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1kits (Ebipipa 10) .
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▎ Enzimba ya Retatrutid
Ensibuko: PubChem |
Omutendera: YA⊃1;QGTFTSDYSI-L⊃2;LDKK4AQA⊃1;AFIEYLLEGGPSSGAPPPS⊃3; Ensengekera ya molekyu: C 221H 342N 46O68 Obuzito bwa molekyu: 4731 g/mol Ennamba ya CAS: 2381089-83-2 PubChem CID: 171390338. Enkola y’okukuuma eddagala lino Ebigambo ebikwatagana:LY3437943 |
▎ Okunoonyereza ku Retatrutid
Ensibuko y’okunoonyereza eya Retatrutid eri etya?
Obunene bw’omugejjo ne sukaali ow’ekika eky’okubiri mu nsi yonna bukyagenda mu maaso n’okulinnya, ekireeta okusoomoozebwa okw’amaanyi mu by’obulamu bw’abantu. Eddagala eririwo eririna ekigendererwa kimu oba bibiri lirina obuzibu mu kukola n’obukuumi. Okusinziira ku ndowooza ya multi-target synergistic regulation okuyita mu gastrointestinal insulin axis, okunoonyereza kuzudde emirimu egy’okujjuliza egya GLP-1, GIP, ne glucagon mu metabolic regulation, okuwa omusingi gw’enzikiriziganya okukola multi-receptor agonists.
Nga bazimba ku bumanyirivu obw’edda mu kukola eddagala eririna ebigendererwa bibiri, abanoonyereza baakola era ne balongoosa Retatrutid nga basinziira ku mpisa z’enzimba n’enkola y’obubonero bw’ebirungo bino eby’emirundi esatu. Nga ekola mu kiseera kye kimu GLP-1R, GIPR, ne GCGR, etuuka ku kufuga glycemic okw’amaanyi n’okukendeeza ku buzito.
Enkola ki ey’okukola ku Retatrutid?
Obulwadde bwa Receptor Agonism
Retatrutid ekola nga triple receptor agonist egenderera GLP-1, GCGR, ne GIP receptors [1] ..
GLP-1 receptor gonism: GLP-1 ye hormone ya incretin efulumizibwa obutoffaali bwa L obw’ekyenda. Nga yeesibye ku bikwata GLP-1, Retatrutid etumbula okufulumya insulini mu ngeri eyeesigama ku glucose-concentration. Mu kiseera ky’okulinnya kwa sukaali, Retatrutid yeekwata ku bikwata GLP-1, n’ekola amakubo agalaga obubonero wansi agasitula obutoffaali bwa β obw’olubuto okufulumya insulini n’okukendeeza ku glucose mu musaayi. Era kiziyiza okufulumya glucagon n’okukendeeza ku glucose afuluma mu kibumba, okwongera okutebenkeza glucose mu musaayi. GLP-1 receptor gonism era elwawo okufulumya amazzi mu lubuto, eyongera okukkuta, n’okukendeeza ku mmere, ekiyamba mu kuddukanya obuzito [2]..
GCGR receptor gonism: Glucagon etera okukola mu kiseera ky’okukendeera kwa sukaali okulinnyisa emiwendo gya glucose mu musaayi. Ekikolwa kya Retatrutid ekya agonist ku GCGR kizibu. Mu bitundu by’amasavu, kitumbula lipolysis era kyongera ku fatty acid oxidation, bwe kityo ne kyongera ku nsaasaanya y’amasoboza. Mu kibumba, GCGR agonism ey’ekigero eyinza okulungamya enkola nga gluconeogenesis, okulongoosa enkola y’okukyusakyusa ekibumba. Kino kiremesa gluconeogenesis eyitiridde okuleeta hyperglycemia ate nga ekuuma glucose mu musaayi nga enywevu okumala okusobola okutuukiriza amaanyi omubiri gwe gwetaaga [1]..
GIP receptor gonism: GIP, obusimu obulala obuyitibwa incretin hormone, bufulumizibwa obutoffaali bwa K mu duodenum ne jejunum oluvannyuma lw’okulya. Retatrutid’s GIP receptor gonism eyongera ku kufulumya insulini, nga ekwatagana ne GLP-1 okulongoosa enkola ya glucose. Okwawukana ku ekyo, okukola kwa GIP receptor kuyinza okukosa enkyukakyuka y’amasavu n’okutebenkeza amaanyi. Okunoonyereza kwa Brzozowska P kulaga nti GIP etumbula okutwala glucose n’okusengejja amasavu mu adipocytes. Naye wansi w’obuyinza bwa Retatrutid, obubonero bwa GIP bukyusibwakyusibwa okusobola okulongoosa enkozesa y’amasoboza okusinga okutumbula okutereka amasavu gokka, bwe kityo ne kiyamba okuddukanya obuzito [1]..
Ekifaananyi 1 Enkola za Retatrutid ez’okukola [3]..
Okulungamya okujjuvu kw’enkola z’enkyukakyuka mu mubiri
Okulungamya Enkyukakyuka y’Amaaso: Nga ekola ku bikwata ebisatu ebyogeddwako waggulu, Retatrutid etereeza mu bujjuvu enkyukakyuka y’amasoboza. Kitumbula lipolysis, okwongera okuyingira kwa asidi w’amasavu mu mitochondria okusobola okukola β-oxidation n’okutumbula ensaasaanya y’amasoboza. Kikendeeza ku lipogenesis nga kiziyiza okuyingira kwa asidi w’amasavu n’okukola triglyceride mu adipocytes, bwe kityo ne kikyusa okutereka amaanyi mu mubiri n’ensaasaanya y’ensimbi okusobola okwanguyiza okugejja. Mu kunoonyereza okukwatagana ku bisolo n’okugezesebwa mu malwaliro okwakolebwa Jastreboff AM, okugaba Retatrutid kwayongera ku miwendo gy’ensaasaanya y’amaanyi era ne kukendeeza mpolampola amasavu mu mubiri mu bantu abagejjulukuka [4]..
Okulungamya Enkyukakyuka ya Glucose: Retatrutid ekyusa glucose mu musaayi ng’eyita mu makubo agawerako. Okusukka ku kusitula okufulumya insulini okuyita mu GLP-1 ne GIP receptor activation, ekwata ku nkyukakyuka ya glucose mu kibumba nga etereeza GCGR. Kiziyiza gluconeogenesis esukkiridde mu kibumba, kikendeeza ku glucose output, ate mu kiseera kye kimu kyongera ku peripheral tissue glucose uptake and utilization, bwe kityo ne kikuuma glucose mu musaayi nga bulijjo. Kino kikulu nnyo naddala eri abalwadde abagejjulukuka abalina ssukaali ow’ekika eky’okubiri, okufuga obulungi glucose mu musaayi n’okulongoosa embeera za sukaali [2]..
Liver Metabolic Regulation: Munda mu kibumba, Retatrutid tekoma ku kukyusakyusa mu nkyukakyuka ya glucose wabula era ekwata ku nkyukakyuka y’amasavu. Kikendeeza ku kusengejja n’okukuŋŋaanyizibwa kwa triglyceride mu kibumba, kitereeza okuzimba ekibumba, era kikwata omugaso oguyinza okujjanjaba obulwadde bw’ekibumba obutali bwa masavu (NAFLD). Mu kugezesebwa okw’obujjanjabi okwazingiramu abeetabye mu kugezesebwa abalina obulwadde bw’ekibumba obukwatagana n’obutakola bulungi mu mubiri (MDAFLD), Retatrutid yakendeeza nnyo ku masavu mu kibumba, ekiraga nti ekola bulungi mu kulungamya ku nkyukakyuka y’ekibumba [5]..
Ebikosa Enkola y’Olubuto n’Ekyenda
Retatrutid elwawo okufulumya amazzi mu lubuto nga ekola ku bikwata GLP-1. Okufulumya emmere mu lubuto mpola kiwangaaza obudde emmere gy’emala mu lubuto, ne kivaamu okukkuta okuwangaala n’okukendeeza ku mmere gy’olya oluvannyuma. Mu kiseera kye kimu, kiyinza okukosa okufulumya obusimu bw’omu byenda n’okutambula kw’ekyenda, okwongera okulung’amya enkola y’okugaaya kw’omu lubuto n’okunyiga ebiriisa, bwe kityo ne kikosa nnyo amaanyi agayingira n’obuzito bw’omubiri [2]..
Enkola ki ey’okukwatagana wakati w’ebikolwa bya Retatrutid eby’okuziyiza ku GLP-1, GCGR, ne GIP receptors?
Enkolagana mu kulungamya enkyukakyuka y’amasoboza
Okwongera ku nsaasaanya y’amaanyi: Okukola GCGR kitumbula glycogenolysis ne gluconeogenesis okulinnyisa emiwendo gya glucose mu musaayi. Era kyongera ku nsaasaanya y’amaanyi nga kyongera ku nkyukakyuka y’amasavu n’okunyigiriza emmere eyitira mu kukkuta wakati. GLP-1R agonists zisitula okufulumya insulini era zikola ebikolwa eby’okukuuma omutima n’okukuuma obusimu, ate nga era zikendeeza ku maanyi agayingira nga zilwawo okufulumya amazzi mu lubuto n’okuziyiza okwagala okulya. Wadde nga okukola kwa GIPR mu bitundu by’amasavu kutumbula okukuŋŋaanyizibwa kw’amasavu, okukola kwayo okw’omu makkati kukendeeza ku mmere gye balya n’okukendeeza ku kugejja. Retatrutid mu kiseera kye kimu etunuulira ebitundu bino ebisatu, n’eteekawo emyenkanonkano empya wakati w’amasoboza agayingira n’ensaasaanya. Kino kituuka bulungi ku bbula ly’amaanyi, bwe kityo ne kyanguyira okugejja.
Okulungamya enkyukakyuka y’amasavu: GCGR gonism eyongera ku nkyukakyuka y’amasavu, ate nga GIPR activation mu adipose tissue nakyo kikwata ku nkyukakyuka y’amasavu. GLP-1R agonists ziyinza okukosa mu ngeri etali butereevu mu nkyukakyuka y’amasavu nga ziyita mu nkola nga okulongoosa okuwuliziganya kwa insulini. Ekikolwa kyazo eky’okukwatagana kitereeza bulungi okukola amasavu, okumenya, n’okutambuza, okukendeeza ku kukuŋŋaanyizibwa kw’amasavu n’okulongoosa ensaasaanya y’amasavu mu mubiri. Okugeza, okunoonyereza ku balwadde abagejjulukuka kwalaga nti oluvannyuma lw’okukozesa Retatrutid okumala ekiseera, ebitundu by’amasavu mu mubiri byakendeera era n’ebifaananyi by’amasavu ne bitereera okutuuka ku ddaala eritali limu, ekiraga nti bikola ku kukwatagana mu kulungamya enkyukakyuka y’amasavu [6]..
Ebikosa Ebikwatagana mu Kulungamya Glucose
Enhanced Insulin Secretion: GLP-1R agonists zikendeeza ku glucose mu musaayi nga zisiba ku GLP-1 receptors ne zitumbula okufulumya insulin. GIP mu ngeri y’emu esitula obutoffaali bwa β obw’olubuto okukola ebikolwa by’okufulumya insulini ebifaananako n’ebyo ebiva mu kulya emmere. Retatrutid, ekola GLP-1R ne GIPR mu kiseera kye kimu, eyongera nnyo okufulumya insulini, bwe kityo n’ekendeeza bulungi emiwendo gya glucose mu musaayi. Wadde nga GCGR etera okukwatagana ne glucose eyali waggulu mu musaayi, ebivaamu —nga okutumbula ensaasaanya y’amaanyi —biyinza okuyamba mu ngeri etali butereevu ku kutebenkera kwa glucose nga ekola mu ngeri ey’okukwatagana n’ebikwata nga GLP-1R. Ekirala, okukozesa awamu GLP-1 ne GCGR mu ngeri elondamu okuziyiza akabi k’okulinnya kwa sukaali akaleetebwa GCGR, okusobozesa okulungamya glucose mu ngeri entuufu era ennungi.
Okulungamya Glucose Homeostasis: Okukolagana kw’ebikwata bino ebisatu kusukka ku kufulumya insulini kwokka okuzingiramu okulungamya okujjuvu kwa glucose homeostasis. Nga ekwata ku kukwatibwa kwa glucose, okukozesa, n’okutereka mu bitundu ebingi omuli ekibumba, ebinywa, n’amasavu, Retatrutid ekuuma glucose mu musaayi mu bbanga eritali ddene, okuziyiza enkyukakyuka ez’amaanyi. Mu kunoonyereza okwakolebwa Nicholls S okwali kuzingiramu abalwadde ba sukaali ow’ekika eky’okubiri, okuweebwa Retatrutid kwavaamu okukendeera okw’amaanyi mu miwendo gya glycated hemoglobin, ekiraga nti kikwata bulungi ku kufuga glycemic okumala ebbanga eddene era nga kiraga ebikolwa eby’okukwatagana eby’ebirungo ebisatu mu kulungamya glucose homeostasis [6]..
Okukola mu ngeri ey’okugatta amakubo g’okukyusa obubonero
Common Signal Pathway Activation: GLP-1R, GCGR, ne GIPR okusinga zikola obubonero okuyita mu puloteyina za G (Gαs). Retatrutid bw’ekola ku bikwata bino ebisatu, ekwatagana okukola amakubo agagabana wansi nga ekkubo lya cAMP-PKA. Okukola kuno okw’ekkubo okugabana kwongera ku bulungibwansi n’amaanyi g’okukyusa obubonero, okugaziya ebikosa okulungamya ku nkyukakyuka y’obutoffaali n’emirimu gy’omubiri.
Okukwasaganya amakubo ag’enjawulo: Nga bwe bagabana amakubo ag’awamu, buli kifo ekikwata era kikola emikutu egy’enjawulo egy’obubonero. Retatrutid modulates amakubo gano ag’enjawulo synergistically mu kiseera receptor activation, okusobozesa coordinated metabolic regulation.
Okulungamya enkola y’omu lubuto n’ekyenda mu ngeri ey’okukwatagana
Okukwata ku kufulumya obusimu mu lubuto: Ebirungo ebiziyiza GLP-1R bisitula okufulumya kwa GLP-1, ate ebiziyiza GIPR bitereeza okufuluma kwa GIP. Obusimu buno obw’omu lubuto bukola kinene nnyo mu kukyusa entambula y’olubuto, okugaaya emmere, n’okunyiga. Nga ekola omulundi gumu ebikwata byombi, Retatrutid egaba okulungamya okusingawo okujjuvu ku kufulumya obusimu bw’omu lubuto, bwe kityo n’ekwata ku nkola y’omu lubuto. Kiyinza okukendeeza ku kunywa amangu ebiriisa nga kikyusakyusa emiwendo gy’okufulumya amazzi mu lubuto n’okutambula kw’ekyenda, ne kiyamba mu kufuga obuzito ne glucose mu musaayi.
Okulongoosa embeera y’enkyukakyuka mu lubuto: Nga etereeza okufulumya obusimu mu lubuto, Retatrutid era eyongera ku mbeera y’enkyukakyuka mu mubiri munda mu nkola y’omu lubuto. Kitumbula okukula n’okukyusakyusa mu mubiri kwa bakitiriya ez’omugaso mu byenda era ne kikyusa enkola y’okuziyiza ekyenda. Enkyukakyuka zino ziyinza okwongera okukosa embeera y’omubiri okutwalira awamu. Nga zikolagana n’ebikosa ku nkyukakyuka y’amaanyi n’okulungamya glucose mu musaayi, enkola zino okutwalira awamu ziyamba ku bikolwa eby’obujjanjabi ku mugejjo n’obuzibu obukwatagana mu nkyukakyuka y’emmere.
Enkola za Retatrutid ze ziruwa?
Obujjanjabi bw'omugejjo
Ebikulu ebiva mu kugejja: Okugezesebwa okungi kulaga nti Retatrutid ekola bulungi mu kujjanjaba omugejjo. Mu kugezesebwa okwa Phase 2 double-blind, randomized, placebo-controlled trial okwakolebwa Jastreboff AM okwazingiramu abantu abakulu 338, abeetabye mu kugezesebwa baafuna Retatrutid buli wiiki ku dose ez’enjawulo oba placebo okumala wiiki 48. Ebivuddemu biraga nti mu wiiki 24, ekibinja kya 1mg kyatuuka ku kugejja kwa wakati okwa 7.2%, ekibinja kya 4mg combination kyakendeera 12.9%, ekibinja kya 8mg combination kyafiirwa 17.3%, ate ekibinja kya 12mg kyakendeera 17.5%, ate ekibinja kya placebo kyafiirwa 1.6% zokka. We bwatuukira mu wiiki 48, ekibinja kya 1mg kyatuuka ku kugejja kwa wakati okwa 8.7%, ekibinja kya 4mg combination kyakendeera 17.1%, ekibinja kya 8mg combination kyakendeera 22.8%, ekibinja kya 12mg kyakendeera 24.2%, ate ekibinja kya placebo kyakendeera 2.1%. Mu beetabye mu kugezesebwa abaafuna 4mg, 8mg, ne 12mg Retatrutid, 92%, 100%, ne 100% baatuuka ku kugejja ebitundu 5% oba okusingawo. 75%, 91%, ne 93% baatuuka ku kugejja ebitundu 10% oba okusingawo. ne 60%, 75%, ne 83% baatuuka ku kugejja ebitundu 15% oba okusingawo, bw’ogeraageranya ne 27%, 9%, ne 2% mu kibinja kya placebo. Ebiwandiiko bino biraga bulungi obulungi bwa Retatrutid mu kukendeeza ku buzito eri abalwadde abagejjulukuka [4]..
Obujjanjabi bwa sukaali obw’ekika eky’okubiri
Obulung’amu bw’okufuga Glycemic: Okunoonyereza okwakolebwa Lopez DC et al. kiraga nti Retatrutid ekwata bulungi ku kufuga glycemic mu balwadde ba sukaali ow’ekika eky’okubiri. Mu kugezesebwa okwalimu abantu 353, Retatrutid yakendeeza ku glycated hemoglobin (HbA1c) ebitundu 1.64% bw’ogeraageranya ne placebo. Kino kiraga obulungi bwa Retatrutid mu kukendeeza ku mutindo gwa glucose mu musaayi mu balwadde ba sukaali ow’ekika eky’okubiri, bwe kityo ne kiyamba mu kulongoosa ebiva mu bujjanjabi [7]..
Enkizo y’enkola ey’okugatta: Retatrutid ekola ku bikwata ebingi, ng’ewa enkizo ey’enjawulo ku agonists ezikwata omugatte okuyita mu nkola yaayo ey’okugatta. Tekikoma ku kukendeeza glucose mu musaayi nga kisitula okufulumya insulini wabula era kyongera ku kuwulira kwa insulini, okusobozesa obutoffaali bw’omubiri okukozesa obulungi insulini okufuga glycemic mu ngeri ey’enjawulo. Ebikolwa byayo eby’okukendeeza ku buzito byongera okulongoosa embeera y’enkyukakyuka y’emmere mu balwadde ba sukaali ow’ekika eky’okubiri, kubanga omugejjo kintu kya bulabe nnyo eri embeera eno era okugejja kyanguyiza okuddukanya obulungi glucose mu musaayi [5]..
Obujjanjabi bw’obulwadde bw’ekibumba obutaliimu masavu
Okukendeeza ku masavu mu kibumba: Retatrutid yalaga obusobozi okukendeeza ku masavu mu kibumba mu balwadde abalina obulwadde bw’amasavu mu kibumba (MDAFLD) n’amasavu mu kibumba ≥10%. Mu kugezesebwa okwa randomized, double-blind, placebo-controlled trial, 98 abeetabye mu kugezesebwa baaweebwa randomly okuweebwa empiso za Retatrutid (1mg, 4mg, 8mg, oba 12mg) oba placebo buli wiiki wansi w’olususu okumala wiiki 48. Ebivuddemu biraga nti mu wiiki 24, enkyukakyuka eya wakati mu masavu mu kibumba okusinziira ku ntandikwa yali -42.9% mu kibinja kya 1mg, -57.0% mu kibinja kya 4mg, -81.4% mu kibinja kya 8mg, ne -82.4% mu kibinja kya 12mg, bw’ogeraageranya ne +0.3% mu kibinja kya placebo. Ebizuuliddwa bino biraga nti Retatrutid ekendeeza nnyo amasavu mu kibumba, ekiraga omugaso oguyinza okujjanjaba obulwadde bw’ekibumba obutaliimu masavu [8]..
Okulongoosa enkola y’enkyukakyuka y’ekibumba: Retatrutid eyongera ku nkola y’enkyukakyuka y’ekibumba ng’etereeza amaanyi n’enkyukakyuka y’amasavu. Kitumbula okuzimba n’okumenya amasavu g’ekibumba, kikendeeza okukuŋŋaanyizibwa kw’amasavu mu kibumba, kikyusa okuddamu kw’okuzimba n’emiwendo gy’okunyigirizibwa okw’okwokya munda mu kibumba, era kikola ekikolwa ekimu ekiziyiza okukulaakulana kwa NAFLD, bwe kityo ne kikuuma obulamu bw’ekibumba ky’abalwadde.
Mu bufunzi
Nga triple receptor agonist ya GLP-1R/GIPR/GCGR, Retatrutid ekola ebikolwa eby’okulungamya metabolic okuyita mu nkola ey’okukwatagana ey’ebigendererwa ebingi. Ebikolwa byayo bizingiramu okukola GLP-1R okuziyiza okwagala okulya n’okulwawo okufulumya amazzi mu lubuto, bwe kityo ne kikendeeza ku maanyi agayingira; okukola GIPR okutumbula okufulumya insulini n’okulongoosa okuwuliziganya kwa insulini; n’okukola GCGR okutumbula lipolysis n’okusaasaanya amaanyi ate nga kitereeza hepatic glucose ne lipid metabolism okukendeeza ku kukuŋŋaanyizibwa kw’amasavu. Enkolagana eno ey’emirundi esatu etuuka ku bikolwa ebijjuvu omuli okufuga glycemic okw’amaanyi, okugejja ennyo, n’okulongoosa mu nkyukakyuka y’amasavu n’amasavu mu kibumba. Omugaso gwayo omukulu guli mu bujjanjabi bw’omugejjo, okutuuka ku kukendeeza ku buzito okusinziira ku ddoozi ng’okufiirwa okusinga obunene mu wiiki 48 kwa bitundu 24.2%. Ku ssukaali ow’ekika eky’okubiri, akendeeza bulungi ku glycated hemoglobin n’okulongoosa glycemic homeostasis. Mu bulwadde bw’ekibumba obw’amasavu obukwatagana n’obutakola bulungi mu nkyukakyuka y’emmere, bukendeeza nnyo ku masavu mu kibumba, ekiraga obulungi obw’amaanyi mu buzibu bw’enkyukakyuka y’emmere eziwera.
Ebikwata ku Muwandiisi
Ebintu ebyogeddwako waggulu byonna binoonyerezeddwako, birongooseddwa era ne bikung’aanyizibwa kkampuni ya Cocer Peptides.
Omuwandiisi wa Scientific Journal
Arun J. Sanyal musawo w’ekibumba era munoonyereza ng’akuguse mu ndwadde z’ekibumba naddala obulwadde bw’ekibumba obutali bwa masavu (NAFLD) n’obulwadde bwa steatohepatitis obutali bwa mwenge (NASH). Alina akakwate n’essomero ly’obusawo erya Virginia Commonwealth University School of Medicine, gy’abadde omusomesa okuva mu 1989. Sanyal awandiise ebitabo nga 1,000 mu bitabo ebikulu nga Cell Metabolism, Nature Medicine, The New England Journal of Medicine, ne The Lancet. Omulimu gwe gubadde gujuliziddwa emirundi egisukka mu 104,000, nga kino kiraga nti akwata nnyo ku by’ekibumba. Abadde afuna ensimbi obutasalako okuva mu kitongole ky’ebyobulamu ekya National Institutes of Health okuva mu 1995 era ye munoonyereza omukulu ku nsimbi nnya eza NIH ezikola. Sanyal era abadde amanyiddwa olw’obukulembeze bwe mu kunoonyereza ku bujjanjabi n’ebintu by’akoze mu kukola enkola z’okujjanjaba endwadde z’ekibumba. Arun J. Sanyal awandiikiddwa mu kiwandiiko ekijuliziddwa [5].
