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1kits （10Ibikoresho）
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▎ Imiterere ya GLP-1
Inkomoko: PubChem |
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-Tr-Arp-Leu Inzira ya molekulari: C 187H 291N 45O.59 Uburemere bwa molekuline: 4114 g / mol Numero ya CAS: 910463-68-2 CIDC Pub Chem: 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) analogue, iri mubyiciro byimiti ya GLP-1 reseptor agonist. GLP-1 ni imisemburo isanzwe ibaho isohorwa na selile zo munda nyuma yo kurya, itera insuline kandi ikabuza gusohora glucagon kugirango igabanye urugero rwa glucose. Iterambere rya GLP-1 ryaturutse ku bushakashatsi bwimbitse ku mikorere ya physiologiya ya GLP-1. GLP-1 ifite ubuzima bucye bwigihe gito mumubiri, nkiminota 1-2, kuko yangirika byoroshye na enzyme ya dipeptidyl peptidase-4 (DPP-4) mumubiri. Kugira ngo ibyo bigabanye, abahanga mu bya siyansi bahinduye imiterere ya GLP-1, bashiraho insimburangingo ya aside amine kandi bongeraho amatsinda yo gukingira kugira ngo barwanye imisemburo ya DPP-4, bityo bongere igihe cyo gukora mu mubiri [1] . Mu miterere ya GLP-1, alanine iri ku mwanya wa 8 isimburwa na acide α-aminoisobutyric (Aib), ntabwo iteza imbere umutekano w’ibiyobyabwenge gusa ahubwo inongerera imbaraga imbaraga zayo hamwe na reseptor ya GLP-1 [2] . Urunigi rudasanzwe rwa aside irike yongewe kuri C-terminus ya GLP-1, ihuza ibisigisigi bya lysine ikoresheje γ-glutamine, bikongerera ubuzima igice cya kabiri cy’ibiyobyabwenge kandi bikemerera guterwa inshuro imwe mu cyumweru cyangwa gufatwa mu kanwa rimwe ku munsi [1] . GLP-1 yabanje gukorwa hashingiwe ku bushakashatsi no guhindura GLP-1 karemano, igamije gutanga ubuvuzi bunoze ku barwayi ba diyabete yo mu bwoko bwa 2 [1, 2] . Binyuze muri ubwo buryo bwiza, GLP-1 ntigumana gusa ibikorwa bya physiologique ya GLP-1 ahubwo inatezimbere cyane imiti ya farumasi, ihinduka igihe kirekire GLP-1 reseptor agonist ifite agaciro gakomeye kivuriro. Iterambere rya GLP-1 nigikorwa gikomeye, kizana uburyo bushya bwo kuvura abarwayi ba diyabete yo mu bwoko bwa 2. Muguhindura imiterere ya GLP-1 karemano, irenga imbogamizi yubuzima bwayo bwigihe gito kandi igateza imbere imiti nigihe ikora.
Ni ubuhe buryo bwo gukora bwa GLP-1?
GLP-1 ni glucagon-ndende ikora nka peptide-1 (GLP-1) reseptor agonist, kandi uburyo bwibikorwa byayo bugerwaho ahanini muburyo bukurikira:
Amaraso ya glucose:
GLP-1 nigitabo GLP-1 reseptor agonist (GLP-1RA). Uburyo bwibanze bwayo ni ukurinda irari ryibiryo muguhagarika ubushake bwo kurya, kugabanya ibyifuzo byibiribwa birimo amavuta menshi, no guhindura ikigo cyo kugaburira hypothalamic kugabanya ibiryo. Yongera kandi guhaga, gutinda gusiba gastric, no kugabanya umuvuduko wa gastrointestinal, bityo bikagabanuka. Kugabanya ibiro byongera insuline kandi bigafasha kugabanya glucose yamaraso [3] . GLP-1 itera kugabanuka mubibabi binyuze mumihanda ikwirakwizwa. Ubushakashatsi bwerekana ko bukora ku bwonko, septal nucleus, na hypothalamus ariko ntiburenga inzitizi y'amaraso n'ubwonko. Ahubwo, ikorana n'ubwonko binyuze mu ngingo zizenguruka no mu bice byegeranye. GLP-1 ikora c-Fos mubice icumi byubwonko, harimo uduce twinyuma twibasiwe nu turere twa kabiri nka nucleus ya parabrachial nucleus idafite GLP-1R itaziguye. Isesengura ryikora ryerekana ko gukora birimo parabrachial nucleus neurons igenzura iherezo ryibiryo, bityo bikagenga glucose yamaraso [4] .
Gastrointestinal regulation:
GLP-1 ikora kuri reseptor ya GLP-1 mu mara, ikoresheje inzira ya vagus nervice inzira kugirango ihindure moteri ya gastrointestinal. Irwanya kugabanuka kwa antral, itera pyloric sphincter guhagarika umutima, kandi ikongerera kugaburira ibiryo byo mu gifu, gutinda kwinjira munda no kwirinda indwara ya glucose nyuma yamaraso, bigatuma urwego ruhamye [5] . Byongeye kandi, GLP-1 igira ingaruka kuri GLP-1 yo hagati, cyane cyane muri hypothalamic arcuate na nuclei paraventricular. Irabuza ibintu bitera ubushake bwo kurya nka neuropeptide Y (NPY) hamwe na poroteyine ifitanye isano na agouti (AgRP), mugihe ikora neuron ya proopiomelanocortin (POMC) kugirango yongere imisemburo ya alpha-melanocyte itera imbaraga (α-MSH ) . Ibi bikorwa bitera guhaga, kugabanya inzara, no kugabanya ibiryo, bifasha gucunga ibiro no kunoza mu buryo butaziguye kugenzura amaraso glucose.
Kurinda umutima n'imitsi:
GLP-1 iteza imbere irekurwa rya aside nitide (OYA) hamwe na vasodilator ziva mu ngirabuzimafatizo ya endoteliyale, bikongera vasodilasiya n'amaraso. Irinda kandi gutwika no guhagarika umutima, kugabanya kwangirika kwa endoteliyale hamwe na risque ya aterosklerose. Mu kugabanya ubushake bwo kurya no gufata ibiryo, bifasha kugabanya ibiro, kunoza diyabete ya lipide, kugabanya triglyceride na cholesterol ya lipoprotein nkeya (LDL-C), kandi ikazamura cholesterol ya lipoproteine (HDL-C). Byongeye kandi, birashobora kugirira akamaro umuvuduko wamaraso muguhindura hemodinamike yimpyiko nimikorere ya neuroendocrine, kugabanya ibyago byumuvuduko ukabije wamaraso no kugabanya ingaruka ziterwa nindwara z'umutima . .
GLP-1 no gutondekanya inyandiko ya WAT kuri BAT ihinduka no gukora BAT.
Inkomoko: Byatangajwe [13]
Ubushakashatsi bwingenzi nubushakashatsi
Kubijyanye no gushushanya imiterere yimiti no kuyitezimbere, mugihe cyo gushushanya GLP-1, hakoreshejwe uburyo bwo guhuza byimazeyo na albumin kugirango hongerwe igihe ibikorwa byibiyobyabwenge. Muguhitamo uburyo bwiza bwo guhuza aside irike hamwe nu muhuza, ubushobozi bwo guhuza albumin bwarushijeho kuba bwiza mugihe hagumijwe gukora neza kuri reseptor ya GLP-1 (GLP-1R) (Knudsen LB, 2019).
Kubijyanye no gukoresha ibiyobyabwenge, GLP-1 ifite ingaruka nziza zo kugabanya ibiro. GLP-1 ni glucagon imeze nka peptide-1 yakira reseptor agonist (GLP-1 RA) hamwe no kurandura igihe kirekire igice cyubuzima, ikemerera gutera inshinge buri munsi. Ingaruka yo kugabanya ibiro iratangaje. Ku barwayi barwaye diyabete yo mu bwoko bwa 2 (T2DM), gutera inshinge buri munsi ya GLP-1 bisa nkibifite akamaro mu kugabanya ibiro kurusha izindi GLP-1RAs buri cyumweru. Mu cyiciro cya II ikigereranyo cyo gushakisha abarwayi bafite umubyibuho ukabije udafite T2DM, inshuro imwe buri munsi yo gutera inshinge munsi ya GLP-1 byagize akamaro cyane mu kugabanya ibiro kuruta placebo na rimwe kumunsi 3.0mg liraglutide. Kugabanya ibiro byatewe na GLP-1 muri ubu bushakashatsi byarenze igipimo cy’imiti igabanya ubukana bwashyizweho n’ikigo cy’ubuvuzi cy’ibihugu by’Uburayi (EMA) n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), nta kibazo cy’umutekano kigaragaza, cyerekana ko inshuro imwe buri munsi gutera inshinge munsi ya GLP-1 ifite amahirwe yo kuba ibiyobyabwenge bigabanya ibiro [7] .
GLP-1 irashobora kunoza imikorere yumutima kandi ikoreshwa mukuvura indwara zifata umutima. Ibyavuye mu igeragezwa rya STEP-HFpEF byatangajwe, aho urugero rwinshi rwa antidiabete glucagon imeze nka peptide 1 agonist GLP-1 yazamuye cyane ibimenyetso byo kunanirwa k'umutima hamwe n'uduce duto two gusohora (HFpEF) kandi bigabanya urwego rwa N-terminal rwitwa natriuretic peptide (NT-proBNP). Ubushakashatsi bwagaragaje ingaruka z’ubuvuzi bukabije bwa GLP-1 kuri trabeculae y’umuntu ku giti cye kandi bwerekanye ko GLP-1 yongereye ubukana bwa trabeculae yo mu bwoko bwa trabeculae inshuro zirenga eshatu mu buryo buterwa n’imiti, nta kongera ubushake bwo kurwara. Izi ngaruka birashoboka cyane kubera kwiyongera kwa sarcoplasmic reticulum Ca2 + gufata. Ubuvuzi bukabije bwa GLP-1 kubarwayi bananirwa kumutima birashobora kunoza imikorere yumubiri bityo bikagabanya ibimenyetso [8] .
GLP-1 irimo kwigwa kugirango ivurwe na steatohepatite itari inzoga (NASH). Igishushanyo mbonera cyacyo cyagize uruhare runini mugutezimbere glucose yamaraso, uburemere, umuvuduko wamaraso, lipide, imikorere ya selile, hamwe na sisitemu yumutima nimiyoboro y'amaraso kubarwayi barwaye diyabete yo mu bwoko bwa 2. Byongeye kandi, iterambere ry’imvugo ya GLP-1 rishobora gutanga inyungu zinyongera ku barwayi mu bijyanye no kubahiriza imiti [9] .
Itandukaniro mu gutakaza ibiro Ingaruka za GLP-1 Hafi yabaturage
Ingaruka zo Kugabanya Ibiro Kubantu Bakuze Indwara Yumutima Yumutima, Umubyibuho ukabije cyangwa Umubyibuho ukabije udafite diyabete:
Mu igeragezwa ry’ibisubizo by’umutima-damura, GLP-1 yagabanije 20% ku bintu bikomeye by’imitsi n’umutima (MACE) ku kigero cya 20% ku bantu 17,604 bakuze bafite indwara zifata umutima n’umutima, umubyibuho ukabije cyangwa umubyibuho ukabije, kandi nta diyabete [10] . Muri iri sesengura ryerekanwe mbere, abashakashatsi basuzumye ingaruka za GLP-1 ku buremere, ibisubizo bya antropometrike, umutekano, no kwihanganira ibipimo fatizo by’umubiri (BMI). Abarwayi bakira GLP-1 bahuye n'ibiro bikabije mu byumweru 65, bikomeza imyaka 4. Mugihe cibyumweru 208, GLP-1 yatumye habaho kugabanuka cyane muburemere (-10.2%), kuzenguruka mu kibuno (-7,7 cm), no kugereranya umubyimba-uburebure (-6.9%) ugereranije na placebo (-1.5%, -1.3 cm, na -1.0%; kugereranya kwose byari bifite imibare mibi. buri cyiciro cya BMI (<30, 30 kugeza <35, 35 kugeza <40, na ≥40 kg / m²), GLP-1 yari ifite ibipimo bibi byibyabaye (ibyabaye kumuntu 100-imyaka: 43.23, 43.54, 51.07, na 47.06 v ikigeragezo, GLP-1 yatumye ibiro bigabanuka cyane mubuvuzi no kunoza antropometrike ugereranije na placebo mu byumweru 208, hamwe no kugabanya ibiro bikomeza imyaka 4.
Ingaruka zo Gutakaza Ibiro Kubyibushye cyangwa Biremereye Abantu badafite diyabete:
Isuzuma rifatika ryasuzumye imikorere n'umutekano bya GLP-1 ku bantu bafite umubyibuho ukabije cyangwa ufite ibiro byinshi badafite diyabete [11] . Iri suzuma ryashushanyije ibisubizo bivuye mu bigeragezo byinshi by’amavuriro, byerekana ingaruka za GLP-1 ku kugabanya ibiro, ibipimo bya metabolike, hamwe n’ibisubizo by’ubuzima muri rusange. Ibyavuye mu bushakashatsi byagaragaje ko GLP-1 ifitanye isano no kugabanya ibiro no kunoza ibipimo by’ubuzima bijyanye n’umubyibuho ukabije, byerekana ko ishobora kuba uburyo bwiza bwo kuvura abarwayi bafite umubyibuho ukabije.
Ingaruka zo gutakaza ibiro kubarwayi badafite diyabete (Ibimenyetso biva muri RCT nyinshi):
Ibigeragezo bine byateganijwe (RCTs) birimo abarwayi bafite uburemere bwibanze bwa kg 96-105 basuzumaga buri cyumweru 2,4 mg munsi ya GLP-1 hiyongereyeho uburyo bwo kubaho (ubujyanama, indyo, imyitozo ngororamubiri) kugirango bagabanye ibiro [12] . RCT imwe mu barwayi badafite diyabete (N = 1,961) yavuze ko igabanuka ry'uburemere bwa 15% (15 kg) na 2% (3 kg) hamwe na platbo nyuma y'ibyumweru 68 (bifite imibare ikomeye). Umubare w'abarwayi bagera kuri ≥5% gutakaza ibiro ni 86% na 32% (umubare ukenewe mu kuvura [NNT] = 2), naho ≥10% gutakaza ibiro byari 69% na 12% (NNT = 2). Kugabanya ibiro byashyizwe ku byumweru ~ 60. Ibintu bibi bya Gastrointestinal (AEs) byabaye muri 74% na 48% (umubare ukenewe kugirango wangize [NNH] = 3). Guhagarika kubera AEs byari 7% na 3% (NNH = 25). Ibisubizo nkibi byagaragaye muyindi RCT hamwe nubuzima bukomeye (N = 611): GLP-1 yatumye 16% (17 kg) na 6% (6 kg) bigabanuka. Muri dose-ubushakashatsi RCT ku barwayi badafite diyabete (N = 1,210), buri cyumweru 2,4 mg GLP-1, 1.0 mg GLP-1, cyangwa umwanya wawo watanze bivuze gutakaza ibiro 10%, 7%, na 3% nyuma yibyumweru 68. Ibipimo bigera kuri ≥5% gutakaza ibiro byari 69% (2,4 mg), 57% (1.0 mg), na 29% (umwanya). Kuri 2,4 mg na 1.0 mg, NNT = 9. Umwirondoro wa AE wasaga na dosiye. Mu kubungabunga ibiro RCT (N = 803), abitabiriye badafite diyabete bahawe mg 2,4 mg GLP-1 buri cyumweru mu byumweru 20, hanyuma bahitamo gukomeza GLP-1 cyangwa guhindukira kuri placebo. Nyuma yibyumweru 48, abakoresha GLP-1 bakomeje gutakaza 8% nabakoresha umwanya wa 7%.
Muncamake, GLP-1 ni GLP-1 reseptor agonist ifite agaciro ka domeni nyinshi. Mu kuvura diyabete, ihuza reseptor ya GLP-1 kugirango iteze imbere gusohora insuline no kubuza gusohora glucagon, igenzura neza urugero rwa glucose mu maraso kandi itanga uburyo bukomeye bwo kuvura abarwayi ba diyabete yo mu bwoko bwa 2. Mu rwego rwo kuvura umubyibuho ukabije, GLP-1 irashobora kugabanya cyane gufata ingufu binyuze mu buryo bwo guhagarika ubushake bwo kurya no gutinda gusohora gastrica, gufasha abarwayi bafite umubyibuho ukabije guta ibiro no kuzamura imitekerereze yabo. Byongeye kandi, GLP-1 yerekana amahirwe yo gukoreshwa muburyo bwo gukumira no kuvura indwara zifata umutima, no kunoza ibintu bishobora gutera indwara z'umutima n'imitsi bitanga uburyo bushya bwo kugabanya indwara ziterwa n'umutima. Kugaragara kwa GLP-1 ntabwo bikungahaza uburyo bwo kuvura indwara zifitanye isano gusa ahubwo bizana ibyiringiro bishya byo kuzamura imibereho y’abarwayi n’ubuzima.
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 murutonde rwibisobanuro [8].
