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▎ Imiterere ya GLP-1
Inkomoko: Pub Chem |
Urukurikirane: 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-Aru Inzira ya molekulari: C 187H 291N 45O.59 Uburemere bwa molekuline: 4114 g / mol CAS Umubare 910463-68-2 PubChem CID 56843331 Synonyme: Rybelsus; Ozempic; Wegovy |
Ubushakashatsi bwa GLP -1
Ni ubuhe bushakashatsi bwakozwe na GLP-1?
GLP-1 ni glucagon yumuntu isa na peptide-1 (GLP-1) igereranya, ishyirwa mubikorwa nka GLP-1 reseptor agonist. GLP-1 ni imisemburo karemano isohoka mu ngirangingo zo munda nyuma yo kurya. Ifite uruhare mu guteza imbere imisemburo ya insuline no guhagarika imisemburo ya glucagon, bityo igenga urugero rwa glucose mu maraso. Iterambere rya GLP-1 ryaturutse mubushakashatsi bwimbitse bwimikorere ya physiologique ya GLP-1. Nyamara, GLP-1 ifite igice gito cyane cyubuzima bwumubiri, kimara iminota 1 kugeza kuri 2 gusa, ibyo bikaba biterwa no kwandura kwangirika na enzyme ya dipeptidyl peptidase-4 (DPP-4) mumubiri. Kugira ngo iyi mbogamizi igerweho, abahanga bahinduye imiterere ya GLP-1 binyuze mu gusimbuza aside amine yihariye no kongeramo amatsinda akingira, byongera imbaraga zo kurwanya imisemburo ya DPP-4 bityo byongerera igihe ibikorwa byayo [1] . Mu miterere ya GLP-1, alanine kumwanya wa 8 isimburwa na α-aminoisobutyric aside (Aib). Iri hinduka ntiritezimbere gusa ibiyobyabwenge ahubwo binashimangira guhuza kwa reseptor ya GLP-1 (Ma H, 2020). Byongeye kandi, urunigi rudasanzwe rwa aside irike ihuza C-terminus, ihuza binyuze kuri γ-glutamine n'ibisigazwa bya lysine, bikomeza ubuzima bwa kimwe cya kabiri, bigatuma inshinge imwe mu cyumweru cyangwa ubuyobozi bwa buri munsi [1] . Ku ikubitiro hashingiwe ku bushakashatsi no guhindura GLP-1 karemano, GLP-1 igamije gutanga uburyo bunoze bwo kuvura abarwayi ba diyabete yo mu bwoko bwa 2 [1, 2] . Nyuma yuburyo bwiza, bugumana ibikorwa bya physiologique ya GLP-1 mugihe itezimbere cyane imiti ya farumasi, ihinduka ingirakamaro ya GLP-1 yakira reseptor agonist. Ubushakashatsi niterambere rya GLP-1 bifite akamaro kanini mukuvura diyabete yo mu bwoko bwa 2, bitanga amahitamo mashya kubarwayi. Mugutezimbere imiterere, itsinze ikibazo cyigihe gito cyubuzima bwa GLP-1 karemano, byongera imiti ihamye nigihe cyo gukora.
Ni ubuhe buryo bwo gukora bwa GLP-1?
GLP-1 ni glucagon-ndende ikora nka peptide-1 (GLP-1) reseptor agonist, kandi uburyo bwayo bwo gukora nuburyo bukurikira:
Amaraso ya Glucose Amabwiriza: Nkigitabo gishya cyitwa glucagon kimeze nka peptide-1 reseptor agonist (GLP-1RA), GLP-1 igabanya cyane cyane abarwayi bifuza ibiryo kandi bikagabanya guhitamo ibiryo birimo amavuta menshi muguhashya ubushake bwo kurya. Igenga ikigo cyo kugaburira muri hypothalamus, kugabanya gufata ibiryo, kongera guhaga, kubuza gusohora gastric, no kugabanya umuvuduko wa gastrointestinal, bityo ukagera ku ntego yo kugabanya ibiro. Kugabanuka ibiro bifasha kunoza insuline no kurushaho kugabanya urugero rwa glucose yamaraso [3] (Kim HS, 2021). GLP-1 itera kugabanuka mubibabi binyuze mumihanda yagabanijwe. Ubushakashatsi bwerekanye ko GLP-1 ikora mu buryo butaziguye nk'ubwonko, septal nucleus, na hypothalamus. Nubwo itarenga inzitizi yubwonko bwamaraso, ikorana nubwonko ikoresheje ingingo zuzenguruka hamwe nuturere tumwe na tumwe hafi ya ventricles. Itera ibikorwa bya c-Fos hagati yibice 10 byubwonko, harimo uturere twinyuma twibasiwe na GLP-1 nakarere ka kabiri nta GLP-1R itaziguye, nka nucleus ya parabrachial. Isesengura ryikora ryerekana ko gukora bishobora kuba bifitanye isano no guhagarika amafunguro agenzurwa na neuron muri nucleus ya parabrachial, bityo bikagenga urugero rwa glucose yamaraso [4].
Amabwiriza ya Gastrointestinal: GLP-1 ikora kuri reseptor ya GLP-1 mu nzira ya gastrointestinal. Binyuze mu nzira ya afferent ya nervice ya vagus, ikora mubice byubwonko nka nucleus yumuhanda wonyine hamwe na moteri ya dorsal nucleus ya nervice ya vagus kugirango igabanye umuvuduko wa gastrointestinal. Irashobora kubuza kugabanuka kwa antrum gastrica, kongera ubukana bwa pyloric sphincter, kongera igihe cyo gutura ibiryo mu gifu, no gutinda kwinjira muri duodenum, bikarinda kwiyongera byihuse glucose yamaraso nyuma yindwara kandi bigatuma glucose yamaraso ihinduka neza [5] (Katsurada K, 2016). Byongeye kandi, GLP-1 ikora kuri reseptor ya GLP-1 muri sisitemu yo hagati yo hagati, cyane cyane mubice nka arcuate nucleus na paraventricular nucleus ya hypothalamus. Irabuza kurekura ibintu bitera ubushake bwo kurya nka neuropeptide Y (NPY) hamwe na poroteyine ifitanye isano na agouti (AgRP), kandi icyarimwe ikora neurone ya pro-opiomelanocortin (POMC), igatera imisemburo ya hormone itera α-melanocyte (α-MSH) [5] . Izi ngaruka zitanga ibyiyumvo byo guhaga, kugabanya inzara, no kugabanya ibiryo, ku buryo butaziguye bigira ingaruka nziza ku kugenzura amaraso glucose.
Kurinda indwara z'umutima: GLP-1 irashobora guteza imbere ingirabuzimafatizo ya endoteliyale irekura ibintu biva mu mitsi nka aside nitide (OYA), byongera ubushobozi bwo kwaguka kw'amaraso no kunoza amaraso. Muri icyo gihe, irabuza ibisubizo bitera umuriro hamwe na stress ya okiside, igabanya kwangirika kwingirabuzimafatizo ya endoteliyale, kandi ikagabanya ibyago byo kurwara aterosklerose. Byongeye kandi, mu kugabanya ubushake bwo kurya no gufata ibiryo, GLP-1 ifasha mu kugabanya ibiro, itezimbere indwara ya diyabete ya lipide, igabanya urugero rwa triglyceride na cholesterol ya lipoprotein nkeya (LDL-C), kandi ikongera urugero rwa cholesterol ya lipoprotein nyinshi (HDL-C). Irashobora kandi kugira ingaruka nziza kumuvuduko wamaraso muguhindura impyiko yimpyiko nimirimo ya neuroendocrine, bikagabanya ibyago byo kurwara hypertension nindwara ziterwa numutima nimiyoboro [6].
GLP-1 no gutondekanya inyandiko-mvugo ya WAT guhinduranya BAT no gukora BAT.
Inkomoko: Byatangajwe [12]
Ni ubuhe bushakashatsi bw'ingenzi n'ubushakashatsi?
Gutegura no Kunoza Imiterere ya Shimi: Mugihe hateguwe GLP-1, hakoreshejwe uburyo bwo guhinduranya alubumu kugirango hongerwe igihe ibiyobyabwenge. Mu kumenya uburyo bwiza bwo guhuza aside irike hamwe n’ibihuza, mugihe hagumijwe gukora neza ya reseptor ya GLP-1 (GLP-1R), ubushobozi bwo guhuza albumin bwarushijeho kuba bwiza [7].
Gushyira mu bikorwa ibiyobyabwenge: GLP-1 ni glucagon imeze nka peptide-1 yakira reseptor agonist (GLP-1 RA) ifite igihe kirekire cyo kurandura igice cyubuzima, ikemerera gutera inshinge rimwe mu cyumweru. Ku barwayi barwaye diyabete yo mu bwoko bwa 2 (T2DM), ingaruka zo kugabanya ibiro byo gutera inshuro imwe mu cyumweru inshinge za GLP-1 ziruta iz'izindi GLP-1RAs rimwe mu cyumweru. Mu cyiciro cya II dose-ubushakashatsi ku barwayi bafite umubyibuho ukabije udafite T2DM, inshuro imwe buri munsi yo guterwa munsi ya GLP-1 yerekanaga ingaruka nziza yo kugabanya ibiro kuruta placebo na rimwe kumunsi 3.0 mg liraglutide. Urwego rwo kugabanya ibiro rwatewe na GLP-1 muri ubu bushakashatsi rwarenze igipimo cy’imiti igabanya ibiro yashyizweho n’ikigo cy’ubuvuzi cy’ibihugu by’Uburayi (EMA) n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), kandi gifite umutekano, byerekana ko inshuro imwe buri munsi yo gutera inshinge munsi ya GLP-1 ifite amahirwe yo kuzaba imiti igabanya ibiro [8].
Kuvura Indwara z'umutima n'imitsi mu kunoza imikorere yumutima: Ibyavuye mu igeragezwa rya STEP-HFpEF byagaragaje ko urugero rwinshi rwa antidiabete glucagon imeze nka peptide 1 agonist GLP-1 yazamuye cyane ibimenyetso bifitanye isano no kunanirwa k'umutima hamwe n'uduce twinshi twabitswe (HFpEF) kandi bigabanya urwego rwa N-terminal pro-B-natriuretic peptide. Ubushakashatsi bwakozwe bwerekanye ko kuvura cyane hamwe na GLP-1 bishobora kongera ubukana bwa trabeculae yo mu bwoko bwa trabeculae inshuro zirenga eshatu mu buryo buterwa na dose, nta kwiyongera kwa aritite. Izi ngaruka zishobora guterwa no kwiyongera kwa Ca2 + na sarcoplasmic reticulum. Kuvura hamwe na GLP-1 ikabije ku barwayi bafite ikibazo cy'umutima birashobora kunoza imikorere ya atiri, bityo bikagabanya ibimenyetso [9].
GLP-1 iri gukorwa iperereza ku kuvura steatohepatite idafite inzoga (NASH): Igishushanyo mbonera cya GLP-1 cyagize uruhare runini mu kunoza igenzura rya glucose yamaraso, uburemere bwumubiri, umuvuduko wamaraso, lipide yamaraso, imikorere ya selile, na sisitemu yumutima nimiyoboro y'amaraso ku barwayi ba diyabete yo mu bwoko bwa 2. Byongeye kandi, iterambere ry’imvugo ya GLP-1 rishobora gutanga inyungu zinyongera mubijyanye no kuvura abarwayi [7].
Ni irihe tandukaniro mu ngaruka zo kugabanya ibiro bya GLP-1 mubantu batandukanye?
Abakuze bafite indwara z'umutima-damari zabayeho mbere, umubyibuho ukabije cyangwa umubyibuho ukabije ariko udafite diyabete: Mu igeragezwa ry’ibisubizo by’umutima-damura SELECT, GLP-1 yagabanije 20% by’indwara zikomeye zifata umutima n’amaraso ku bantu 17,604 bakuze bafite indwara zifata umutima-mitsi, umubyibuho ukabije cyangwa umubyibuho ukabije, kandi nta diyabete [10] (Ryan DH, 2024). Muri iri sesengura ryabanje gusobanurwa, abashakashatsi basuzumye ingaruka za GLP-1 ku buremere bw'umubiri, ibisubizo bya antropometrike, umutekano, no kwihanganira ukurikije ibipimo fatizo by'umubiri (BMI). Abarwayi bahabwa GLP-1 bahuye nigabanuka ryuburemere bwumubiri mugihe cyibyumweru 65, bikageza kumyaka 4. Mugihe cibyumweru 208, ugereranije nitsinda rya placebo, GLP-1 yatumye igabanuka ryikigereranyo cyibiro byumubiri (-10.2%), umuzenguruko wikibuno (-7,7 cm), hamwe nu rukenyerero -kuburebure (-6.9%), mugihe itsinda rya placebo ryagabanutseho (-1.5%, -1,3 cm, na -1.0%), kandi byose byagereranijwe na statisto. Kugabanya ibiro bifite akamaro byagaragaye kubagabo nabagore, amoko yose, ubwoko bwumubiri, nakarere. GLP-1 yahujwe nibintu bike bikomeye byabaye bibi. Kuri buri cyiciro cya BMI (<30, 30 kugeza <35, 35 kugeza <40, na ≥40 kg / m²), umubare w’ibintu bibi byakorewe GLP-1 (umubare wibyabaye byagaragaye ku myaka 100-umuntu) byari bike (43.23, 43.54, 51.07, na 47.06 kuri GLP-1, na 50.48, 49.66, 52.73, na 60.85). GLP-1 yajyanye no kwiyongera kwihagarikwa ryibicuruzwa byageragejwe. Mugihe icyiciro cya BMI cyagabanutse, igipimo cyo guhagarika cyariyongereye. Mu igeragezwa RYITONDERWA, mu byumweru 208, GLP-1 yabyaye ibiro byinshi by’amavuriro no kunoza indangagaciro za antropometrike ugereranije na placebo, kandi gutakaza ibiro byakomeje imyaka 4.
Abantu bafite umubyibuho ukabije cyangwa ufite ibiro byinshi ariko badafite diyabete: Isuzuma ryakozwe ryasuzumye imikorere n'umutekano bya GLP-1 ku bantu bafite umubyibuho ukabije cyangwa ufite ibiro byinshi ariko badafite diyabete [11] . Iri suzuma ryagaragaje ibisubizo by’ibigeragezo byinshi by’amavuriro, byibanda ku ngaruka za GLP-1 ku kugabanya ibiro, ibipimo bya metabolike, hamwe n’ubuzima rusange muri rusange. Ibisubizo byagaragaje ko GLP-1 yajyanye no kugabanya ibiro cyane no kunoza ibipimo byubuzima bijyanye n'umubyibuho ukabije, kandi birashobora kuba uburyo bwiza bwo kuvura abarwayi bafite umubyibuho ukabije.
Abarwayi badafite diyabete (ibimenyetso biva muri RCT nyinshi): Mu bigeragezo 4 byateganijwe byateganijwe, abarwayi bafite ibiro fatizo by’ibiro 96 kugeza kuri 105 bahawe inshinge zo munsi ya mg 2,4 za GLP-1 hamwe n’ubuzima bwabo (ubujyanama, imirire, n’ibikorwa by’umubiri) kugira ngo bavure ibiro. Igeragezwa rimwe ryateganijwe ku barwayi badafite diyabete (N = 1961) ryerekanye ko nyuma y'ibyumweru 68, ikigereranyo cyo kugabanya ibiro cyari 15% (15 kg), ibyo bikaba byari bitandukanye cyane na 2% (3 kg) mu itsinda rya placebo. Umubare w'abarwayi bafite ibiro ≥5% wari 86% ugereranije na 32% mu itsinda rya placebo, n'umubare ukenewe kuvura (NNT) = 2; igipimo cy’abarwayi bafite ibiro ≥10% cyari 69% ugereranije na 12% mu itsinda rya placebo, na NNT = 2. Kugabanya ibiro byagabanutse mu byumweru 60. Indwara ziterwa na gastrointestinal (AEs) zari 74% ugereranije na 48% mu itsinda rya placebo, kandi umubare ukenewe kugira ngo ugirire nabi (NNH) = 3. Umubare w’abarwayi bahagarika kwivuza bitewe n’ibihe bibi wari 7% ugereranije na 3% mu itsinda rya placebo, na NNH = 25. Mu kindi kigeragezo cyagenzuwe n’ubuzima bukomeye (N = 611), uburemere bwa 16P) itandukanye na 6% (6 kg) mumatsinda ya placebo. Mu bushakashatsi bwakozwe ku bushakashatsi bwakozwe ku barwayi ba diyabete (N = 1210), abarwayi bahawe buri cyumweru 2,4 mg ya GLP-1, buri cyumweru 1.0 mg ya GLP-1, cyangwa umwanya wabo. Nyuma yibyumweru 68, impuzandengo yo gutakaza ibiro yari 10% (2,4 mg), 7% (1.0 mg), na 3% (placebo). Umubare w'abarwayi bafite ibiro bya ≥5% wari 69% (2,4 mg), 57% (1.0 mg) ugereranije na 29% mu itsinda rya placebo. Kuri dosiye ya 2,4 mg na 1.0 mg, NNT = 9. Ibyabaye bibi byari bisa na dosiye zitandukanye. Mu kubungabunga ibiro byateganijwe kugenzurwa (N = 803), abitabiriye badafite diyabete bavuwe buri cyumweru hamwe na mg 2,4 za GLP-1 mu byumweru 20, hanyuma bagabanywa mu itsinda ryakomeje kuvura GLP-1 cyangwa itsinda rya placebo. Nyuma yibyumweru 48, itsinda rikomeje kuvura GLP-1 ryatakaje 8% byuburemere bwumubiri, mugihe itsinda rya placebo ryiyongereyeho 7% byuburemere bwumubiri.
Mu gusoza, GLP-1 ni GLP-1 reseptor agonist imiti ifite agaciro gakoreshwa mubice byinshi. Mu rwego rwo kuvura diyabete, igenzura neza urugero rwa glucose mu maraso ihuza reseptor ya GLP-1, igatera imisemburo ya insuline, ikanabuza gusohora glucagon, itanga uburyo bw'ingenzi bwo kuvura abarwayi ba diyabete yo mu bwoko bwa 2. Mu rwego rwo kuvura umubyibuho ukabije, GLP-1 igabanya cyane gufata ingufu binyuze mu buryo bwo guhagarika ubushake bwo kurya no gutinda gusohora gastrica, gufasha abarwayi bafite umubyibuho ukabije guta ibiro no kuzamura imiterere ya metabolike. Byongeye kandi, GLP-1 irerekana kandi amahirwe yo gukoreshwa mugukumira no kuvura indwara zifata umutima. Gutezimbere kwingaruka zumutima nimiyoboro yimitsi itanga uburyo bushya bwo kugabanya indwara zifata umutima.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Hegner P ni umushakashatsi muri kaminuza ya Regensburg. Ibikorwa bye bikubiyemo Chimie, Sisitemu Yumutima, na Cardiology. Muri Chimie, akora ubushakashatsi bujyanye nubuzima bwumutima. Mu bushakashatsi bwimikorere yumutima, asuzuma imikorere yumutima nimiyoboro, ashakisha ubushishozi bwo kuvura. Ubushakashatsi bwe bw'umutima bwibanze ku kwirinda indwara z'umutima, gusuzuma, no kuvura.
Umusanzu wa Hegner urakomeye. Ubushishozi bwe bwimiti bwatumye imiti mishya yumutima itera. Ibikorwa bye kumikorere yumutima nubwato byongereye gusobanukirwa indwara zifata umutima. Mubuvuzi, ubushakashatsi bwe bwateje imbere imicungire yindwara z'umutima, bizamura ibipimo byita ku barwayi. Muri rusange, uburyo bwa Hegner butandukanye buratungisha imiti yumutima nimiyoboro y'amaraso, bitanga ibyiringiro byo kugabanya imitwaro yindwara nibisubizo byiza byabarwayi. Hegner P yanditse kurutonde rwerekana [9].
