This is a working overview of incretin, written for readers who want more than a one-paragraph summary but less than a textbook.
Reviewed 2025-08-06. Anything still debated is marked as such rather than presented as settled.
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.
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。
| 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 |
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.
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.
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 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.
Rosei Kantsubaki (寒椿 狼星, Kantsubaki Rōsei) Voiced by: Shogo Sakata, Miyuri Shimabukuro (childhood) (Japanese); Alejandro Saab, Emily Fajardo (childhood) (English) The Agent of Winter and currently the longest serving Agent. He possesses the ability "Life Coagulation". Being the cause of the kidnapping of his first love, Hinagiku, torments him. Itecho Kangetsu (寒月 凍蝶, Kangetsu Itechō) Voiced by: Satoshi Hino (PV, anime) (Japanese); Christopher Wehkamp (English) The Agent of Winter's Guard. He has been Rosei's servant since he was a child, and was also Sakura's sword master. Like Rosei, he condemns himself for failing to protect the Hinagiku. Ruri Hazakura (葉桜 瑠璃, Hazakura Ruri) Voiced by: Sumire Uesaka (Japanese); Alexis Tipton (English) The Agent of Summer, possesses the ability of "Life Operation". She has a sunny and kind nature, but she can't be honest with her older twin sister Ayame, because she doesn't want her to give up her role as her Guard. Ayame Hazakura (葉桜 あやめ, Hazakura Ayame) Voiced by: Ranko Baba (Japanese); Hayden Daviau (English) The Agent of Summer's Guard. She is Ruri's older twin sister and her attendant. She plans to leave her post as a Guard on the occasion of her wedding. Despite being a victim of her sister's whims, she wishes for her happiness. Nadeshiko Iwaizuki (祝月 撫子, Iwaizuki Nadeshiko) Voiced by: Hime Sawada (Japanese); Emi Lo (English) The Agent of Autumn, possesses the ability of "Life Putrefaction". She is the youngest and the shortest-serving deity. She has immense trust and affection for Rindou.
Anti-obesity medication or weight loss medications are pharmacological agents that reduce excess body fat and cause weight loss. These medications alter one of the fundamental processes of weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories. Weight loss drugs have been developed since the early twentieth century, and many have been banned or withdrawn from the market due to adverse effects, including deaths; other drugs proved ineffective. Although many earlier drugs were stimulants such as amphetamines, in the early 2020s, GLP-1 receptor agonists became popular for weight loss. As of 2023, the medications liraglutide, naltrexone/bupropion, orlistat, semaglutide, tirzepatide and phentermine/topiramate are approved by the US Food and Drug Administration (FDA) for weight management in combination with reduced-calorie diet and increased physical activity. Medications to treat obesity may be considered in those with a body mass index above 30, or above 27 with obesity related complications (such as hypertension, hyperlipidemia, cardiovascular disease, or obstructive sleep apnea). As of 2022, no medication has been shown to be as effective at long-term weight reduction as bariatric surgery.
A safety modification to Mark 39 Mod 2 weapons known as Alt 197 had been approved in January 1960, but not yet applied to all deployed weapons prior to the Goldsboro accident, and was not applied to the weapons involved in the accident. Alt 197 replaced the MC-772 Arm/Safe switch with the MC-1288 Arm/Safe switch, with the main change being that the latter would prevent the charging of the low-voltage thermal battery when the Arm/Safe switch was in the "Safe" position, and as such would make sure that no electrical current was available anywhere within the bomb to power additional switches or hardware, legitimately or not. After the accident, all other Mark 39 Mod 2 weapons without the modification were taken off of deployment status ("red-lined") until the modification could be applied to the remaining inventory of the weapons.
Only 249Bk is available in large quantities; it has a relatively short half-life of 330 days and emits mostly soft β-particles, which are inconvenient for detection. Its alpha radiation is rather weak (1.45×10−3% with respect to β-radiation), but is sometimes used to detect this isotope. 247Bk is an alpha-emitter with a long half-life of 1,380 years, but it is hard to obtain in appreciable quantities; it is not formed upon neutron irradiation of plutonium because β-decay of curium isotopes with mass number below 248 is not known. (247Cm would actually release energy by β-decaying to 247Bk, but this has never been seen.) The 20 isotopes of californium with mass numbers 237–256 are formed in nuclear reactors; californium-253 is a β-emitter and the rest are α-emitters. The isotopes with even mass numbers (250Cf, 252Cf and 254Cf) have a high rate of spontaneous fission, especially 254Cf of which 99.7% decays by spontaneous fission. Californium-249 has a relatively long half-life (352 years), weak spontaneous fission and strong γ-emission that facilitates its identification. 249Cf is not formed in large quantities in a nuclear reactor because of the slow β-decay of the parent isotope 249Bk and a large cross section of interaction with neutrons, but it can be accumulated in the isotopically pure form as the β-decay product of (pre-selected) 249Bk. Californium produced by reactor-irradiation of plutonium mostly consists of 250Cf and 252Cf, the latter being predominant for large neutron fluences, and its study is hindered by the strong neutron radiation.
=== A10BD Combinations of oral blood glucose lowering drugs === A10BD01 Phenformin and sulfonylureas A10BD02 Metformin and sulfonylureas A10BD03 Metformin and rosiglitazone A10BD04 Glimepiride and rosiglitazone A10BD05 Metformin and pioglitazone A10BD06 Glimepiride and pioglitazone A10BD07 Metformin and sitagliptin A10BD08 Metformin and vildagliptin A10BD09 Pioglitazone and alogliptin A10BD10 Metformin and saxagliptin A10BD11 Metformin and linagliptin A10BD12 Pioglitazone and sitagliptin A10BD13 Metformin and alogliptin A10BD14 Metformin and repaglinide A10BD15 Metformin and dapagliflozin A10BD16 Metformin and canagliflozin A10BD17 Metformin and acarbose A10BD18 Metformin and gemigliptin A10BD19 Linagliptin and empagliflozin A10BD20 Metformin and empagliflozin A10BD21 Saxagliptin and dapagliflozin A10BD22 Metformin and evogliptin A10BD23 Metformin and ertugliflozin A10BD24 Sitagliptin and ertugliflozin A10BD25 Metformin, saxagliptin and dapagliflozin A10BD26 Metformin and lobeglitazone A10BD27 Metformin, linagliptin and empagliflozin A10BD28 Metformin and teneligliptin A10BD29 Sitagliptin and dapagliflozin A10BD30 Gemigliptin and dapagliflozin A10BD31 Metformin, sitagliptin and dapagliflozin A10BD32 Glimepiride and dapagliflozin A10BD33 Pioglitazone and dapagliflozin A10BD34 Metformin and enavogliflozin
Sources: en.wikipedia.org
This could provide a pathway from fatty acids to glucose, but whether this actually happens in the human body is controversial. Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting. The gluconeogenesis pathway is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the pathway leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from fatty acid catabolism via beta oxidation.
The Royal Netherlands East Indies Army Air Force received 40 P-51Ds and flew them in the course of the Indonesian National Revolution, particularly during the two Dutch police actions: Operation Product in 1947 and Operation Kraai in 1948–1949. When the conflict was over, Indonesia received 26 of these Mustangs. New Zealand
The Protein Structure Initiative (PSI) was a USA based project that aimed at accelerating discovery in structural genomics and contribute to understanding biological function. Funded by the U.S. National Institute of General Medical Sciences (NIGMS) between 2000 and 2015, its aim was to reduce the cost and time required to determine three-dimensional protein structures and to develop techniques for solving challenging problems in structural biology, including membrane proteins. Over a dozen research centers have been supported by the PSI for work in building and maintaining high-throughput structural genomics pipelines, developing computational protein structure prediction methods, organizing and disseminating information generated by the PSI, and applying high-throughput structure determination to study a broad range of important biological and biomedical problems. The project has been organized into three separate phases. The first phase of the Protein Structure Initiative (PSI-1) spanned from 2000 to 2005, and was dedicated to demonstrating the feasibility of high-throughput structure determination, solving unique protein structures, and preparing for a subsequent production phase. The second phase, PSI-2, focused on implementing the high-throughput structure determination methods developed in PSI-1, as well as homology modeling and addressing bottlenecks like modeling membrane proteins.
where "ads" stands for "adsorbed", "m" stands for "monolayer equivalence" and "vap" is reference to the vapor pressure of the liquid adsorptive at the same temperature as the solid sample. The unit function creates the definition of the molar energy of adsorption for the first adsorbed molecule by:
=== 16 April === The SBU claimed to have destroyed a Russian Nebo-U radar system in Bryansk Oblast using drones. Russian-installed officials in Zaporizhzhia Oblast said that Anton Yakimenko, a member of the district council of occupied Yakymivka, was lightly injured in a bomb attack as part of an assassination attempt. Ukraine announced that it was testing an "unmanned submarine" that can be fitted with a warhead, stealth features and sensors, carry up to 10 divers, carry six torpedoes or missiles and has an endurance of 54 hours/1000 km, with a speed of up to 50 km/h underwater. Zelenskyy signed the revised mobilization bill into law. Denmark announced a new military aid package for Ukraine valued at 2.2 billion kroner ($313 million) that is partly aimed at weapons production in the Czech Republic.
Sources: en.wikipedia.org
==== Metabotype informs about treatment outcomes ==== Pharmacometabolomics may be used in a predictive manner to determine the correct course of action in regards to a patient about to undergo some type of drug treatment. This involves determining the metabolic profile of a patient prior to treatment, and correlating metabolic signatures with the outcome of a pharmaceutical treatment course. Analysis of a patient's metabolic profile can reveal factors that may contribute to altered drug metabolism, allowing for predictions of the overall efficacy of a proposed treatment, as well as potential drug toxicity risks that may differ from the general population. This approach has been used to identify novel or previously characterized metabolic biomarkers in patients, which can be used to predict the expected outcome of that patient following treatment with a pharmaceutical compound. One example of the clinical application of pharmacometabolomics are studies that looked to identify a predictive metabolic marker for the treatment of major depressive disorder (MDD)., In a study with antidepressant Sertraline, the Pharmacometabolomics Network illustrated that metabolic profile at baseline of patients with major depression can inform about treatment outcomes. In addition the study illustrated the power of metabolomics for defining response to placebo and compared response to placebo to response to sertraline and showed that several pathways were common to both.
=== Pharmacodynamics === Carisoprodol's structural similarity to meprobamate indicates GABAergic activity, including GABAA agonism, similar to the mechanism of benzodiazepines but distinct (benzodiazepines are positive allosteric modulators of the GABA A receptor, and have no direct agonist activity but rather increase the potency of the endogenous agonist GABA at this receptor). Carisoprodol thus not only works as a muscle relaxant but also helps with anxiety. Unlike benzodiazepines, carisoprodol does not treat or prevent seizures. In fact, it increases the risk of seizures, with the risk being even higher when discontinuing the drug after long-term use, especially if it is stopped suddenly, precipitating withdrawal.
=== January === 1 January – A driver runs over two police officers on a foot patrol in Nelson, killing one and injuring the other. A 32-year-old man is arrested. 3 January: A 32-year old man is charged with the murder of Nelson police officer Senior Sergeant Lyn Fleming. Biosecurity New Zealand launches a major biosecurity operation after an oriental fruit fly is detected in South Auckland. Thousands attend a vigil in Nelson for slain police officer Lyn Fleming. Air New Zealand flight NZ677 from Auckland to Dunedin is cancelled due to a phone threat, affecting 170 passengers. 4 January – Interislander and Bluebridge cancel a total of seven ferry crossings in response to rough weather conditions in the Cook Strait. 5 January – Interislander and Bluebridge cancel five ferry crossings in response to continuing rough weather in the Cook Strait. 6 January: The Desert Road closes for two months of repairs. Interislander and Bluebridge suspend ferry crossings due to rough weather in the Cook Strait. 8 January – Over 2,070 customers in the Kaipara District experience internet outages after a digger damages the main fibre optic cable between Whangārei and Dargaville. 9 January: In response to significant public interest, New Zealand Parliament's justice select committee extends the submission deadline for the Treaty Principles Bill to 1pm on 14 January. A fire engulfs 20 hectares (49 acres) of scrubland in Whangārei, leading to the evacuation of two houses.
Endogenous Originating from within an organism, tissue, or cell. In neuroscience, it typically refers to naturally occurring neurotransmitters or signaling molecules. Endorphins Endogenous opioid peptides that bind to opioid receptors and act as natural painkillers and mood enhancers. Engram A theoretical physical trace or biological substrate of memory in the brain. The term is used in memory research to describe the neural changes underlying a specific memory. Enteric nervous system A subdivision of the autonomic nervous system that governs the function of the gastrointestinal system. Sometimes called the "second brain." Epinephrine A hormone and neurotransmitter (also known as adrenaline) involved in the body’s fight-or-flight response. Produced in the adrenal medulla. EPSP (Excitatory Postsynaptic Potential) A depolarizing event in a postsynaptic neuron caused by the influx of positive ions, making the neuron more likely to fire an action potential. Equilibrium potential The membrane potential at which there is no net flow of a particular ion across the cell membrane. It can be calculated using the Nernst equation. Estrogen A steroid hormone that, in addition to reproductive functions, affects brain structure, cognition, and neuroprotection, particularly in areas such as the hippocampus. Evoked potential A measured electrical response of the nervous system to a specific sensory, motor, or cognitive stimulus, commonly recorded with EEG. Excitability The ability of a neuron or muscle cell to respond to a stimulus and generate an action potential.
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。