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▎ Imiterere ya GLP-2
Inkomoko: PubChem |
Urukurikirane: Tyr- {Aib} -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile- {Aib} -Leu-Asp-Lys-Ile-Ala-Gln- {diacid-C20-gamm a-Glu- (AEEA) 2-Lys} -Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Inzira ya molekulari: C 225H 348N 48O.68 Uburemere bwa molekuline: 4813 g / mol Numero ya CAS: 2023788-19-2 PubChem CID: 163285897 Synonyme: Zepbound; Mounjaro |
G GLP-2 Ubushakashatsi
Ni ubuhe bushakashatsi bwakozwe na GLP-2?
GLP-2 nibiyobyabwenge bya polypeptide. Iterambere ryayo rituruka ku gusobanukirwa byimazeyo aho ubushobozi bwa GLP-1 bwakira reseptor agoniste mu kuvura ubwoko bwa 2 metabolism mellitus (T2DM) n'umubyibuho ukabije. Nubwo agoniste ya GLP-1 yerekanye imikorere myiza mugucunga glucose yamaraso no kugabanya ibiro, abahanga basanze imikorere yabo ya reseptor ya GIP idakomeye, ibyo bikaba bigabanya ingaruka zo kuvura imiti. Niyo mpamvu, itsinda ry’ubushakashatsi n’iterambere ryiyemeje guteza imbere ubwoko bushya bw’ibiyobyabwenge bushobora gukora icyarimwe GIPR na GLP-1R, bigamije kugera ku buryo bunoze kandi bunoze bwo kurwanya glucose y’amaraso no gucunga ibiro [1].
Mugihe cyubushakashatsi niterambere, abahanga bakoze umubare munini wubushakashatsi bwibanze nubushakashatsi bwamavuriro. Mu cyiciro cy’ubushakashatsi bwibanze, imiti ya farumasi ya GLP-2 yasuzumwe neza binyuze mu bushakashatsi bw’inyamaswa, igenzura ubushobozi bwayo mu kugenzura amaraso glucose no kugabanya ibiro. Ibisubizo byerekanye ko bishobora kugabanya cyane urugero rwa glucose yamaraso mubyitegererezo byinyamanswa kandi bikerekana imikorere myiza mugucunga ibiro, bigashyiraho urufatiro rwibizamini byakurikiyeho.
Icyakurikiyeho, icyiciro cyo kugerageza kwa clinique cyarimo icyiciro cya mbere, II, na III. Ikigeragezo cyo mu cyiciro cya mbere cyasuzumye cyane cyane umutekano, kwihanganira, hamwe n’imiti ya farumasi. Ibisubizo byagaragaje ko GLP-2 yari ifite umutekano mwiza no kwihanganira. Ikigeragezo cyo mu cyiciro cya II cyongeye gukora ubushakashatsi ku mikorere n’umutekano bya dosiye zitandukanye za GLP-2 ku barwayi barwaye T2DM, byerekana mbere na mbere urugero rwiza rwabyo. Ikigeragezo gikomeye cyicyiciro cya gatatu cyamavuriro, nka SURPASS yubushakashatsi, cyarimo umubare munini wabarwayi bafite T2DM. Ibisubizo byerekanye ko GLP-2 yarutaga cyane GLP-1 yakira reseptor agoniste, nka GLP-1, mu kugabanya glucose yamaraso nuburemere, itanga ibimenyetso bifatika byerekana ko GLP-2 ikoreshwa mu kwamamaza ..
Ni ubuhe buryo bwo gukora bwa GLP-2?
GLP-2 igabanya glucose yamaraso binyuze muburyo bwinshi bukorera hamwe. Iyo ukora GLP-1, GLP-2 ihuza reseptor ya GLP-1 kuri pancreatic β-selile, bigana ibikorwa bya GLP-1 bisanzwe. GLP-1 ni imisemburo ikorwa mu mara kandi ni ingenzi mu kubungabunga glucose homeostasis. Irashobora guteza imbere insuline ya insuline, gusohora, hamwe no kumva glucose, kugabanya imisemburo ya glucagon kugirango iteze guhaga, kandi igabanye ubushake bwo kurya.
Iyi activation irashobora guteza imbere gusohora insuline. Insuline ni imisemburo nyamukuru ya hypoglycemic mu mubiri, ishobora kongera gufata no gukoresha glucose na selile, bityo bikagabanya urugero rwa glucose. Ku barwayi barwaye T2DM, gusohora kwa insuline ntibihagije cyangwa ingirabuzimafatizo zo kumva insuline zigabanuka, bigatuma glucose yamaraso yiyongera. Mugukoresha reseptor ya GLP-1, GLP-2 yongera imisemburo ya insuline, ifasha kunoza igenzura ryamaraso glucose.
Muri icyo gihe, ibikorwa bya GLP-1 byakira nabyo bibuza kurekura glucagon. Ubusanzwe Glucagon itera glycogenolysis na gluconeogenez mugihe cyo kwiyiriza ubusa, byongera umusaruro wamaraso glucose. Muguhagarika ibikorwa bya glucagon, GLP-2 iragabanya kandi inkomoko ya glucose yamaraso, ikagira uruhare mu kurwanya glucose yamaraso [2].
Iyo ukora reseptor ya GIP, GLP-2 ikora icyarimwe cya GIP icyarimwe. Nyuma yo gukora, irashobora kongera insuline no gusohora. GIP reseptor igaragara cyane mubice nka pancreatic β-selile. Nyuma yo gukora, binyuze mu kwanduza inzira zerekana ibimenyetso, insuline ziyongera, kandi selile yitabira insuline iratera imbere, bityo bikagabanya neza glucose yamaraso.
GLP-2 ni icyiciro cya mbere mu byiciro bibiri bya glucagon isa na peptide-1 hamwe na glucose iterwa na insulineotropique polypeptide (GIP), yemejwe kuvura abarwayi bakuze bafite T2DM nk'umugereka w'imirire no gukora siporo. GLP-2 ni imiterere yimiti yubukorikori ishingiye kumurongo wa GIP, igizwe na peptide ya aside amine 39. Yongera imisemburo ya insuline, igabanya irekurwa rya glucagon muburyo buterwa na glucose, igabanya kwiyiriza ubusa hamwe na glucose yamaraso nyuma yinyuma, itera guhaga, kugabanya ibiro byumubiri, no gutinda gusohora gastric. Izi ngaruka ebyiri za reseptor agonist zituma GLP-2 ikora neza kuruta GLP-1 yakira reseptor agonist mugutezimbere insuline no kubuza glucagon gusohora [2].
GLP-2 irashobora kandi gutinza igifu no kongera guhaga. Irashobora gutinza gusiba gastrica, ikongerera igihe cyo gutura ibiryo mu gifu kandi igabanya umuvuduko wo kwinjiza intungamubiri, bityo ikirinda kuzamuka gukabije kwa glucose yamaraso nyuma yinyuma. Mu bushakashatsi butari amavuriro n’ubuvuzi, ingaruka za GLP-2 ku gusiba gastrica ziragereranywa n’iza GLP-1 reseptor agonist. Imbeba zifite umubyibuho ukabije ziterwa nimirire, urugero rwo gutinda kwa gastrica na GLP-2 rusa nubwa GLP-1, ariko izi ngaruka zikomeye zo kubuza zirashira nyuma yibyumweru 2 bivuwe.
Abitabiriye amahugurwa hamwe na T2DM kandi badafite, rimwe mu cyumweru GLP-2 (mg5 mg na ≥4.5 mg,) batinze gusohora gastric nyuma yo kunywa inshuro imwe. Mu bitabiriye ubuzima bwiza, ingaruka zagaragaye nyuma yimiti myinshi ya GLP-2 cyangwa dulaglutide (Urva S, 2020). Muri icyo gihe, irashobora kandi gukora kuri sisitemu yo hagati yo hagati, kongera guhaga, kugabanya ubushake bwo kurya, no gufata ibiryo. Mu kugenzura ibiryo, bifasha mu buryo butaziguye kugenzura urugero rwa glucose yamaraso, cyane cyane bikwiranye n’ikibazo cy’umubyibuho ukabije gikunze guherekezwa n’abarwayi barwaye T2DM, kandi kigafasha kunoza insuline ndetse n’imiterere rusange ya metabolike [2].
GLP-2 yasanze yongera urwego rwa adiponectine, adipocytokine ijyanye no kumva insuline. Kwiyongera kwa adiponectine bifasha kunoza insuline, bigatuma selile zakira insuline, bityo gufata neza no gukoresha glucose no kugabanya glucose yamaraso [2] . Byongeye kandi, GLP-2 irashobora kandi kunoza imiterere ya lipide kandi ishobora kugira ingaruka zo kurinda ubuzima bwumutima. GLP-2 byagaragaye ko ishobora kuzamura umuvuduko w'amaraso, kugabanya cholesterol ya lipoprotein (LDL) nkeya na triglyceride [3] , bikomeza gushyigikira inyungu zayo zose mu micungire ya glucose.
Inkomoko: PubMed [5]
Ubushakashatsi bujyanye
Ingaruka zo gucunga ibiro kubarwayi bafite umubyibuho ukabije nubwoko bwa 2 metabolism mellitus
Ubushakashatsi bwinshi bw’amavuriro bwemeje imikorere ya GLP-2 mu micungire y’ibiro by’umubiri ku barwayi bafite umubyibuho ukabije na T2DM. Mu bushakashatsi bwiswe 'SURMOUNT-2 ', bwari Icyiciro cya 3, impumyi ebyiri, zidahwitse, zagenzuwe na platbo zakozwe mu bihugu birindwi. Abakuze (bafite imyaka 18) bafite icyerekezo rusange cy'umubiri (BMI) cya 27 kg / m² cyangwa hejuru hamwe na glycated hemoglobine (HbA₁c) urwego rwa 7 - 10% bahawe amahirwe yo kwakira inshuro imwe mucyumweru inshinge za GLP-2 (10 mg cyangwa 15 mg) cyangwa umwanya wa byumweru 72.
Ibisubizo byerekanye ko ku cyumweru cya 72, ijanisha ryo kugabanuka ibiro muri GLP-2 10 mg na 15 mg byari -12.8% na -14.7%, ugereranije na -3.2% mumatsinda yabobo. Ikigereranyo cyo kuvura cya GLP-2 10 mg na mg 15 ugereranije na placebo cyari -9,6 ku ijana na -11,6 ku ijana, byombi byari bifite imibare (p <0.0001). Byongeye kandi, umubare munini w’abarwayi bahabwa imiti ya GLP-2 wageze ku ntera yo kugabanuka ibiro 5% cyangwa birenga (79 - 83% vs 32%) [4].
Mu bushakashatsi bwa 'SURMOUNT-2 ', uburemere bw'ibanze bwari ibiro 100.7, BMI yari 36.1 kg / m², naho HbA₁c yari 8.02%. Nyuma yibyumweru 72 bivurwa, GLP-2 ntabwo yagabanije cyane ibiro byumubiri ahubwo yanagize ingaruka nziza mugucunga glucose yamaraso [4].
Ingaruka nziza kuri metabolism ijyanye na neuropathie
ubushakashatsi bwa ome bwerekanye ko GLP1-RAs ishobora kugabanya ibyago byo guta umutwe ku barwayi barwaye T2DM mu kunoza kwibuka, kwiga, no gutsinda ubumuga bwo kutamenya. Nka GIP-RA / GLP-1RA ebyiri, GLP-2 yakozwe mu murongo w'akagari ka neuroblastoma (SHSY5Y) kubera ingaruka zayo ku bimenyetso byo gukura kw'imitsi (CREB na BDNF), apoptose (igipimo cya BAX / Bcl2), gutandukanya (pAkt, MAP2, GAP43, na AGBL4), GLUT1, GLUT1, GLUT4
Ibisubizo ku nshuro ya mbere byibanze ku ruhare rwa GLP-2 mu gukora inzira ya pAkt / CREB / BDNF no kumanuka werekana kasake, ndetse no gukora neza kwa neuroprotective. Yagaragaje kandi ko GLP-2 yashoboye guhangana n'ingaruka zijyanye na hyperglycemia hamwe na insuline irwanya urwego rwa neuronal. Kubwibyo, GLP-2 irashobora guteza imbere neurodegeneration iterwa na hyperglycemia kandi igatsinda insuline irwanya insuline, igatanga ubumenyi bushya bwo kunoza imitekerereze ya neuropathie iterwa na metabolism [5].
Iterambere ryubushakashatsi mukuvura ubwoko bwa 2 metabolism mellitus
Ubushakashatsi bumwe bwerekanye ko nk'ubwoko bushya bw'imiti ya hypoglycemic, GLP-2 ibaye agoniste ya mbere ya GIP / GLP-1R yemewe yo kuvura metabolism muri Amerika. Byemejwe ko bifite ingaruka zikomeye mu kugabanya glucose yamaraso no kugabanya ibiro byumubiri mugupima kwinshi kwamavuriro, kandi hari ibimenyetso byerekana ko nayo ifite imbaraga nyinshi mukurinda umutima.
Mubyongeyeho, igitekerezo cya peptide ya syntetique yafunguye ibintu byinshi bitazwi kuri GLP-2. Ibigeragezo bikomeje (NCT04166773) n'ibimenyetso byerekana ko bigaragara ko ari imiti itanga icyizere mu bice nk'indwara y'umwijima idafite inzoga (NAFLD), kurinda impyiko, na neuroprotection [6].
Ingaruka ndende za GLP-2 kubuzima bwumutima
GLP-2 irashobora kugabanya ibyago byindwara zifata umutima nimiyoboro itera kugabanya ibiro. Ubushakashatsi bwasuzumye ingaruka GLP-2 igira ku mubyibuho ukabije n'indwara z'umutima n'imitsi ku bantu bakuze b'Abanyamerika (Wong ND, 2024). Ubushakashatsi bwerekanye ko mu Banyamerika bakuze bemerewe kuvurwa GLP-2, nyuma yo kuvurwa hamwe na mg 15 za GLP-2, byagereranijwe ko 70,6% na 56.7% by’abantu bakuru bafite ibiro byibura ≥15% na 20%, bivuze ko umubare w’abantu bafite umubyibuho ukabije wagabanutseho 58.8%.
Mu badafite indwara z'umutima n'imitsi, bivugwa ko imyaka 10 y’indwara zifata umutima n’umutima zagabanutse ziva kuri 10.1% 'mbere yo kuvurwa ' zigera kuri 7.7% 'nyuma yo kuvurwa ', ibyo bikaba byerekana ko igabanuka ry’ibyago ryagabanutseho 2,4% ndetse n’ikigereranyo cyo kugabanuka kwa 23,6%, bivuze ko miliyoni 2 z’indwara zifata umutima zishobora gukumirwa mu myaka 10.
Mu gusoza ， GLP-2 ni agashya kabili agonist ya GIP na GLP-1 yakira, ifite akamaro kanini mukuvura T2DM n'umubyibuho ukabije. Irashobora guteza imbere neza gusohora kwa insuline, ikabuza gusohora glucagon, kugenzura neza glucose yamaraso, kugabanya ibyago byingaruka, kunoza imikorere ya pancreatic β-selile, no gutinza iterambere rya metabolism. Ifite kandi ingaruka zo gukingira sisitemu yumutima.
Mu kuvura umubyibuho ukabije, irashobora kugabanya neza gufata ibiryo, kugabanya ubushake bwo kurya, kongera guhaga, gufasha abarwayi bafite umubyibuho ukabije guta ibiro, no kugabanya ibyago by’ingaruka ziterwa n'umubyibuho ukabije. Irashobora kandi kunoza insuline irwanya na metabolism ya lipide. Byongeye kandi, yerekanye ubushobozi mu kuvura indwara ziterwa na metabolike ziterwa na metabolike nka steatohepatite itari inzoga, syndrome de apnea, no kunanirwa k'umutima. Irashobora kunoza ibipimo byinshi bya metabolike icyarimwe, itanga gahunda yuzuye yo kuvura.
Uburyo bwa buri cyumweru bwo gutera inshinge biroroshye gukoresha kandi birashobora kunoza uburyo bwo kuvura abarwayi.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Dr. William T. Garvey ni intiti n’umushakashatsi uzwi cyane bifitanye isano n’ibigo byinshi bizwi, birimo kaminuza ya Alabama i Birmingham, kaminuza ya Aston, n’ikigo nderabuzima cya Birmingham. Amashuri ye n'uburambe bw'umwuga bikubiyemo amasomo atandukanye mu buvuzi na siyansi. Dr. Garvey yagize uruhare runini mu bijyanye na endocrinology na metabolism, imirire n’imirire, ibinyabuzima na biyolojiya y’ibinyabuzima, ndetse n’ubuvuzi rusange ndetse n’imbere, yibanda cyane kuri sisitemu yumutima nimiyoboro y’umutima. Ibikorwa bye byamenyekanye cyane kandi byubahwa, cyane cyane byiswe Umushakashatsi wavuzwe cyane mu cyiciro cyambukiranya imipaka mu myaka ya 2023 na 2024, byerekana ingaruka n’ingaruka z’ubushakashatsi bwe ku muryango mugari wa siyansi.
Ubushakashatsi bwa Dr. Garvey n'ubuhanga bugera no mu bice bitandukanye by'indwara ziterwa na metabolike. Yagize uruhare runini mu kwiga metabolism mellitus, umubyibuho ukabije, hamwe n’ibibazo bifitanye isano nayo, agamije kuvumbura ingamba zo kuvura udushya no kunoza umusaruro w’abarwayi. Ibikorwa bye bikubiyemo ubushakashatsi bwibanze bwa siyansi, ibizamini by’amavuriro, n’ubushakashatsi bw’ubuhinduzi, bikuraho itandukaniro riri hagati y’ibyavuye muri laboratoire hamwe n’ubuvuzi busanzwe ku isi. Binyuze mu bushakashatsi bwe bwimbitse, Dr. Garvey yagize uruhare mu gusobanukirwa byimbitse n’uburyo bw’imiterere y’imihindagurikire y’imihindagurikire y’ikirere kandi yafashije gushyiraho umurongo ngenderwaho w’amavuriro na protocole y’ubuvuzi mu bijyanye na endocrinology na metabolism. Dr. William T. Garvey yanditse ku rutonde rw'ibitekerezo [4].
