing therapy on a child was documented. It was used to treat Severe Carbamoyl Phosphate Synthetase 1 Deficiency. It was administered At Children's Hospital of Philadelphia and is currently successful in its use to counteract the disease. "Advanced Gene Editing: CRISPR-Cas9" (PDF). Congressional Research Service. Archived from the original (PDF) on 5 December 2017. Retrieved 24 October 2017. "Jennifer Doudna talk: Genome Engineering with CRISPR-Cas9: Birth of a Breakthrough Technology". 10 September 2022. Archived from the original on 25 November 2016. Retrieved 24 November 2016. "Human Nature". NOVA. Season 47. Episode 9. 9 September 2020. PBS. WGBH. Retrieved 7 April 2023.
== Pharmacology == Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5–2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10% of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. Oxidation of midazolam is the major metabolite in human liver microsome (HLM). The half-life (t1⁄2) of midazolam in HLM is 3.3 minutes. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the endogenous neurotransmitter GABA on the GABAA receptors (increasing the frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.
1 by the Minister, after consultation with such bodies representative of those interests as he may think fit, to represent the interests of persons using bicycles and tricycles, not being motor vehicles, within the London Traffic Area. † An A Licence entitled the holder to drive a motorcycle; a B Licence a motor car; and a C licence a heavy goods vehicle. The Committee and Traffic Area were abolished in 1965 by the London Government Act 1963.
On 15 June 2022, Michael Duff was appointed head coach of Barnsley on a three-year contract. In May 2022, it was revealed that Pacific Media Group did not actually own all the shares they claimed to own, and were simply a nominee for a group of 4 investors who owned 20% of the club. Following this revelation, Neerav Parekh purchased the shares of 2 of the investors, while Matt Edmonds purchased the shares of the 4th investor. Following the purchases and further equity raises, the new ownership of the club is now understood to be split between Neerav Parekh (61.14%), the Cryne family (21.30%), Julie Anne Quay and Matt Edmonds (11%), Chien Lee (4.60%), and Conway's company Pacific Media Group (1.96%). With this reconstituted shareholding and a loss of majority control, Paul Conway, Chien Lee, Grace Hung and Dickson Lee were voted off the board of Barnsley Football Club, and were replaced by Jean Cryne and Julie Anne Quay in May 2022. In July 2023, the EFL charged Barnsley with 5 breaches of the EFL Regulations related to the ownership of the club under Conway and Lee's tenure, whilst also charging Conway and Lee individually with causing these breaches in regulations.
Sources: en.wikipedia.org
It acts as a dual agonist at the GIP receptor and the GLP-1 receptor. This broader targeting profile distinguishes it from selective GLP-1 agonists, which engage only one receptor.
A fatty diacid side chain promotes binding to albumin, which delays clearance from circulation. The half-life of roughly five days makes a weekly schedule practical.
No. It is a synthetic peptide whose backbone is based on the natural incretin hormone GIP. Non-natural residues and the lipid side chain were engineered to improve stability and duration of action.
It is a synthetic linear peptide that acts as a dual agonist at the GIP and GLP-1 receptors. It combines a modified incretin backbone with a fatty diacid side chain that extends its circulation time. It is not a small-molecule drug and is not orally absorbed in its native form.