Everything below concerns Aib substitution. We keep the language plain, cite what the science says, and separate well-supported claims from open questions.
Updated 2025-12-23. Numbers and descriptions here follow the published literature rather than marketing material.
Pharmacological activity arises from agonism at the glucagon-like peptide-1 receptor, a G protein-coupled receptor expressed in the pancreas, the gastrointestinal tract, and the brainstem. Receptor activation raises intracellular cyclic adenosine monophosphate and enhances insulin release in a glucose-dependent manner, an effect that diminishes when blood glucose concentration is low. Other effects include slowed gastric emptying and hypothalamic satiety signalling. These pathways are described well. Receptor desensitisation rates across tissues, relative to the endogenous hormone, are still under investigation, and reported findings differ between laboratories.
The company that developed the compound filed it as a long-acting analogue, and it gained first approval in 2017 for type 2 diabetes. Later authorisations from several regulators extended the indication to chronic weight management, and the World Health Organization added the glucagon-like peptide-1 receptor agonist drug class to its model list of essential medicines in 2023. Production uses solid-phase peptide synthesis followed by side-chain conjugation and chromatographic purification. Supply constraints and cost differences across regions are well documented. Literature on long-term outcomes continues to grow, with many trials reporting surrogate endpoints rather than hard clinical endpoints.
该分子作为 GLP-1 受体的选择性激动剂发挥作用，受体属于 B 类 G 蛋白偶联受体家族，激活后经 Gs 通路提升细胞内环腺苷酸水平。在胰腺 β 细胞，信号促进葡萄糖依赖性的胰岛素释放，血糖偏低时该作用明显减弱。在胰岛 α 细胞，胰高血糖素分泌受到抑制。中枢神经系统与胃肠道同样存在受体表达，相应信号参与食欲调节以及胃排空速率的降低。
皮下注射后吸收相对缓慢，绝对生物利用度约为百分之八十九，血药浓度峰值通常出现在给药后一到三天。与白蛋白结合使清除减慢，终末半衰期约为一百六十五小时，接近一周。连续给药约四到五周后达到稳态暴露水平。表观分布容积约为每千克零点二五升，血浆蛋白结合率超过百分之九十九。代谢以蛋白水解切割和脂肪二酸侧链的 β-氧化为主，相关产物主要经尿液与粪便排出。
序列层面的改动同时解决了两个问题，即酶解稳定性与肾脏清除速度。天然 GLP-1 在循环中的半衰期仅约两分钟，主要被二肽基肽酶-4 迅速灭活。酰化侧链与白蛋白的可逆结合形成循环储库，使分子缓慢释放并持续激活受体。这种设计思路后来被广泛用于同类长效肽的开发，属于该类药物化学改造的典型范式。
| Property | Value | Notes |
|---|---|---|
| Molecular class | 31-amino-acid peptide | Modified glucagon-like peptide-1 analogue |
| Molecular mass | approximately 4114 Da | Calculated for the free peptide backbone |
| Appearance | white to off-white powder | Typical of purified lyophilised peptide batches |
| Solubility class | freely soluble in water | Aqueous solubility improves at slightly alkaline pH |
| Typical storage | -20 degrees Celsius, dry, dark | Protect from repeated freeze-thaw cycles |
The primary target is the GLP-1 receptor, a class B G protein-coupled receptor expressed on pancreatic beta cells, in the gut, and in several brain regions. Receptor activation raises intracellular cyclic AMP, which potentiates glucose-dependent insulin secretion and lowers glucagon release when blood glucose is elevated. Signalling in the hypothalamus and brainstem is associated with reduced appetite and slower gastric emptying. Because the insulinotropic effect depends on prevailing glucose levels, the hypoglycaemic risk of the peptide alone is described as low in most study settings. The relative contribution of peripheral and central actions remains an active research question.
Large randomised trials in adults with type 2 diabetes and in adults with obesity have reported reductions in body weight and improvements in several cardiovascular risk markers. One outcome trial found a lower incidence of major adverse cardiovascular events in participants with diabetes and established cardiovascular disease. Gastrointestinal effects such as nausea and vomiting are the most frequently reported adverse events and often diminish over time. Changes in lean body mass during weight loss are an area of ongoing investigation. Effects in adolescents and in pregnancy are less well characterised, and current labelling advises against use during pregnancy.
Semaglutide is a synthetic peptide analogue of glucagon-like peptide-1, a gut hormone released after nutrient intake. The molecule contains 31 amino acid residues and differs from the native sequence at several positions. A non-natural residue at position eight resists the enzyme that normally truncates the hormone, while a lysine-linked fatty diacid side chain promotes binding to serum albumin. These two modifications extend the circulating half-life from minutes to roughly one week. The peptide is produced by solid-phase synthesis followed by selective acylation, and its identity and purity are confirmed by spectrometric and chromatographic techniques.
Clinical development of this compound followed earlier short-acting GLP-1 analogues that required frequent injection. Once-weekly subcutaneous formulations entered use after 2017, and an oral formulation using a permeation enhancer later became available. The oral version pairs the peptide with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, a carrier that improves uptake across the gastric epithelium. Interest has expanded from glycaemic control into weight management and metabolic liver disease. Regulatory status and approved indications differ between countries, and the product remains subject to ongoing safety monitoring.
Semaglutide is a synthetic peptide that acts as an agonist at the glucagon-like peptide-1 receptor. It is a structural analogue of human GLP-1(7-37), modified to resist enzymatic degradation by dipeptidyl peptidase-4. The peptide backbone contains alpha-aminoisobutyric acid at position 8, a substitution that stabilises the helix and slows cleavage. A fatty diacid side chain attached through a linker at lysine 34 promotes binding to serum albumin, which extends the circulating half-life. These two modifications together allow less frequent administration than native GLP-1 requires.
Activation of the GLP-1 receptor couples to Gs signalling and raises intracellular cyclic AMP in pancreatic beta cells. The resulting insulin release depends on prevailing glucose concentrations, so the effect is greater when glucose is elevated. Receptor engagement also suppresses glucagon secretion and slows gastric emptying, which flattens post-meal glucose excursions. In the central nervous system, signalling in hypothalamic and brainstem regions is associated with reduced appetite and lower energy intake. Studies continue to examine effects on cardiac, renal and hepatic endpoints; whether those benefits are independent of weight change remains an open question.
=== Economic and social cost === Addiction imposes substantial financial and human costs on individuals and on society. These costs arise from the direct adverse effects of drugs and associated healthcare costs (e.g., emergency medical services and outpatient and inpatient care), long-term complications (e.g., lung cancer from smoking tobacco products, liver cirrhosis and dementia from chronic alcohol consumption, and meth mouth from methamphetamine use), the loss of productivity and associated welfare costs, fatal and non-fatal accidents (e.g., traffic collisions), suicides, homicides, and incarceration, among others. In the United States, an estimated 69,973 people died of drug overdose in 2025, down almost 14% from 81,313 in 2024 and the third consecutive annual decline following the peak reached during the opioid epidemic. Access to treatment is limited worldwide: among countries reporting data to the World Health Organization, the proportion of people with a substance use disorder in contact with treatment services ranged from under 1% to no more than 35%.
=== Clinical outcomes === In clinical trials the outcome of different types of treatment is compared to identify if a compound or regimen is favourable for the patient. The choice of treatment in the conditioning therapy can have a profound impact on progression-free survival (PNS), overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). The studies mentioned summarize key findings comparing various conditioning regimens. Studies on conditioning regimens for hematopoietic cell transplant in primary central nervous system lymphoma (PCNSL) have shown that thiotepa based therapies thiotepa/busulfan/cyclophosphamide (TBC) and thiotepa/carmustine (TT-BCNU) improve progression-free survival of PCNSL compared to traditional therapies carmustine/etoposide/cytarabine/melphalan (BEAM). Research also suggests that in BEAM if carmustine is exchanged for thiotepa no statistical difference was found in PFS, OS and RI. Furthermore, the capacity of thiotepa to pass the blood-brain barrier may allow optimizing the therapy for patients with Central Nervous System involvement of increased CNS relapse risk. Another study compared total body irradiation (TBI) and thiotepa, busulfan and cyclophosphamide/fludarabine (TTB) as a conditioning regimen of patients with acute lymphoblastic leukemia undergoing allogenic hematopoietic stem cell transplantation. No statistical difference was found in the overall survival but the RI was higher in the TBI regimen but the NRM was lower with TTB suggesting that TBB might be a viable alternative to TBI.
== Mechanism == Classified as a metalloexopeptidase, carboxypeptidase A consists of a single polypeptide chain bound to a zinc ion. This characteristic metal ion is located within the active site of the enzyme, along with five amino acid residues that are involved in substrate binding: Arg-71, Arg-127, Asn-144, Arg-145, Tyr-248, and Glu-270. X-ray crystallographic studies have revealed five subsites on the protein. These allosteric sites are involved in creating the ligand-enzyme specificity seen in most bioactive enzymes. One of these subsites induces a conformational change at Tyr-248 upon binding of a substrate molecule at the primary active site. The phenolic hydroxyl of tyrosine forms a hydrogen bond with the terminal carboxylate of the ligand. In addition, a second hydrogen bond is formed between the tyrosine and a peptide linkage of longer peptide substrates. These changes make the bond between the enzyme and ligand, whether it is substrate or inhibitor, much stronger. This property of carboxypeptidase A led to the first clause of Daniel E. Koshland, Jr.’s “induced fit” hypothesis. The S1 sub-site is where catalysis occurs in CPA, and the zinc ion is coordinated by Glu-72, His-69, and His-196 enzyme residues. A plane exists that bisects the active-site groove where residues Glu-270 and Arg-127 are on opposite sides of the zinc-water coupled complex. The zinc is electron rich due to glutamine ligands coordinating the zinc because before substrate binds, Glu-72 coordinates bidentate but shifts to monodentate after substrate binds.
Sources: en.wikipedia.org
If the metabolite only takes the right side new labeling patterns can occur, all in equal proportion. Other proportions can occur depending on how much of the original metabolite follows the left side of the pathway versus the right side of the pathway. Here the proportions are shown for a situation in which half of the metabolites take the left side and half the right, but other proportions can occur. These patterns of labeled atoms and unlabeled atoms in one compound represent isotopomers. By measuring the isotopomer distribution of the differently labeled metabolites, the flux through each reaction can be determined. MFA combines the data harvested from isotope labeling with the stoichiometry of each reaction, constraints, and an optimization procedure resolve a flux map. The irreversible reactions provide the thermodynamic constraints needed to find the fluxes. A matrix is constructed that contains the stoichiometry of the reactions. The intracellular fluxes are estimated by using an iterative method in which simulated fluxes are plugged into the stoichiometric model. The simulated fluxes are displayed in a flux map, which shows the rate of reactants being converted to products for each reaction. In most flux maps, the thicker the arrow, the larger the flux value of the reaction.
She has given a great deal of thought to how women are taught to act as they grow up and how that may impact their career decisions. In an interview in 2004, Osborn said, "In deciding whether to accept new challenges a remark by Diane Britten some years ago in The Times has proved very helpful: "When asked to do something women tend to say `Why me?' Men say `Why not me?' I have learned to say `Why not me?''' Summing up her advice to those in charge of sciences in universities and industry, she said in 2012, "Above all one has to get the argument across that it is wasteful, expensive and unfair to educate and train large numbers of woman scientists and then not use their talents in the job market or provide equal access to the top jobs."
On March 26, 2020, Kennedy voted for the first COVID-19 stimulus package, the CARES Act, saying, "This virus poses a unique health risk, and we know that poverty can also threaten lives. Understanding that, I voted today to protect the well-being of Louisianans now and into the future by investing in medical services, families, workers and businesses." In July 2020, Kennedy voted for the second COVID-19 relief package, saying, "I’m very conservative fiscally, as I think most of you know, but people are in pain and the size of the American economy is just extraordinary. This is the largest economy in all of human history, and government just shut down, just shut it down, and a lot of people have gotten hurt, through no fault of their own, and we need to help them without wasting any money." Kennedy helped draft the Water Resources Development Act of 2020, a bill that determines which projects the Army Corps of Engineers will build. With few options, Louisiana agreed to let the Corps build a flood protection system for the New Orleans region that meets the standards for national flood insurance. He added a provision that allowed Louisiana to renegotiate a loan agreement with the Corps for a flood protection system that saved Louisiana taxpayers $1.3 billion. In 2020, Kennedy helped secure natural disaster aid for Louisiana after Hurricane Laura hit the state. He toured the damaged coastline near Lake Charles, Louisiana, with President Trump, and Trump later issued a major disaster declaration for the state.
== Diagnosis == Initially, the diagnosis was commonly made based on suggestive symptoms and odor, the odor coming from the compound sotolon (sometimes spelled sotolone). These days, affected individuals are now often identified by characteristic elevations on plasma amino acid which do not have the characteristic odor.
Sources: en.wikipedia.org
British Post Office scandal: Court documents reveal that Fujitsu, the company at the centre of the Post Office scandal, won a £184m contract by the Foreign and Commonwealth Office in 2021, despite concerns the system it was offering was "unfit for purpose". Court documents show that former prime minister Sir Tony Blair was warned the Horizon IT system could be "possibly unreliable" before it was rolled out, and raised concerns about it, but gave it the green light after receiving reassurance from others, including his Secretary of State for Trade and Industry Peter Mandelson. 13 January – Yvonne Tracey, a former deputy postmistress from New Malden, south London, announces her intention to stand in the Parliamentary constituency of Kingston and Surbiton, Sir Ed Davey's seat, at the next general election. 14 January – Foreign Secretary David Cameron tells the BBC that military action was taken against Houthi rebels because the strikes were needed after months of attacks against cargo ships, and that the UK is "prepared to back our words with actions". 15 January – Sunak tells Parliament that air strikes against Houthi targets were meant as a "limited, single action" but that the UK "will not hesitate to protect our security, our people and our interests where required". James Stockan announces he is stepping down from the post of leader of Orkney Islands Council, as well as relinquishing his council seat, after six years in the role.
Nicholas Kemmer of the Cambridge team independently proposed the same name, based on the same reasoning as the Berkeley team. Seaborg originally considered the name "plutium", but later thought that it did not sound as good as "plutonium". He chose the letters "Pu" as a joke, in reference to the interjection "P U" to indicate an especially disgusting smell, which passed without notice into the periodic table. Alternative names considered by Seaborg and others were "ultimium" or "extremium" because of the erroneous belief that they had found the last possible element on the periodic table. Hahn and Strassmann, and independently Kurt Starke, were at this point also working on transuranic elements in Berlin. It is likely that Hahn and Strassmann were aware that plutonium-239 should be fissile. However, they did not have a strong neutron source. Element 93 was reported by Hahn and Strassmann, as well as Starke, in 1942. Hahn's group did not pursue element 94, likely because they were discouraged by McMillan and Abelson's lack of success in isolating it when they had first found element 93. However, since Hahn's group had access to the stronger cyclotron at Paris at this point, they would likely have been able to detect plutonium had they tried, albeit in tiny quantities (a few becquerels).
Masculinizing hormone therapy is typically used by transgender men, who desire the development of masculine secondary sex characteristics. Masculinizing hormone therapy usually includes testosterone to produce masculinization and suppress the production of estrogen. Treatment options include oral, subcutaneous injections or implant, and transdermal (patches, gels). Dosing is patient-specific, depending on the patient's rate of metabolism, and is discussed with the physician. The most commonly prescribed methods are intramuscular and subcutaneous injections. This dosing can be daily, weekly or biweekly depending on the route of administration and the individual patient. Unlike feminizing hormone therapy, individuals undergoing masculinizing hormone therapy do not usually require additional hormone suppression such as estrogen suppression. Therapeutic doses of testosterone are usually sufficient to inhibit the production of estrogen to desired physiologic levels. The desired effects of masculinizing hormone therapy focus on the development of masculine secondary sex characteristics. These desired effects include: increased muscle mass, increased bone turnover, development of facial hair, voice deepening, increase and thickening of body hair, and more.
=== Internet === The NOS is also responsible for the news and sports sites of the Dutch public broadcasters. The editorial staff of the internet pages is also responsible for the teletext pages on NPO 1, NPO 2 and NPO 3.
=== Iodine === Iodine is used in chemistry as an indicator for starch. When starch is mixed with iodine in solution, an intensely dark blue colour develops, representing a starch/iodine complex. Starch is a substance common to most plant cells and so a weak iodine solution will stain starch present in the cells. Iodine is one component in the staining technique known as Gram staining, used in microbiology. Used as a mordant in Gram's staining, iodine enhances the entrance of the dye through the pores present in the cell wall/membrane. Lugol's solution or Lugol's iodine (IKI) is a brown solution that turns black in the presence of starches and can be used as a cell stain, making the cell nuclei more visible. Used with common vinegar (acetic acid), Lugol's solution is used to identify pre-cancerous and cancerous changes in cervical and vaginal tissues during "Pap smear" follow up examinations in preparation for biopsy. The acetic acid causes the abnormal cells to blanch white, while the normal tissues stain a mahogany brown from the iodine.
Sources: en.wikipedia.org
It is a glucagon-like peptide-1 receptor agonist, often grouped with the incretin mimetics. Its backbone is modified from the human hormone to resist enzymatic degradation and to bind albumin. These two features distinguish it from the native peptide.
No. It shares high sequence identity but carries non-natural modifications that alter its stability and clearance. The naturally occurring hormone is broken down within minutes, while the synthetic analogue circulates far longer.
Attachment to serum albumin reduces renal filtration of the peptide and shields it from enzymatic breakdown. The consequence is a much longer interval between administrations than unmodified peptides allow. The precise contribution of binding affinity to overall duration is still being quantified.
差别集中在三处：第 8 位残基被非天然氨基酸取代，第 34 位换成精氨酸，第 26 位增加一条脂肪酸侧链。前两处改动降低酶解速率，侧链则通过白蛋白结合延长循环时间。综合结果是半衰期从约两分钟延长到约一周。