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▎ Ọdịdị Retatrutid
Isi mmalite: PubChem |
Usoro: YA⊃1;QGTFTSDYSI-L⊃2;LDKK⁴AQA⊃1;AFIEYLLEGGPSSGAPPPS⊃3; Ụdị mkpụrụ ndụ: C 221H 342N 46O68 Arọ molekụla: 4731 g/mol Nọmba CAS: 2381089-83-2 PubChem CID: 171390338 Ndị otu: LY3437943 |
▎ Nnyocha Retatrutid
Kedu ihe ndabere nyocha maka Retatrutid?
Ọnụnọ nke oke ibu na ụdị ọrịa shuga 2 na-aga n'ihu n'ụwa niile, na-ebute nnukwu ihe ịma aka ahụike ọha. Ọgwụ dị otu ma ọ bụ nke abụọ nwere oke na ịdị mma yana nchekwa. Dabere na tiori nke ụkpụrụ mmekọrịta mmadụ na ibe ya site na axis insulin nke eriri afọ, nyocha ekpughere ọrụ mgbakwunye nke GLP-1, GIP na glucagon na usoro metabolic, na-enye ntọala usoro iwu maka ịzụlite agonists multi-receptor.
N'ịwulite na ahụmịhe mmepe ọgwụ nwere ebumnuche abụọ, ndị nyocha haziri na kachasị Retatrutid dabere na njirimara nhazi yana usoro akara nke ndị nnabata atọ a. Site n'ịgbalite GLP-1R, GIPR na GCGR n'otu oge, ọ na-enweta njikwa glycemic na mbelata ibu.
Gịnị bụ usoro nke Retatrutid?
Nnabata Agonism
Retatrutid na-arụ ọrụ dị ka agonist nnabata atọ na-ezubere GLP-1, GCGR na ndị na-anabata GIP [1].
Agonism nke nnabata GLP-1: GLP-1 bụ homonụ incretin nke mkpụrụ ndụ L intestinal zoro ezo. Mgbe ejikọtara ya na ndị na-anabata GLP-1, Retatrutid na-akwalite mmepụta insulin n'ụzọ dabere na ntinye glucose. N'oge hyperglycemia, Retatrutid na-ejikọ ya na ndị na-anabata GLP-1, na-arụ ọrụ ụzọ mgbama ala nke na-eme ka mkpụrụ ndụ β-pancreatic na-ezochi insulin ma belata ọkwa glucose ọbara. Ọ na-egbochi secretion glucagon ma na-ebelata mmepụta glucose imeju, na-eme ka glucose dị n'ọbara kwụsie ike. Agonism nke nnabata GLP-1 na-egbu oge mkpofu afọ, na-abawanye satiety, ma na-ebelata iri nri, na-enyere aka na njikwa ibu [2].
Ihe mgbu nke nnabata GCGR: Glucagon na-emekarị n'oge hypoglycemia iji bulie ọkwa glucose ọbara. Omume agonist Retatrutid na GCGR dị mgbagwoju anya. N'ime anụ ahụ adipose, ọ na-akwalite lipolysis ma na-abawanye oxidation fatty acid, si otú a na-eme ka mmefu ike dịkwuo elu. N'ime imeju, oke mgbu GCGR na-agafeghị oke nwere ike ịhazi usoro dị ka gluconeogenesis, na-ebuli ọrụ metabolic hepatic. Nke a na-egbochi gluconeogenesis gabigara ókè ịkpata hyperglycemia ebe ị na-edobe nkwụsi ike nke glucose ọbara zuru oke iji gboo mkpa anụ ahụ chọrọ [1]..
Agonism nke nnabata GIP: GIP, hormone incretin ọzọ, bụ nke mkpụrụ ndụ K na-ezobe na duodenum na jejunum mgbe nri gasịrị. Retatrutid's GIP receptor agonism na-akwalite mmepụta insulin, na-emekọrịta ya na GLP-1 iji melite nhazi glucose. N'aka nke ọzọ, ịgbalite GIP nnabata nwere ike imetụta metabolism lipid na nguzozi ike. Nnyocha nke Brzozowska P na-egosi na GIP na-akwalite nnabata glucose na njikọ lipid na adipocytes. Agbanyeghị, n'okpuru mmetụta Retatrutid, a na-ahazi akara ngosi GIP iji kwalite ojiji ike karịa naanị ịkwalite nchekwa abụba, si otú a na-enyere njikwa ibu aka [1].
Ọgụgụ 1 Usoro nke Retatrutid [3].
Iwu zuru oke nke Usoro Metabolic
Iwu Metabolism Energy: Site na ịgbalite ndị nnata atọ a kpọtụrụ aha n'elu, Retatrutid na-achịkwa metabolism ike zuru oke. Ọ na-akwalite lipolysis, ịba ụba acid fatty acid n'ime mitochondria maka β-oxidation na ịkwalite mmefu ike. Ọ na-ebelata lipogenesis site na igbochi nnabata nke fatty acid na njikọ triglyceride na adipocytes, si otú ahụ na-agbanwe nchekwa ike nke anụ ahụ na nguzozi mmefu iji mee ka ọ dị mfe ịbelata ibu. N'ime ọmụmụ anụmanụ dị mkpa na nnwale ụlọ ọgwụ nke Jastreboff AM, nchịkwa Retatrutid mụbara ọnụego mmefu ike ma jiri nwayọ belata ọdịnaya abụba anụ ahụ na isiokwu buru ibu [4].
Iwu Metabolism Glucose: Retatrutid na-agbanwe glucose ọbara site n'ọtụtụ ụzọ. Na mgbakwunye na ntinye insulin na-akpali akpali site na GLP-1 na GIP nnabata nnabata, ọ na-emetụta metabolism nke imeju site na ịhazi GCGR. Ọ na-egbochi gluconeogenesis imeju imeju, na-ebelata mmepụta glucose, ma na-eme ka nnabata glucose dị n'akụkụ anụ ahụ na-arụ ọrụ n'otu oge, si otú a na-edobe ọkwa glucose ọbara nkịtị. Nke a dị oke mkpa maka ndị ọrịa buru oke ibu nwere ụdị ọrịa shuga 2, na-achịkwa glucose ọbara nke ọma ma na-emeziwanye ọnọdụ ọrịa shuga ..
Iwu Metabolic Imeju: N'ime imeju, Retatrutid abụghị naanị na-emezi metabolism metabolism kamakwa na-emetụta metabolism lipid. Ọ na-ebelata njikọ na mkpokọta triglyceride imeju, na-eme ka steatosis imeju dịkwuo mma, ma na-ejide uru ọgwụgwọ maka ọrịa imeju na-adịghị egbu egbu (NAFLD). N'ime ule ụlọ ọgwụ metụtara ndị sonyere na ọrịa imeju abụba na-adịghị arụ ọrụ nke metụtara metabolic (MDAFLD), Retatrutid belatara abụba imeju nke ukwuu, na-egosipụta mmetụta nchịkwa ya dị mma na metabolism imeju [5]..
Mmetụta na Ọrụ Gastrointestinal
Retatrutid na-egbu oge mkpofu afọ site na ịgbalite ndị na-anabata GLP-1. Ịwụsa afọ ntachi nke afọ na-agbatị oge obibi nri n'ime afọ, na-emepụta satiety na-adịgide adịgide ma na-ebelata oriri na-esote. N'otu oge ahụ, ọ nwere ike imetụta nzuzo nzuzo nke homonụ na motility eriri afọ, na-achịkwa mgbaze eriri afọ na usoro nnabata nri, si otú ahụ na-emetụta oke ike na ịdị arọ ahụ [2]..
Kedu usoro mmekọrịta dị n'etiti mmetụta Retatrutid na ndị na-anabata GLP-1, GCGR na GIP?
Mmekọrịta na Iwu Metabolism Energy
Mmefu ike na-abawanye: ịgbalite GCGR na-akwalite glycogenolysis na gluconeogenesis iji bulie ọkwa glucose ọbara. Ọ na-eme ka mmefu ike dịkwuo elu site na ịba ụba nke lipid metabolism na igbochi iri nri site na satiety etiti. GLP-1R agonists na-akpali secretion insulin ma na-arụ ọrụ cardioprotective na neuroprotective mmetụta, na-ebelata oriri ike site na-egbu oge imefusị gastric na igbochi agụụ. Ọ bụ ezie na ịgbalite GIPR n'ime anụ ahụ adipose na-akwalite mkpokọta lipid, ịgbalite ya n'etiti ya na-ebelata oriri oriri ma na-ebelata oke ibu. Retatrutid n'otu oge na-elekwasị anya ndị nnata atọ a, na-ewepụta nha nha ọhụrụ n'etiti oriri ume na mmefu. Nke a na-arụ ọrụ nke ọma karịa mperi ume, si otú ahụ na-eme ka ịbelata ibu dị arọ.
Na-achịkwa metabolism lipid: Agonism GCGR na-akwalite metabolism lipid, ebe GIPR na-arụ ọrụ na anụ ahụ adipose na-emetụtakwa metabolism lipid. GLP-1R agonists nwere ike imetụta metabolism lipid na-apụtaghị ìhè site na usoro dị ka imeziwanye mmetụta insulin. Ha synergistic omume mma regulates abụba njikọ, ndakpọ, na iga, mbenata abụba ìgwè na mma ahu abụba nkesa. Dịka ọmụmaatụ, ọmụmụ ihe na ndị ọrịa buru ibu gosiri na mgbe ejiri Retatrutid mee ihe ruo oge ụfọdụ, pasent abụba ahụ na-ebelata na profaịlụ lipid ka mma ruo n'ókè ụfọdụ, na-atụ aro mmetụta synergistic ya na ịhazi metabolism abụba [6]..
Mmetụta mmekọrịta dị na ụkpụrụ glucose
Ihe nzuzo insulin emelitere: GLP-1R agonists na-ebelata glucose ọbara site na ijikọ ndị na-anabata GLP-1 na ịkwalite nzuzo insulin. N'otu aka ahụ, GIP na-akpali sel β-pancreatic ka ọ mepụta mmetụta nzuzo insulin yiri nke nri nri na-akpalite. Retatrutid, nke na-arụ ọrụ n'otu oge GLP-1R na GIPR, na-eme ka mmepụta insulin dịkwuo elu, si otú ahụ na-ebelata ọkwa glucose ọbara n'ụzọ dị irè karị. Ọ bụ ezie na GCGR na-ejikọta ya na ọkwa glucose ọbara dị elu, mmetụta ya-dị ka ịkwalite mmefu ume ike-nwere ike itinye aka na nkwụsi ike nke glucose mgbe ọ na-emekọrịta ihe na ndị na-anabata ya dị ka GLP-1R. Ọzọkwa, ijikọ GLP-1 na GCGR na-ahọrọ nhọrọ na-egbochi ihe ize ndụ hyperglycemic nke GCGR na-ebute, na-eme ka usoro glucose dịkwuo mma ma dị irè.
Na-achịkwa Glucose Homeostasis: Mgbalite mmekọrịta nke ndị na-anabata atọ ndị a na-agafe karịa nzuzo insulin iji gbasaa ụkpụrụ glucose homeostasis zuru oke. Site na imetụta nnabata glucose, itinye n'ọrụ, na nchekwa n'ọtụtụ anụ ahụ gụnyere imeju, akwara, na adipose, Retatrutid na-edobe glucose ọbara n'ime oke kwụsiri ike, na-egbochi mgbanwe dị ukwuu. N'ime nyocha nke Nicholls S metụtara ụdị ọrịa shuga nke 2, nchịkwa Retatrutid butere mbelata dị ukwuu na ọkwa hemoglobin glycated, na-egosi mmetụta dị mma na njikwa glycemic ogologo oge yana igosipụta mmetụta mmekọrịta nke ndị nnata atọ ahụ n'ịchịkwa glucose homeostasis [6]..
Mgbalite mmekọrịta nke ụzọ ntụgharị mgbaàmà
Ụzọ mgbama a na-ahụkarị: GLP-1R, GCGR, na GIPR bụ isi na-egosi site na protein G (Gαs). Mgbe Retatrutid na-eme ihe na ndị nnata atọ a, ọ na-agbakọta iji mee ka ụzọ ndị dị n'okpuru ala dị ka ụzọ cAMP-PKA. Nkwalite ụzọ a na-ekekọrịta ihe na-eme ka nrụpụta mgbaàmà na ike dị mma, na-abawanye mmetụta nchịkwa na metabolism cellular na ọrụ physiological.
Na-ahazi ụzọ dị iche iche: Mgbe ị na-ekerịta ụzọ ndị nkịtị, onye nnata ọ bụla na-emekwa ka netwọk mgbaàmà pụrụ iche rụọ ọrụ. Retatrutid na-emegharị ụzọ ndị a dị iche iche na-arụkọ ọrụ ọnụ n'oge nnabata nnabata, na-eme ka usoro nhazi nke metabolic na-achịkọta ọnụ.
Usoro mmekọrịta nke ọrụ eriri afọ
Na-emetụta secretion Hormone Gastrointestinal: GLP-1R agonists na-akpali nzuzo GLP-1, ebe GIPR agonists na-achịkwa mwepụta GIP. Hormone eriri afọ ndị a na-arụ ọrụ dị mkpa n'ịkwalite motility eriri afọ, mgbari nri, na absorption. Site n'otu oge na-eme ka ndị na-anabata ya rụọ ọrụ, Retatrutid na-enye nhazi zuru oke nke mmepụta homonụ nke eriri afọ, si otú a na-emetụta ọrụ eriri afọ. Ọ nwere ike ibelata mmịnye nri ngwa ngwa site n'ịgbanwe ọnụego mkpofu gastric na motility nke eriri afọ, na-enyere aka n'ịdị arọ na njikwa glucose ọbara.
Imewanye Gọọmenti Metabolic nke Gastrointestinal: Site n'ịchịkwa mmepụta homonụ nke eriri afọ, Retatrutid na-akwalitekwa ọnọdụ metabolic n'ime eriri afọ. Ọ na-akwalite uto na metabolism nke nje bacteria bara uru ma na-emezi ọrụ mgbochi eriri afọ. Mgbanwe ndị a nwere ike imetụta ọnọdụ metabolic n'ozuzu nke ahụ. Na-arụ ọrụ synergistically na mmetụta na ike metabolism na ọbara glucose ụkpụrụ, ndị a usoro na-enyere aka na ọgwụgwọ mmetụta megide oke ibu na metụtara metabolic ọrịa.
Kedu ihe bụ ngwa Retatrutid?
Ọgwụgwọ oke ibu
Mmetụta Mbelata ịdị arọ dị mkpa: Ọtụtụ nnwale ụlọ ọgwụ na-egosi nrụpụta Retatrutid na ọgwụgwọ oke ibu. N'ime usoro 2 nke kpuru ìsì okpukpu abụọ, randomized, placebo nke Jastreboff AM na-achịkwa nke gụnyere ndị okenye 338, ndị sonyere na-enweta Retatrutid kwa izu n'ụdị dị iche iche ma ọ bụ placebo maka izu 48. Nsonaazụ gosiri na n'izu 24, otu 1mg nwetara nkezi arọ ọnwụ nke 7.2%, 4mg Nchikota otu furu efu 12.9%, 8mg Nchikota otu furu efu 17.3%, na 12mg otu furu efu 17.5%, ebe placebo otu tụfuru nanị 1.6%. N'ime izu 48, otu 1mg nwetara nkezi ibu nke 8.7%, otu 4mg nchikota furu efu 17.1%, otu 8mg furu efu 22.8%, otu 12mg furu efu 24.2%, na placebo otu furu efu 2.1%. N'ime ndị sonyere na-anata 4mg, 8mg, na 12mg Retatrutid, 92%, 100%, na 100% nwetara 5% ma ọ bụ ọnwụ ka ukwuu, n'otu n'otu. 75%, 91%, na 93% nwetara 10% ma ọ bụ oke ibu ibu. na 60%, 75%, na 83% nwetara 15% ma ọ bụ ọnwụ ka ukwuu, ma e jiri ya tụnyere 27%, 9%, na 2% n'ime otu placebo. Ihe data ndị a gosipụtara n'ụzọ zuru oke nrụpụta Retatrutid na mbelata ibu maka ndị ọrịa buru ibu [4].
Ụdị ọgwụgwọ ọrịa shuga 2
Mmetụta nchịkwa glycemic: Ọmụmụ nke Lopez DC et al. Retatrutid na-emetụta njikwa glycemic nke ọma na ndị ọrịa nwere ọrịa shuga 2. N'ime nnwale metụtara ndị sonyere 353, Retatrutid belatara haemoglobin glycated (HbA1c) site na 1.64% ma e jiri ya tụnyere placebo. Nke a na-egosi ịdị irè Retatrutid n'ibelata ọkwa glucose ọbara n'ụdị ndị ọrịa shuga 2, si otú a na-enye aka na nsonaazụ ụlọ ọgwụ ka mma [7]..
Uru Ngwakọta Ngwakọta: Retatrutid na-arụ ọrụ na ọtụtụ ndị na-anabata ya, na-enye uru pụrụ iche karịa ndị otu agonists na-anabata ya site na usoro agonist ya jikọtara ọnụ. Ọ bụghị naanị na ọ na-ebelata glucose ọbara site na mkpali insulin, kamakwa na-eme ka mmetụta insulin dịkwuo elu, na-eme ka mkpụrụ ndụ ahụ nwee ike iji insulin rụọ ọrụ nke ọma maka njikwa glycemic zuru oke. Mmetụta mbelata ibu ya na-emewanyewanye ọnọdụ metabolic na ụdị ọrịa shuga 2, n'ihi na oke ibu bụ ihe dị oke egwu maka ọnọdụ ahụ yana mbelata ibu na-eme ka njikwa glucose ọbara ka mma [5]..
Ọgwụgwọ ọrịa imeju na-adịghị egbu egbu
Mbelata ọdịnaya abụba imeju: Retatrutid gosipụtara ikike iji belata abụba imeju na ndị ọrịa nwere ọrịa imeju na-arịa ọrịa metabolic dysfunction-ejikọtara ọnụ (MDAFLD) na ọdịnaya abụba imeju ≥10%. N'ime usoro nyocha, kpuru ìsì abụọ, ebe a na-achịkwa ebebo, a na-ekenye ndị sonyere 98 ka ha nata injections subcutaneous kwa izu nke Retatrutid (1mg, 4mg, 8mg, ma ọ bụ 12mg) ma ọ bụ placebo maka izu 48. Nsonaazụ gosiri na n'izu 24, mgbanwe mgbanwe nke abụba imeju na-adabere na ntọala bụ -42.9% na 1mg otu, -57.0% na 4mg otu, -81.4% na 8mg otu, na -82.4% na 12mg otu, tụnyere + 0.3% na placebo otu. Nchọpụta ndị a na-egosi na Retatrutid na-ebelata nke ukwuu ọdịnaya abụba imeju, na-egosipụta uru ọgwụgwọ maka ọrịa imeju na-adịghị egbu egbu [8]..
Imelite ọrụ metabolic imeju: Retatrutid na-eme ka ọrụ metabolic dị imeju dịkwuo mma site n'ịhazi ike na metabolism lipid. Ọ na-akwalite oxidation na mmebi nke abụba imeju, na-ebelata mkpokọta abụba n'ime imeju, na-agbanwe nzaghachi mkpali na ọkwa nrụgide oxidative n'ime imeju, ma na-enwe mmetụta mgbochi ụfọdụ na ọganihu nke NAFLD, si otú ahụ na-echebe ahụike imeju ndị ọrịa.
Mmechi
Dị ka onye na-anabata ihe atọ nke GLP-1R/GIPR/GCGR, Retatrutid na-arụ ọrụ nhazi usoro metabolic site na usoro synergistic multi-ledge. Mmetụta ya gụnyere ịgbalite GLP-1R iji gbochie agụụ na igbu oge ịpụsị afọ, si otú ahụ belata oriri ike; GIPR na-arụ ọrụ iji kwalite mmepụta insulin na imeziwanye mmetụta insulin; na ịgbalite GCGR iji kwalite lipolysis na mmefu ume ka ị na-achịkwa glucose imeju na metabolism lipid iji belata mkpokọta abụba. Mmekọrịta atọ a na-enweta mmetụta zuru oke gụnyere njikwa glycemic siri ike, oke ibu dị arọ, yana mmụba lipid na abụba imeju. Isi uru ya dabere na ọgwụgwọ oke ibu, na-enweta mbelata ịdị arọ dabere na dose yana oke 48-izu ọnwụ nke 24.2%. Maka ụdị ọrịa shuga 2, ọ na-ebelata hemoglobin glycated nke ọma ma na-eme ka glycemia homeostasis dịkwuo mma. N'ime ọrịa imeju abụba na-adịghị arụ ọrụ nke metabolic, ọ na-ebelata nke ukwuu ọdịnaya abụba imeju, na-egosipụta arụmọrụ dị ike gafee ọtụtụ nsogbu metabolic.
Banyere Onye dere ya
Ihe niile a kpọtụrụ aha n'elu bụ Cocer Peptides na-enyocha, dezie ma chịkọta ya.
Onye ode akwụkwọ akụkọ sayensị
Arun J. Sanyal bụ ọkachamara n'ọrịa gbasara ọrịa imeju na onye nyocha ọkachamara na ọrịa imeju, karịsịa ọrịa imeju na-adịghị egbu egbu (NAFLD) na steatohepatitis na-adịghị egbu egbu (NASH). Ọ jikọtara ya na Virginia Commonwealth University School of Medicine, ebe ọ bụ onye nkuzi kemgbe 1989. Sanyal edepụtala ihe dị ka akwụkwọ 1,000 na akwụkwọ akụkọ ndị na-eduga dịka Cell Metabolism, Nature Medicine, The New England Journal of Medicine, na The Lancet. A kọwapụtala ọrụ ya ihe karịrị ugboro 104,000, na-egosipụta mmetụta dị ukwuu ọ na-enwe na ngalaba hepatology. Ụlọ ọrụ ahụike mba na-akwado ya kemgbe 1995 ma bụrụ onye isi nyocha nke onyinye NIH anọ na-arụ ọrụ. A matakwara Sanyal maka onye ndu ya na nyocha ụlọ ọgwụ na ntinye aka ya na mmepe nke usoro ọgwụgwọ maka ọrịa imeju. Arun J. Sanyal ka edepụtara n'akwụkwọ ntụaka [5].
