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RetatrutidStructure Imiterere ya
Inkomoko: PubChem |
Urukurikirane: YA⊃1; QGTFTSDYSI-L⊃2; LDKK⁴AQA⊃1; AFIEYLLEGGPSSGAPPPS⊃3; Inzira ya molekulari: C 221H 342N 46O.68 Uburemere bwa molekuline: 4731 g / mol Numero ya CAS: 2381089-83-2 PubChem CID: 171390338 Synonyme ： LY3437943 |
Research Retatrutid Ubushakashatsi
Ni ubuhe bushakashatsi bwakozwe kuri Retatrutid?
Kwiyongera ku isi hose umubyibuho ukabije na diyabete yo mu bwoko bwa 2 bikomeje kwiyongera, bikaba ari ikibazo gikomeye ku buzima rusange. Ibiyobyabwenge biriho cyangwa bibiri-bifite intego bifite aho bigarukira mu mikorere n'umutekano. Hashingiwe ku nyigisho zijyanye no guhuza intego zinyuranye binyuze muri gastrointestinal insuline axis, ubushakashatsi bwerekanye uruhare rwuzuzanya rwa GLP-1, GIP, na glucagon muguhindura metabolike, bitanga umusingi wamahame yo guteza imbere agoniste benshi.
Hashingiwe ku bunararibonye bubiri bwo guteza imbere ibiyobyabwenge, abashakashatsi bakoze kandi banonosora Retatrutid bashingiye kumiterere nuburyo bwo kwerekana ibimenyetso byabakira batatu. Mugukorera icyarimwe GLP-1R, GIPR, na GCGR, igera kuri glycemic ikomeye cyane no kugabanya ibiro.
Nubuhe buryo bwo gukora kuri Retatrutid?
Kwakira Agonism
Imikorere ya Retatrutid nkibice bitatu byakira agonist yibasira GLP-1, GCGR, na GIP yakira [1].
GLP-1 reseptor agonism: GLP-1 ni imisemburo ya incretin isohoka mu ngirabuzimafatizo L. Iyo uhujwe no kwakira GLP-1, Retatrutid itera gusohora insuline muburyo bwa glucose-biterwa. Mugihe cya hyperglycemia, Retatrutid ihuza reseptor ya GLP-1, ikora inzira yerekana inzira yerekana inzira itera pancreatic β-selile gusohora insuline no kugabanya glucose yamaraso. Irabuza kandi gusohora glucagon kandi igabanya glucose ya hepatike, bikomeza glucose yamaraso. GLP-1 reseptor agonism nayo itinda gusiba gastric, ikongera guhaga, kandi igabanya ibiryo, ifasha mugucunga ibiro [2].
GCGR reseptor agonism: Ubusanzwe Glucagon ikora mugihe cya hypoglycemia kugirango izamure glucose yamaraso. Retatrutid's agonist igikorwa kuri GCGR iragoye. Muri tipusi ya adipose, itera lipolysis kandi ikongera okiside ya aside irike, bityo ikongerera ingufu ingufu. Mu mwijima, agonism ya GCGR iringaniye irashobora kugenga inzira nka gluconeogenez, igahindura imikorere ya hepatike. Ibi birinda gluconeogenezi ikabije gutera hyperglycemia mugihe hagumye glucose ihagije kugirango ihuze imbaraga z'umubiri [1].
GIP reseptor agonism: GIP, indi misemburo ya incretin, isohoka na selile K muri duodenum na jejunum nyuma yo kurya. Retatrutid's GIP reseptor agonism yongerera insuline gusohora, igahuza na GLP-1 kugirango tunoze glucose. Ibinyuranye, ibikorwa bya GIP byakirwa bishobora guhindura metabolisme ya lipide no kuringaniza ingufu. Ubushakashatsi bwa Brzozowska P bwerekana ko GIP iteza glucose gufata hamwe na synthesis ya lipid muri adipocytes. Nyamara, bitewe na Retatrutid, ibimenyetso bya GIP byahinduwe kugirango hongerwe ingufu mu gukoresha ingufu aho guteza imbere ububiko bwamavuta gusa, bityo bigafasha gucunga ibiro [1].
Igishushanyo 1 Uburyo bwa Retatrutid bwibikorwa [3].
Kugenzura byimazeyo inzira ya metabolike
Amabwiriza yo Guhindura Ingufu: Mugukoresha reseptors eshatu zavuzwe haruguru, Retatrutid igenga byimazeyo metabolism yingufu. Itera lipolysis, kongera aside irike yinjira muri mitochondriya ya β-okiside no kongera ingufu zikoreshwa. Igabanya lipogenezi mu guhagarika aside irike hamwe na synthesis ya triglyceride muri adipocytes, bityo bigahindura ububiko bwumubiri hamwe nuburinganire bwakoreshejwe kugirango byorohereze ibiro. Mu bushakashatsi bw’inyamaswa n’ibigeragezo byakozwe na Jastreboff AM, ubuyobozi bwa Retatrutid bwongereye igipimo cy’ingufu zikoreshwa kandi kigabanya buhoro buhoro ibinure by’umubiri mu ngingo zifite umubyibuho ukabije [4].
Glucose Metabolism Amabwiriza: Retatrutid ihindura glucose yamaraso binyuze munzira nyinshi. Usibye gutera insuline gusohora binyuze muri GLP-1 na GIP reseptor ya GIP, bigira ingaruka kumyuka ya glucose metabolism igenga GCGR. Irwanya gluconeogenezi ikabije ya hepatike, igabanya glucose isohoka, kandi icyarimwe ikongerera glucose periferique glucose gufata no kuyikoresha, bityo igakomeza urugero rwamaraso glucose. Ibi ni ingenzi cyane ku barwayi bafite umubyibuho ukabije barwaye diyabete yo mu bwoko bwa 2, kugenzura neza glucose yamaraso no kuzamura indwara ya diyabete [2].
Umwijima wo Guhindura Umwijima: Mu mwijima, Retatrutid ntabwo ihindura glucose metabolisme gusa ahubwo inagira metabolisme ya lipide. Igabanya synthesis ya hepatike triglyceride no kwirundanya, itezimbere umwijima, kandi ifite agaciro kavura indwara zumwijima zidafite inzoga (NAFLD). Mu igeragezwa ry’amavuriro ryitabiriwe n’abitabiriye indwara ziterwa n’umwijima (MDAFLD), Retatrutid yagabanije cyane ibinure by’umwijima, byerekana ingaruka nziza zabyo kuri metabolism ya hepatike [5].
Ingaruka ku mikorere ya Gastrointestinal
Retatrutid itinda gusiba gastrica ikora GLP-1 yakira. Gusiba gazi gahoro byongera igihe cyo gutura mu gifu, bikabyara guhaga kandi bikagabanya gufata ibiryo nyuma. Icyarimwe, irashobora kugira uruhare mu gusohora imisemburo yo mu nda no gutembera mu mara, bikarushaho kugenzura igogorwa rya gastrointestinal igogora ndetse nintungamubiri zintungamubiri, bityo bikagira ingaruka zikomeye ku gufata ingufu nuburemere bwumubiri [2].
Nubuhe buryo bwo guhuza imbaraga hagati ya Retatrutid ingaruka za agonistic kuri GLP-1, GCGR, na GIP yakira?
Gukoresha imbaraga mu kugenzura ingufu za metabolism
Kongera ingufu mu gukoresha ingufu: Gukora GCGR bitera glycogenolysis na gluconeogenez kugirango bizamure urugero rwa glucose yamaraso. Yongera kandi ingufu zikoreshwa mukwongera metabolisme ya lipide no guhagarika ibiryo byokunyurwa hagati. GLP-1R agoniste itera ururenda rwa insuline kandi ikagira ingaruka z'umutima ndetse na neuroprotective, mugihe kandi zigabanya gufata ingufu mugutinda gusiba gastrica no guhagarika ubushake bwo kurya. Mugihe ibikorwa bya GIPR muri tipusi ya adipose itera kwirundanya kwa lipide, ibikorwa byayo hagati bigabanya gufata ibiryo kandi bikagabanya kongera ibiro. Retatrutid icyarimwe yibasira aba reseptors batatu, ishyiraho uburinganire bushya hagati yo gufata ingufu nogukoresha. Ibi birushaho kugera ku gihombo cyingufu, bityo bikorohereza kugabanya ibiro.
Kugenga metabolisme ya lipide: Agonism ya GCGR yongerera metabolisme ya lipide, mugihe GIPR ikora mumyanya ya adipose nayo igira ingaruka kuri metabolism. GLP-1R agoniste irashobora kugira ingaruka ku buryo butaziguye metabolisme ya lipide ikoresheje uburyo nko kunoza insuline. Ibikorwa byabo byo guhuza ibikorwa bigenga neza ibinure, gusenyuka, no gutwara, kugabanya ibinure no kunoza ikwirakwizwa ryumubiri. Kurugero, ubushakashatsi bwakozwe kubarwayi bafite umubyibuho ukabije bwerekanye ko nyuma yo gukoresha Retatrutid mugihe runaka, ijanisha ryibinure byumubiri ryaragabanutse kandi imyirondoro ya lipide yateye imbere kuburyo bugaragara, byerekana ingaruka zayo muguhindura metabolisme yibinure [6].
Ingaruka zoguhuza mugutunganya glucose
Kongera insuline ya insuline: GLP-1R agoniste igabanya glucose yamaraso ihuza reseptor ya GLP-1 no guteza imbere gusohora insuline. GIP nayo itera pancreatic β-selile kugirango itange ingaruka zo gusohora insuline zisa nizo ziterwa no gufata indyo. Retatrutid, icyarimwe ikora GLP-1R na GIPR, byongera cyane imisemburo ya insuline, bityo bikagabanya cyane glucose yamaraso. Nubwo GCGR isanzwe ifitanye isano na glucose yamaraso ikabije, ingaruka zayo - nko guteza imbere ingufu zikoreshwa - zirashobora kugira uruhare rutaziguye mu gutuza glucose mugihe ikoranye hamwe niyakira nka GLP-1R. Byongeye kandi, gukoresha hamwe GLP-1 na GCGR guhitamo kurwanya ibyago bya hyperglycemic biterwa na GCGR, bigafasha kugenzura neza glucose.
Kugenga Glucose Homeostasis: Gukorana kwingirangingo yibi byakira bitatu birenze gusohora insuline gusa kugirango bikubiyemo glucose homeostasis. Muguhindura glucose gufata, kuyikoresha, no kubika mubice byinshi birimo umwijima, imitsi, na adipose, Retatrutid ikomeza glucose yamaraso muburyo butajegajega, ikumira ihindagurika rikomeye. Mu bushakashatsi bwakozwe na Nicholls S bwerekeye abarwayi ba diyabete yo mu bwoko bwa 2, ubuyobozi bwa Retatrutid bwatumye igabanuka rikabije ry’imisemburo ya gemoglobine, byerekana ingaruka nziza zayo mu kurwanya indwara ya glycemic igihe kirekire no kwerekana ingaruka ziterwa n’abakira batatu mu kugenzura glucose homeostasis [6].
Gukomatanya Gukora Ibimenyetso byo Kwimura Inzira
Ibikorwa bisanzwe byerekana inzira: GLP-1R, GCGR, na GIPR byerekana mbere na mbere binyuze muri poroteyine G (Gαs). Iyo Retatrutid ikora kuri ziriya reseptors eshatu, irahuza kugirango ikore inzira zisangiwe kumanuka nkinzira ya cAMP-PKA. Uku gusangira inzira gusangira byongera ibimenyetso byogukwirakwiza imbaraga nimbaraga, byongerera imbaraga amategeko agenga imikorere ya metabolism selile nibikorwa bya physiologique.
Guhuza inzira zitandukanye: Mugihe dusangiye inzira zisanzwe, buri reseptor nayo ikora imiyoboro idasanzwe yerekana ibimenyetso. Retatrutid ihindura inzira zinyuranye mugihe kimwe cyo gukora reseptor, bigafasha guhuza metabolike ihuza.
Amabwiriza agenga imikorere ya Gastrointestinal
Kugira uruhare mu gusohora imisemburo ya Gastrointestinal: GLP-1R agoniste itera GLP-1, mugihe aboniste ba GIPR bagenga irekurwa rya GIP. Iyi misemburo ya gastrointestinal igira uruhare runini muguhindura igifu, igogora, no kwinjirira. Mugukora icyarimwe gukora reseptors zombi, Retatrutid itanga amabwiriza arambuye yimisemburo ya gastrointestinal hormone, bityo bikagira ingaruka kumikorere ya gastrointestinal. Irashobora kugabanya kwihuta kwintungamubiri muguhindura igipimo cyo gusiba gastrici no gutembera mu mara, bifasha muburemere no kugenzura glucose yamaraso.
Gutezimbere Ibidukikije bya Gastrointestinal: Mugutunganya imisemburo ya gastrointestinal hormone, Retatrutid nayo yongerera imbaraga metabolike mumyanya yigifu. Itera imbere gukura na metabolisme ya bagiteri yingirakamaro kandi igahindura imikorere yinzitizi yo mara. Ihinduka rishobora kurushaho kugira ingaruka kumubiri muri rusange. Gukorera hamwe hamwe ningaruka ziterwa ningufu za metabolisme no kugenzura amaraso ya glucose, ubwo buryo hamwe bugira uruhare mukuvura ingaruka zumubyibuho ukabije hamwe nindwara ziterwa na metabolike.
Ni ubuhe buryo bukoreshwa muri Retatrutid?
Umuti ufite umubyibuho ukabije
Ingaruka zikomeye zo gutakaza ibiro: Ibigeragezo byinshi byamavuriro byerekana ingaruka za Retatrutid mukuvura umubyibuho ukabije. Mu cyiciro cya 2 impumyi ebyiri, zidahwitse, zigenzurwa na platbo na Jastreboff AM zirimo abantu bakuru 338, abitabiriye amahugurwa bahawe Retatrutid ya buri cyumweru kuri dosiye zitandukanye cyangwa umwanya wibyumweru 48. Ibisubizo byerekanye ko ku cyumweru cya 24, itsinda rya 1mg ryageze ku kigereranyo cyo kugabanya ibiro 7.2%, itsinda rya 4mg ryatakaje 12.9%, itsinda rya 8mg ryatakaje 17.3%, naho itsinda rya 12mg ryatakaje 17.5%, mugihe itsinda rya placebo ryatakaje 1,6% gusa. Mugihe cyicyumweru 48, itsinda rya 1mg ryageze ku kigereranyo cyo kugabanya ibiro 8.7%, itsinda rya 4mg rihuza ryatakaje 17.1%, itsinda rya 8mg ryatakaje 22.8%, itsinda rya 12mg ryatakaje 24.2%, naho itsinda rya placebo ryatakaje 2.1%. Mu bitabiriye amahugurwa bahabwa 4mg, 8mg, na 12mg Retatrutid, 92%, 100%, na 100% bageze kuri 5% cyangwa birenze ibiro. 75%, 91%, na 93% bageze ku 10% cyangwa gutakaza ibiro byinshi. na 60%, 75%, na 83% bageze kuri 15% cyangwa kurenza ibiro, ugereranije na 27%, 9%, na 2% mumatsinda yabobo. Aya makuru yerekana neza imikorere ya Retatrutid mu kugabanya ibiro ku barwayi bafite umubyibuho ukabije [4].
Ubwoko bwa 2 Kuvura Diyabete
Glycemic Igenzura Ingaruka: Ubushakashatsi bwakozwe na Lopez DC n'abandi. erekana Retatrutid igira ingaruka nziza kugenzura glycemic kubarwayi ba diyabete yo mu bwoko bwa 2. Mu rubanza rwitabiriwe n’abitabiriye 353, Retatrutid yagabanije glycated hemoglobine (HbA1c) 1,64% ugereranije na placebo. Ibi byerekana ingaruka za Retatrutid mu kugabanya urugero rwa glucose mu maraso ku barwayi ba diyabete yo mu bwoko bwa 2, bityo bikagira uruhare mu kuzamura amavuriro [7].
Ibyiza bya Mechanism Ibyiza: Retatrutid ikora kubantu benshi bakira, itanga inyungu idasanzwe kurenza reseptor agonist imwe ikoresheje uburyo bwa agoniste. Ntabwo igabanya glucose yamaraso gusa itera insuline isohoka ahubwo inongerera insuline ibyiyumvo, bigatuma ingirabuzimafatizo z'umubiri zikoresha insuline neza kugirango igenzure glycemic. Ingaruka zayo zigabanya ibiro birusheho kunoza imiterere ya metabolike ku barwayi ba diyabete yo mu bwoko bwa 2, kubera ko umubyibuho ukabije ari ikintu gikomeye gishobora gutera iyo ndwara kandi kugabanya ibiro byorohereza imiyoborere myiza ya glucose mu maraso [5].
Kuvura Indwara Zumwijima Zidafite Inzoga
Kugabanya ibinure byumwijima: Retatrutid yerekanye ubushobozi bwo kugabanya ibinure byumwijima kubarwayi bafite metabolike idakora neza ifitanye isano nindwara yumwijima (MDAFLD) hamwe nibinure byumwijima ≥10%. Mu igeragezwa ryateganijwe, rihumye-rihumye, rigenzurwa na platbo, abitabiriye 98 bahawe amahirwe yo kwakira inshinge zo munsi ya buri munsi ya Retatrutid (1mg, 4mg, 8mg, cyangwa 12mg) cyangwa umwanya wa byumweru 48. Ibisubizo byerekanye ko ku cyumweru cya 24, impinduka zingana n’ibinure bya hepatike ugereranije n’ibanze byari -42,9% mu itsinda rya 1mg, -57.0% mu itsinda rya 4mg, -81.4% mu itsinda rya 8mg, na -82.4% mu itsinda rya 12mg, ugereranije na + 0.3% mu itsinda rya placebo. Ubu bushakashatsi bwerekana ko Retatrutid igabanya cyane ibinure bya hepatike, bikerekana agaciro ko kuvura indwara z’umwijima zidafite inzoga [8].
Kunoza imikorere ya Hepatique Metabolic: Retatrutid yongera imikorere yumwijima muguhindura ingufu na metabolism ya lipide. Itera okiside hamwe no gusenyuka kw'amavuta ya hepatike, igabanya ibinure mu mwijima, igahindura ibisubizo byokongoka hamwe nurwego rwo guhagarika umutima mu mwijima, kandi ikagira ingaruka zimwe na zimwe zibuza iterambere rya NAFLD, bityo bikarinda ubuzima bwumwijima w’abarwayi.
Umwanzuro
Nka triple reseptor agonist ya GLP-1R / GIPR / GCGR, Retatrutid igira ingaruka zoguhindura metabolike binyuze muburyo bwinshi bwo guhuza ibikorwa. Ingaruka zayo zikubiyemo gukora GLP-1R kugirango igabanye ubushake bwo kurya no gutinza igifu, bityo bigabanye gufata ingufu; gukora GIPR kugirango yongere imisemburo ya insuline no kunoza insuline; no gukora GCGR kugirango iteze imbere lipolysis nogukoresha ingufu mugihe ugenga glucose hepatike na metabolisme ya lipide kugirango ugabanye ibinure. Ubu busabane butatu bugera ku ngaruka zuzuye zirimo kurwanya glycemic ikomeye, kugabanya ibiro cyane, no kunoza amavuta ya lipide na hepatike. Agaciro kacyo kibanze mu kuvura umubyibuho ukabije, kugera ku kugabanya ibiro biterwa no kugabanya ibiro hamwe no gutakaza ibyumweru 48 byibura 24.2%. Kuri diyabete yo mu bwoko bwa 2, igabanya neza glycated hemoglobine kandi igateza imbere homeostasis ya glycemic. Indwara ya metabolike idakora neza ifitanye isano nindwara yumwijima, igabanya cyane ibinure byumwijima, byerekana imbaraga zikomeye mubibazo byinshi byo guhindagurika.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Arun J. Sanyal ni umuhanga mu kuvura indwara z’umwijima n’umushakashatsi w’inzobere mu ndwara z’umwijima, cyane cyane indwara y’umwijima idafite inzoga (NAFLD) na steatohepatitis idafite inzoga (NASH). Yifatanije n’ishuri ry’ubuvuzi rya kaminuza ya Virginia Commonwealth, aho yabaye umunyeshuri kuva mu 1989. Sanyal yanditse ibitabo bigera ku 1.000 mu binyamakuru bikomeye nka Cell Metabolism, Medicine Nature, Ikinyamakuru New England Journal of Medicine, na The Lancet. Ibikorwa bye byavuzwe inshuro zirenga 104.000, byerekana ingaruka zikomeye yagize mu bijyanye na hepatologiya. Yakomeje guterwa inkunga n’ikigo cy’igihugu cy’ubuzima kuva mu 1995 kandi ni we ushinzwe iperereza ry’impano enye zikora NIH. Sanyal yamenyekanye kandi ku buyobozi bwe mu bushakashatsi bw’amavuriro n’uruhare yagize mu gushyiraho ingamba zo kuvura indwara z’umwijima. Arun J. Sanyal yanditse kurutonde rwerekana [5].
