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1 kits (10 Vials)
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▎ Tsarin GLP-1
Source: Pub Chem |
Jerin: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-lys (Aeea-Aeea-γ-glu-octadecanedioic)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH Tsarin kwayoyin halitta: C 187H 291N 45O59 Nauyin Kwayoyin: 4114 g/mol Lambar CAS 910463-68-2 Farashin 56843331 Ma'ana: Rybelsus; Ozempic ; Wegovy |
▎ GLP-1 Bincike
Menene asalin bincike na GLP-1?
GLP-1 analog ne na ɗan adam glucagon-kamar peptide-1 (GLP-1), wanda aka rarraba shi azaman agonist mai karɓa na GLP-1. GLP-1 hormone ne na halitta wanda ƙwayoyin hanji ke ɓoye bayan cin abinci. Yana taka rawa wajen haɓaka siginin insulin da hana fitar glucagon, ta haka ne ke daidaita matakan glucose na jini. Haɓaka GLP-1 ya samo asali ne daga zurfafa bincike na ayyukan physiological na GLP-1. Duk da haka, GLP-1 yana da ɗan gajeren rabin rayuwa a cikin jiki, yana da kusan minti 1 zuwa 2 kawai, wanda aka danganta ga rashin lafiyarsa ga lalacewa ta hanyar dipeptidyl peptidase-4 (DPP-4) enzymes a cikin jiki. Don shawo kan wannan ƙayyadaddun, masana kimiyya sun gyara tsarin GLP-1 ta hanyar takamaiman amino acid da aka maye gurbinsu da ƙari na ƙungiyoyi masu kariya, suna haɓaka juriya ga enzymes DPP-4 kuma don haka ya tsawaita tsawon lokacin aiki [1] . A cikin tsarin GLP-1, alanine a matsayi na 8 an maye gurbinsa da α-aminoisobutyric acid (Aib). Wannan canjin ba kawai yana inganta kwanciyar hankali na miyagun ƙwayoyi ba har ma yana ƙarfafa ɗaurin sa ga mai karɓar GLP-1 (Ma H, 2020). Bugu da ƙari, sarkar gefen fatty acid na musamman da aka haɗa da C-terminus, wanda aka haɗa ta hanyar γ-glutamine zuwa ragowar lysine, yana ƙara tsawon rabin rayuwa, yana ba da damar yin allura sau ɗaya a mako ko kuma gudanar da baki na yau da kullum [1] . Da farko dangane da bincike da gyare-gyare na GLP-1 na halitta, GLP-1 yana nufin samar da zaɓuɓɓukan magani mafi inganci ga marasa lafiya da nau'in ciwon sukari na 2 [1,2] . Bayan inganta tsarin, yana riƙe da aikin ilimin lissafin jiki na GLP-1 yayin da yake haɓaka kaddarorin sa na harhada magunguna, yana zama muhimmin agonist mai karɓa na GLP-1 mai tsayi. Bincike da haɓaka GLP-1 suna da matukar mahimmanci don kula da nau'in ciwon sukari na 2, yana ba da sabbin zaɓuɓɓuka ga marasa lafiya. Ta hanyar inganta tsarin, yana shawo kan matsalar gajeriyar rabin rayuwar GLP-1 na halitta, yana haɓaka kwanciyar hankali na miyagun ƙwayoyi da tsawon lokacin aiki.
Menene tsarin aikin GLP-1?
GLP-1 shine agonist mai karɓar glucagon-kamar peptide-1 (GLP-1), kuma tsarin aikinsa shine kamar haka:
Tsarin Glucose na Jini: A matsayin sabon glucagon-kamar peptide-1 agonist mai karɓa (GLP-1RA), GLP-1 galibi yana rage sha'awar abinci ga marasa lafiya kuma yana rage fifikon abinci mai kitse ta hanyar hana ci. Yana daidaita cibiyar ciyarwa a cikin hypothalamus, rage cin abinci, ƙara yawan gamsuwa, hana zubar da ciki, da rage motsin ciki, don haka cimma burin asarar nauyi. Rashin nauyi yana taimakawa haɓaka juriya na insulin kuma yana ƙara daidaita matakan glucose na jini [3] (Kim HS, 2021). GLP-1 yana haifar da asarar nauyi a cikin rodents ta hanyoyin jijiyoyi da aka rarraba. Nazarin ya nuna cewa GLP-1 yana aiki kai tsaye a kan yankuna kamar kwakwalwar kwakwalwa, tsakiya na septal, da hypothalamus. Ko da yake ba ya ketare shingen kwakwalwar jini, yana hulɗa da kwakwalwa ta hanyar gabobin dawakai da takamaiman yankuna kusa da ventricles. Yana haifar da kunnawar c-Fos na tsakiya a cikin yankuna na kwakwalwa na 10, gami da yankuna na baya-bayan nan kai tsaye da GLP-1 da yankuna na sakandare ke niyya ba tare da hulɗar GLP-1R kai tsaye ba, kamar tsakiyar tsakiya na parabrachial. Bincike ta atomatik yana nuna cewa kunnawa na iya kasancewa yana da alaƙa da ƙarewar abinci da ƙwayoyin cuta ke sarrafa su a cikin tsakiya na parabrachial na gefe, don haka daidaita matakan glucose na jini [4].
Dokokin Gastrointestinal: GLP-1 yana aiki akan masu karɓar GLP-1 a cikin sashin gastrointestinal. Ta hanyar jijiyar jijiyar ƙwayar cuta, yana aiki akan yankunan da ke cikin kwakwalwa irin su tsakiya na sashin jiki da kuma dorsal motor tsakiya na jijiyar vagus don daidaita motsin ciki. Yana iya hana ƙanƙarar antrum na ciki, haɓaka tashin hankali na pyloric sphincter, tsawaita lokacin zama na abinci a cikin ciki, da jinkirta shigarsa cikin duodenum, yana hana saurin haɓakar glucose na jini na jini da kuma sanya glucose jini ya canza mafi kwanciyar hankali [5] (Katsurada K, 2016). Bugu da ƙari, GLP-1 yana aiki akan masu karɓa na GLP-1 a cikin tsarin kulawa na tsakiya, musamman a cikin yankunan da suka hada da arcuate nucleus da paraventricular nucleus na hypothalamus. Yana hana sakin abubuwan da ke motsa sha'awa irin su neuropeptide Y (NPY) da furotin da ke da alaƙa da agouti (AgRP), kuma a lokaci guda yana kunna pro-opiomelanocortin (POMC) neurons, yana haɓaka ɓoyewar α-melanocyte-stimulating hormone (α-MSH) [5] . Wadannan tasirin suna haifar da jin daɗi, rage yunwa, da rage yawan abinci, a kaikaice suna da tasiri mai kyau akan sarrafa glucose na jini.
Kariyar Kariya na zuciya: GLP-1 na iya inganta ƙwayoyin endothelial na jijiyoyi don saki abubuwan vasodilatory irin su nitric oxide (NO), haɓaka ƙarfin haɓakar jijiyoyin jini da inganta haɓakar jini. A lokaci guda, yana hana amsawar kumburi da damuwa na oxidative, yana rage lalacewa ga sel endothelial na jijiyoyin jini, kuma yana rage haɗarin atherosclerosis. Bugu da ƙari, ta hanyar rage ci da cin abinci, GLP-1 yana taimakawa tare da asarar nauyi, yana inganta cututtuka na ciwon sukari, yana rage matakan triglycerides da low-density lipoprotein cholesterol (LDL-C), kuma yana ƙara yawan ƙwayar lipoprotein cholesterol (HDL-C). Hakanan yana iya samun tasiri mai amfani akan cutar hawan jini ta hanyar daidaita aikin hemodynamics na renal da ayyukan neuroendocrine, rage haɗarin hauhawar jini da cututtukan cututtukan zuciya [6].
GLP-1 da ƙa'idar rubutun WAT zuwa juyar da BAT da kunna BAT.
Source: PubMed [12]
Menene mabuɗin gwaji da karatu?
Zane da Inganta Tsarin Sinadarai: Lokacin zayyana GLP-1, an ɗauki hanyar da za a iya jujjuyawa ga albumin don tsawaita tsawon lokacin aikin. Ta hanyar ƙayyade mafi kyawun haɗin fatty acids da masu haɗin gwiwa, yayin kiyaye ingancin mai karɓa na GLP-1 (GLP-1R), ƙarfin ɗaure ga albumin ya haɓaka [7].
Aikace-aikacen Magunguna: GLP-1 shine glucagon-kamar peptide-1 agonist mai karɓa (GLP-1 RA) tare da ƙarancin kawar da rabin rayuwa, yana ba da izinin allurar subcutaneous sau ɗaya-mako. A cikin marasa lafiya da ke da nau'in ciwon sukari na 2 (T2DM), tasirin asarar nauyi na allurar subcutaneous na GLP-1 sau ɗaya mako-mako ya fi na sauran GLP-1RAs sau ɗaya-mako-mako. A cikin gwajin bincike na kashi na II na marasa lafiya masu kiba ba tare da T2DM ba, allurar subcutaneous na GLP-1 na yau da kullun ya nuna mafi kyawun asarar nauyi fiye da placebo kuma sau ɗaya a rana 3.0 MG liraglutide. Matsayin asarar nauyi da GLP-1 ya haifar a cikin wannan binciken ya zarce ka'idodin magungunan rage kiba da Hukumar Kula da Magunguna ta Turai (EMA) da Hukumar Kula da Abinci da Magunguna ta Amurka (FDA) suka kafa, kuma ba shi da lafiya, yana nuna cewa allurar GLP-1 na subcutaneous sau ɗaya a rana yana da yuwuwar zama magani na asarar nauyi na gaba [8].
Maganin cututtuka na zuciya da jijiyoyin jini ta hanyar inganta aikin zuciya: Sakamakon gwajin gwaji na STEP-HFpEF ya nuna cewa babban maganin antidiabetic glucagon-like peptide 1 agonist GLP-1 ya inganta haɓakar alamun da ke da alaka da ciwon zuciya tare da raguwar fitarwar da aka adana (HFpEF) kuma ya rage matakin N-terminal natype-NTP-BNP. Gwaje-gwajen bincike sun gano cewa m jiyya tare da GLP-1 na iya ƙara tashin hankali na atrial trabeculae na mutum fiye da sau uku a cikin nau'i-nau'i-nau'i, ba tare da haɓakar arrhythmia ba. Wannan tasiri na iya zama saboda karuwa a cikin ɗaukar Ca2+ ta hanyar sarcoplasmic reticulum. Yin jiyya tare da babban adadin GLP-1 a cikin marasa lafiya da ke fama da gazawar zuciya na iya inganta aikin atrial, ta haka yana kawar da alamun cutar [9].
GLP-1 yana ƙarƙashin bincike don maganin steatohepatitis maras barasa (NASH): Tsarin ma'ana na GLP-1 ya ba da gudummawa mai yawa don inganta sarrafa glucose na jini, nauyin jiki, hawan jini, lipids na jini, aikin β-cell, da tsarin zuciya na zuciya a cikin marasa lafiya da ciwon sukari na 2. Bugu da ƙari, haɓakar ƙirar baki na GLP-1 na iya ba da ƙarin fa'ida dangane da yarda da jiyya na marasa lafiya [7].
Menene bambance-bambance a cikin tasirin asarar nauyi na GLP-1 tsakanin al'ummomi daban-daban?
Manya da cututtukan zuciya da suka rigaya, kiba ko kiba amma ba tare da ciwon sukari ba: A cikin SELECT sakamakon sakamakon cututtukan zuciya, GLP-1 ya rage manyan cututtukan cututtukan zuciya da 20% a cikin manya 17,604 tare da cututtukan zuciya da suka rigaya, kiba ko kiba, kuma ba tare da ciwon sukari ba [10] (Ryan DH, 2024). A cikin wannan ƙayyadaddun ƙayyadaddun ƙayyadaddun bayanai, masu bincike sun bincika tasirin GLP-1 akan nauyin jiki, sakamakon anthropometric, aminci, da haƙuri bisa ga ma'aunin ma'aunin jiki (BMI). Marasa lafiya da ke karɓar GLP-1 sun sami ci gaba da raguwar nauyin jiki a cikin makonni 65, yana dawwama har zuwa shekaru 4. A cikin makonni 208, idan aka kwatanta da ƙungiyar placebo, GLP-1 ya haifar da raguwa a matsakaicin nauyin jiki (-10.2%), kewayen kugu (-7.7 cm), da kuma tsayi-da-tsawo rabo (-6.9%), yayin da ƙungiyar placebo ta sami raguwa na (-1.5%, -1.3 cm, da -1.0%) bi da bi, kuma duk an kwatanta su tare da placebo. Rashin nauyi mai ma'ana na asibiti ya faru a cikin maza da mata, duk kabilanci, nau'ikan jiki, da yankuna. GLP-1 yana da alaƙa da ƙananan munanan abubuwan da suka faru. Ga kowane nau'in BMI (<30, 30 zuwa <35, 35 zuwa <40, da ≥40 kg/m²), abubuwan da suka faru na mummunan abubuwan da suka faru na GLP-1 (yawan abubuwan da aka lura a cikin shekaru 100 na mutum) ya kasance ƙasa (43.23, 43.54, 51.01-4, da GLP-1. 49.66, 52.73, da 60.85 don placebo). GLP-1 yana da alaƙa da ƙarin ƙimar katsewar samfurin gwaji. Yayin da nau'in BMI ya ragu, adadin dakatarwa ya karu. A cikin gwaji na SELECT, a makonni 208, GLP-1 ya haifar da asarar nauyi na asibiti mai mahimmanci da haɓakawa a cikin ƙimar anthropometric idan aka kwatanta da placebo, kuma asarar nauyi ya ci gaba har tsawon shekaru 4.
Mutanen da ke da kiba ko kiba amma ba tare da ciwon sukari ba: Binciken na yau da kullun ya kimanta inganci da amincin GLP-1 a cikin mutanen da ke da kiba ko kiba amma ba tare da ciwon sukari ba [11] . Wannan bita ya haɗa sakamakon gwaje-gwaje na asibiti da yawa, yana mai da hankali kan tasirin GLP-1 akan asarar nauyi, sigogi na rayuwa, da sakamakon kiwon lafiya gabaɗaya. Sakamakon ya nuna cewa GLP-1 yana da alaƙa da babban asarar nauyi da haɓakawa a cikin alamun kiwon lafiya masu alaƙa da kiba, kuma yana iya zama zaɓi mai mahimmanci na jiyya ga marasa lafiya masu kiba.
Marasa lafiya marasa ciwon sukari (shaida daga RCT da yawa): A cikin 4 gwaje-gwajen da bazuwar bazuwar, marasa lafiya da nauyin nauyin jiki na 96 zuwa 105 kg sun karbi allurar subcutaneous mako-mako na 2.4 MG na GLP-1 da kuma salon rayuwa (nasihar, abinci, da aikin jiki) don maganin asarar nauyi. Ɗaya daga cikin gwaje-gwajen da aka bazu don marasa lafiya marasa ciwon sukari (N = 1961) ya nuna cewa bayan makonni 68, asarar nauyi shine 15% (15 kg), wanda ya bambanta da 2% (3 kg) a cikin rukunin placebo. Matsakaicin marasa lafiya tare da asarar nauyi na ≥5% shine 86% idan aka kwatanta da 32% a cikin rukunin placebo, kuma adadin da ake buƙata don magance (NNT) = 2; Matsakaicin marasa lafiya tare da asarar nauyi na ≥10% shine 69% idan aka kwatanta da 12% a cikin rukunin placebo, da NNT = 2. Rashin asarar nauyi ya tashi a kusan makonni 60. Abubuwan da suka faru na cututtukan cututtuka na gastrointestinal (AEs) sun kasance 74% idan aka kwatanta da 48% a cikin rukunin placebo, da kuma adadin da ake bukata don cutar da su (NNH) = 3. Yawan marasa lafiya da ke dakatar da magani saboda abubuwan da ba su da kyau shine 7% idan aka kwatanta da 3% a cikin ƙungiyar placebo, da NNH = 25. A cikin wani nau'i mai nauyin nauyin nauyi a cikin 1 da aka yi amfani da shi a cikin gwaji na 1 (N. Ƙungiyar GLP-1 ta kasance 16% (kg 17), wanda ya bambanta sosai da 6% (6 kg) a cikin rukunin placebo. A cikin gwajin gwajin bazuwar kashi-bincike don masu ciwon sukari (N = 1210), an ba marasa lafiya 2.4 MG na GLP-1 mako-mako, 1.0 mg na GLP-1 mako-mako, ko placebo. Bayan makonni 68, matsakaicin asarar nauyi shine 10% (2.4 mg), 7% (1.0 mg), da 3% (placebo) bi da bi. Adadin marasa lafiya tare da asarar nauyi na ≥5% shine 69% (2.4 mg), 57% (1.0 mg) idan aka kwatanta da 29% a cikin rukunin placebo. Don 2.4 MG da 1.0 MG allurai, NNT = 9. Abubuwan da ba su da kyau sun kasance iri ɗaya a tsakanin allurai daban-daban. A cikin nauyin kulawa da bazuwar gwajin gwaji (N = 803), mahalarta marasa ciwon sukari sun sami magani na mako-mako tare da 2.4 MG na GLP-1 na makonni 20, sannan kuma an raba su cikin bazuwar zuwa rukuni na ci gaba da jiyya na GLP-1 ko ƙungiyar placebo. Bayan makonni 48, rukunin da ke ci gaba da jiyya na GLP-1 ya rasa kashi 8% na nauyin jikinsu, yayin da rukunin placebo ya sami kashi 7% na nauyin jikinsu.
A ƙarshe, GLP-1 magani ne mai karɓa na GLP-1 tare da ƙimar aikace-aikacen a fagage da yawa. A fagen jiyya na ciwon sukari, yana sarrafa matakan glucose na jini yadda ya kamata ta hanyar ɗaure ga masu karɓar GLP-1, haɓaka ƙwayar insulin, da hana sakin glucagon, yana ba da zaɓin mahimmancin magani ga marasa lafiya masu ciwon sukari na 2. Dangane da batun jiyya na kiba, GLP-1 yana rage yawan kuzari ta hanyar hanyoyin kamar hana ci abinci na tsakiya da jinkirta zubar da ciki, yana taimakawa masu kiba su rasa nauyi da haɓaka matsayinsu na rayuwa. Bugu da ƙari, GLP-1 kuma yana nuna yuwuwar aikace-aikacen aikace-aikacen a cikin rigakafi da maganin cututtukan zuciya. Ingantawarsa na abubuwan haɗari na zuciya da jijiyoyin jini yana ba da sabuwar hanya don rage abubuwan da ke faruwa na cututtukan zuciya.
Game da Marubuci
Abubuwan da aka ambata a sama duk bincike ne, gyara su kuma Cocer Peptides ne suka haɗa su.
Mawallafin Jaridar Kimiyya
Hegner P mai bincike ne a Jami'ar Regensburg. Ayyukansa sun haɗa da Chemistry, Tsarin zuciya, da Ilimin zuciya. A cikin Chemistry, yana bincika halayen da ke da alaƙa da lafiyar zuciya. A cikin nazarin tsarin zuciya na zuciya, yana bincikar zuciya da ayyuka na jirgin ruwa, yana neman fahimtar hanyoyin warkewa. Binciken ilimin zuciyarsa yana mai da hankali kan rigakafin cututtukan zuciya, ganowa, da magani.
Gudunmawar Hegner tana da mahimmanci. Bayanan sinadarai nasa sun haifar da sabon ci gaban magungunan cututtukan zuciya. Ayyukansa akan hanyoyin zuciya da na jirgin ruwa sun inganta fahimtar cututtukan zuciya. A asibiti, bincikensa ya inganta tsarin kula da cututtukan zuciya, yana haɓaka matakan kula da marasa lafiya. Gabaɗaya, tsarin koyarwa da yawa na Hegner yana wadatar da maganin cututtukan zuciya, yana ba da bege don rage nauyin cututtuka da ingantacciyar sakamako mai haƙuri. An jera Hegner P a cikin ambaton ambaton [9].
