incretin is one of those subjects where the details matter more than the headlines. This page pulls together the background, the mechanisms, and the practical points readers ask about most.
Updated 2026-01-01. Numbers and descriptions here follow the published literature rather than marketing material.
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.
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。
Semaglutide 是一种经结构修饰的胰高血糖素样肽-1 类似物，其主链与内源性 GLP-1(7-36) 约有百分之九十四的序列一致性。第 8 位丙氨酸被 α-氨基异丁酸取代，使二肽基肽酶-4 无法识别原有切割位点。第 34 位赖氨酸换为精氨酸，进一步降低酶解速率。第 26 位赖氨酸经间隔基连接一条含十八个碳的二酸脂肪链，该侧链赋予分子与血浆白蛋白结合的能力。
| Property | Value | Notes |
|---|---|---|
| Molecular class | Acylated GLP-1 receptor agonist | 31-residue synthetic peptide |
| Molecular formula | C187H291N45O59 | established for the free peptide |
| Appearance | White to off-white powder | as supplied before formulation |
| Solubility | Freely soluble in water | aqueous buffers near neutral pH |
| Typical storage | 2 to 8 degrees Celsius, protected from light | powder and solution forms differ in shelf life |
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.
Semaglutide is a synthetic peptide of thirty-one amino acids that shares roughly ninety-four percent sequence identity with human glucagon-like peptide-1. Two substitutions resist enzymatic cleavage by dipeptidyl peptidase-4, and a fatty diacid side chain attached through a linker promotes binding to serum albumin. That albumin binding slows renal clearance and extends the circulating half-life from minutes to approximately one week. The structural changes are well established in the published literature. Whether the same modifications affect receptor signalling bias in ways that matter clinically remains an open question.
Lyophilized semaglutide is typically stored at temperatures between minus 20 and minus 80 degrees Celsius for long-term preservation. Short-term storage at 2 to 8 degrees Celsius is common for working aliquots. Repeated freeze-thaw cycles can degrade the peptide and are usually avoided. The molecule is hygroscopic in its solid form, so containers should remain sealed with desiccant. Solutions are less stable than powders and are generally prepared fresh. Light exposure is limited because aromatic residues can undergo photo-oxidation.
Semaglutide dissolves readily in water and in aqueous buffers near neutral pH. Solubility decreases near the isoelectric point, where net charge is minimal. Common laboratory solvents include phosphate-buffered saline and dilute ammonium bicarbonate. Strongly acidic or basic conditions may accelerate hydrolysis. Working concentrations are usually prepared by diluting a concentrated stock. Vial surfaces can adsorb small amounts of peptide at low concentrations, so carrier proteins or low-binding tubes are sometimes used.
Reverse-phase high-performance liquid chromatography is the standard method for purity assessment, separating the peptide from truncated or oxidized variants. Mass spectrometry confirms molecular mass and detects modifications, while ultraviolet absorbance near 280 nanometers supports concentration measurement through tryptophan and tyrosine residues. Circular dichroism can indicate secondary structure, though the peptide is largely helical in solution, and ion-exchange chromatography resolves charge variants. Purity values above 95 percent are typical for research-grade material. Stability studies track degradation over time under defined conditions.
Semaglutide is a synthetic peptide analogue of glucagon-like peptide-1, a gut hormone released by intestinal L cells after food intake. The natural hormone acts on pancreatic and central receptors but is degraded within minutes by dipeptidyl peptidase-4 and other peptidases. Semaglutide belongs to the class of long-acting GLP-1 receptor agonists, a group distinguished by structural changes that slow breakdown and extend circulation time. Its development followed earlier short-acting analogues and reflects a general strategy in peptide drug design: preserve receptor activity while blocking proteolytic clearance.
Three structural changes define the molecule. At position 8 an alpha-aminoisobutyric acid residue replaces alanine, which blocks dipeptidyl peptidase-4 cleavage. At position 34 arginine replaces lysine, and at position 26 a lysine carries a C18 fatty diacid attached through a short linker. The fatty chain binds serum albumin, and this albumin association reduces renal filtration and enzymatic attack. The unchanged backbone retains the receptor contacts that produce signalling. The free base has the formula C187H291N45O59 and a molecular weight near 4114 daltons.
Receptor activation follows the canonical Gs pathway: binding increases intracellular cyclic AMP, which promotes protein kinase A activity. In pancreatic beta cells this amplifies glucose-dependent insulin release, so secretion rises when blood glucose is high and changes little when it is low. The same signalling suppresses glucagon release from alpha cells and slows gastric emptying. Receptors in the hypothalamus and brainstem are thought to contribute to reduced appetite and lower energy intake. Which of these effects dominates clinical outcomes remains an area of active study.
Narrated by Paul Daneman, directed by Julian Nott, made by Peninsula Films 9 October The Rubber Universe, in 1929 Hubble's law was discovered, but the Hubble constant was not fully known - about the Hubble constant, which could be between 50 and 85, which meant that the universe could be 14 billion years old, not 8 billion years old, for a constant of 50; scientists were highly protective of any discoveries that they made, or not, but that did not always lead to good outcomes for all concerned - such as the relationship between Allan Sandage, who thought the Hubble constant was about 50, and the French Gérard de Vaucouleurs; Canadian Sidney van den Bergh looked at the Hubble constant as well; Tod R.
=== Selected articles === Ajayaghosh, Ayyappanpillai, Subi J. George (2001). “First phenylenevinylene based organogels: self-assembled nanostructures via cooperative hydrogen bonding and π-stacking”. J. Am. Chem. Soc. 2001, 123, 21, 5148-5149. https://doi.org/10.1021/ja005933+. Ajayaghosh, Ayyappanpillai, Priya Carol, and Sivaramapanicker Sreejith (2005) “A Ratiometric Fluorescence Probe for Selective Visual Sensing of Zn2+”. J. Am. Chem. Soc. 2005, 127, 43, 14962-14963. https://doi.org/10.1021/ja054149s. Ajayaghosh, Ayyappanpillai, Vakayil K. Praveen, Chakkooth Vijayakumar, Subi J. George (2007). “Molecular Wire Encapsulated into π Organogels: Efficient Supramolecular Light-Harvesting Antennae with Color-Tunable Emission”. Angew. Chem. Int. Ed. 2007, 46, 6260-6265. https://doi.org/10.1002/anie.200701925. Ajayaghosh, Ayyappanpillai, Vakayil K. Praveen (2008). “π-Organogels of Self-Assembled p-Phenylenevinylenes: Soft Materials with Distinct Size, Shape, and Functions”. Acc. Chem. Res. 2007, 40, 8, 644-656. https://doi.org/10.1021/ar7000364 Vijayakumar, Chakkooth; Praveen, Vakayil K.; Kartha, Kalathil K.; Ajayaghosh, Ayyappanpillai (2011). "Excitation energy migration in oligo(p-phenylenevinylene) based organogels: structure-property relationship and FRET efficiency". Physical Chemistry Chemical Physics. 13 (11): 4942–4949. Bibcode:2011PCCP...13.4942V. doi:10.1039/C0CP02110E. PMID 21321716. S2CID 19328938. Kartha, Kalathil K.; Babu, Sukumaran S.; Srinivasan, Sampath; Ajayaghosh, Ayyappanpillai (2012).
In the case of the simians, the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders Haplorrhini (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the Strepsirrhini ("wet-nosed" primates), which retained the ability to make vitamin C. According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago. Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines. Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, placing it between these two marker points (63 to 58 million years ago). It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down uric acid, also a characteristic of primates. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.
Sources: en.wikipedia.org
== Verification status removals == On March 23, 2023, Twitter announced that on April 1, 2023, it would begin winding down its legacy verification program and removing legacy verified checkmarks. The New York Times reported that exceptions would be made for Twitter's top 500 advertisers and its 10,000 most-followed organizations that had been previously verified. BuzzFeed News reported that multiple news organizations like The New York Times, The Washington Post and The Los Angeles Times had no plans to pay for Twitter's "Verified Organizations" service nor would they reimburse reporters for having Twitter Blue. Similarly, Axios reported that White House digital strategy director Rob Flaherty sent an internal email to staffers saying "[t]here are ongoing trials for the program that we are monitoring, but we will not enroll in it." Twitter did not immediately begin removing checkmarks on April 1, 2023. The Washington Post reported that "[the removal] of verification badges is a largely manual process powered by a system prone to breaking" and "[i]n the past, there was no way to reliably remove badges at a bulk scale", according to former Twitter employees. Twitter also updated the language previously used to distinguish between legacy and Twitter Blue-verified users, merging them into a single description, and later unfollowed all legacy-verified accounts. On April 11, 2023, Musk announced the final date for removing legacy blue checkmarks to be April 20.
wrapped up the two-and-a-half-month Battle of Okinawa (which cost the lives of 260,000 people, including 150,000 civilians), it was faced with the prospect of invading the Japanese home islands in an operation codenamed Operation Downfall. Based on the U.S. casualties from the preceding island-hopping campaigns, American commanders estimated that between 50,000 and 500,000 U.S. troops would die and at least 600,000–1,000,000 others would be injured while invading the Japanese home islands. The U.S. manufacture of 500,000 Purple Hearts from the anticipated high level of casualties during the U.S. invasion of Japan gave a demonstration of how deadly and costly it would be. President Harry S. Truman realized he could not afford such a high casualty rate, especially since over 400,000 American combatants had already died fighting in both the European and the Pacific theaters of the war. On July 26, 1945, the United States, the United Kingdom, and the Republic of China issued a Potsdam Declaration that called for the unconditional surrender of Japan. It stated that if Japan did not surrender, it would face "prompt and utter destruction". The Japanese government ignored this ultimatum, sending a message that they were not going to surrender. In response to the rejection, President Truman authorized the dropping of the atomic bombs. At the time of its use, there were only two atomic bombs available, and despite the fact that more were in production back in mainland U.S., the third bomb wouldn't be available for combat until September.
=== Targeted protein degradation === Based on the finding that thalidomide and related analogues bind CRBN, heterobifunctional molecules were designed linking thalidomide to ligands for other proteins of interest. These molecules, termed proteolysis targeting chimeras (PROTACs) or protein degraders, recruit CRBN to a protein of interest, leading to its ubiquitination and subsequent degradation. This technology is being explored in clinical trials by a number of biotechnology companies such as Arvinas, C4 Therapeutics, and Kymera Therapeutics.
The endocrine reproductive system consists of the hypothalamus, the pituitary, the gonads, and the adrenal glands, with input and regulation from many other body systems. True puberty is often termed "central puberty" because it begins as a process of the central nervous system. A simple description of hormonal puberty is as follows:
Sources: en.wikipedia.org
=== Key-wind, key-set movements === The first pocket watches, since their creation in the 16th century, up until the third quarter of the 19th century, had key-wind and key-set movements. A watch key was necessary to wind the watch and to set the time. This was usually done by opening the caseback and putting the key over the winding-arbor (which was set over the watch's winding-wheel, to wind the mainspring) or by putting the key onto the setting-arbor, which was connected with the minute-wheel and turned the hands. Some watches of this period had the setting-arbor at the front of the watch, so that removing the crystal and bezel was necessary to set the time. Watch keys are the origin of the class key, common paraphernalia for American high-school and university graduation. Many keywind watch movements make use of a fusee, to improve isochronism. The fusee is a specially cut conical pulley attached by a fine chain to the mainspring barrel. When the spring is fully wound (and its torque the highest), the full length of the chain is wrapped around the fusee and the force of the mainspring is exerted on the smallest diameter portion of the fusee cone. As the spring unwinds and its torque decreases, the chain winds back onto the mainspring barrel and pulls on an increasingly larger diameter portion of the fusee. This provides a more uniform amount of torque on the watch train, and thus results in more consistent balance amplitude and better isochronism.
== Function == According to Marvin et al. sHSPs independently express not only in heat shock response but also have developmental roles in embryonic or juvenile stages of mammals, teleost fish and some lower vertebral genomes. hspb1 (HSP27) is expressed during stress and during the development of embryo, somites, mid-hindbrain, heart and lens in zebrafish. Expression of the hspb4 gene, which codes for alpha crystallin, increases considerably in the lens in response to heat shock.
Techniques like hand washing, wearing gowns, and wearing face masks can help prevent infections from being passed from one person to another. Aseptic technique was introduced in medicine and surgery in the late 19th century and greatly reduced the incidence of infections caused by surgery. Frequent hand washing remains the most important defense against the spread of unwanted organisms. There are other forms of prevention such as avoiding the use of illicit drugs, using a condom, wearing gloves, and having a healthy lifestyle with a balanced diet and regular exercise. Antimicrobial substances used to prevent transmission of infections include:
Sources: en.wikipedia.org
Native GLP-1 is degraded within minutes by dipeptidyl peptidase-4 and neutral endopeptidases. Semaglutide carries a non-natural amino acid at position eight that blocks that cleavage, and a fatty diacid side chain that binds albumin. The result is a much longer duration of action than the native hormone.
The fatty diacid chain associates strongly with serum albumin, which keeps the peptide in circulation and shields it from rapid renal clearance. Bound peptide is released gradually, producing a sustained receptor signal. This mechanism also reduces the peak-to-trough variation seen with shorter-acting analogues.
The balance between peripheral receptor activation and signalling in the central nervous system is not fully resolved. The extent to which slowed gastric emptying accounts for reduced energy intake, compared with direct effects on appetite circuits, is debated. Long-term effects on lean mass and on tissues outside the gut and brain are still under study.
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。