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1kits (Ebipipa 10) .
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▎ Enzimba ya Tirzepatid
Ensibuko: PubChem |
Omutendera: Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{diaasidi-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 Ensengekera ya molekyu: C 225H 348N 48O68 Obuzito bwa molekyu: 4813 g/mol Ennamba ya CAS: 2023788-19-2 Ekitongole kya PubChem CID: 163285897 Ebigambo ebifaanagana: Zepbound; Mounjaro nga bwe |
▎ Okunoonyereza ku Tirzepatid
Kiki ekiva mu kunoonyereza ku Tirzepatid?
Tirzepatid ddagala lya polypeptide erikolebwa, era okukula kwalyo kusibuka mu kutegeera okw’amaanyi ku buzibu obuliwo obuziyiza GLP-1 receptor agonists mu kujjanjaba ekika kya 2 metabolism mellitus n’omugejjo. Wadde nga GLP-1 receptor agonists zalaga dda omulimu omulungi ennyo mu kufuga glucose mu musaayi n’okugejja, bannassaayansi bakizudde nti wadde nga zikola GLP-1 receptor, activation effect yazo ku GIP receptor nafu nnyo, ekituuka ku kigero ekimu kikoma ku bujjanjabi bw’eddagala lino. N’olwekyo, ttiimu y’okunoonyereza n’okukulaakulanya yeewaddeyo okukola ekika ky’eddagala ekipya ekiyinza okukola GIPR ne GLP-1R omulundi gumu, nga basuubira okutuuka ku kufuga kwa glucose mu musaayi n’okuddukanya obuzito mu ngeri enzijuvu era ennungi [1]. .
Mu nkola y’okunoonyereza n’okukulaakulanya Tirzepatid, bannassaayansi bakoze okunoonyereza okusookerwako okungi n’okugezesa mu malwaliro. Okusookera ddala, mu mutendera gw’okunoonyereza nga tegunnabaawo, engeri za Tirzepatid ez’eddagala zaali zeekenneenyezebwa nnyo okuyita mu kugezesa ebisolo, era obusobozi bwayo mu kufuga glucose mu musaayi n’okugejja bwakakasibwa. Ebivuddemu biraga nti Tirzepatid esobola okukendeeza ennyo ku glucose mu musaayi mu bikolwa by’ebisolo era era yakola bulungi mu kuddukanya obuzito. Ebintu bino ebirungi ebyazuulibwa byassaawo omusingi omunywevu ogw’okugezesebwa okw’obujjanjabi okwaddirira.
Oluvannyuma, Tirzepatid yayingira mu mutendera gw’okugezesebwa mu malwaliro, omuli okugezesebwa okw’omutendera I, II, ne III. Mu kugezesebwa okw’omutendera I, obukuumi, okugumiikiriza, n’engeri y’eddagala lino okusinga kwekenneenyezebwa, era ebyavuddemu biraga nti Tirzepatid yalina obukuumi obulungi n’okugumiikiriza. Okugezesebwa okw’omutendera II kwayongera okunoonyereza ku bulungibwansi n’obukuumi bwa ddoozi ez’enjawulo eza Tirzepatid mu balwadde abalina ekika kya 2 metabolism mellitus, era ne kusooka okuzuula ddoozi zaayo ezikola obulungi. Okugezesebwa okusinga obukulu mu mutendera III, nga SURPASS series of studies, kwakwata ku balwadde bangi abalina type 2 metabolism mellitus. Ebivuddemu biraga nti Tirzepatid yali esinga nnyo eddagala eriweweeza ku GLP-1 receptor agonists eryaliwo, nga semaglutide, mu kukendeeza glucose mu musaayi n’obuzito. Ekivaamu kino eky’okumenyawo kyawa obujulizi obw’amaanyi obuwagizi ku nkola y’okutunda Tirzepatid [1]..
Tirzepatid ye polypeptide erimu amino acids 39, nga mu zo amino acids ssekinnoomu zikyusiddwa mu nsengeka okulongoosa obutebenkevu bwayo n’obulungi bwayo. Ensengeka eno ey’enjawulo ey’enzimba esobozesa Tirzepatid okugatta ebikolwa by’obusimu bubiri obwa incretin, GIP ne GLP-1, mu molekyu emu, n’okukola ebitundu ebikwata obusimu ebikwatibwako mu kufuga glucose mu musaayi ng’ayita mu nkola bbiri ez’okukola. Okusingira ddala, Tirzepatid esobola okukola ku pancreas n’obusimu obw’omu makkati. Ku ludda olumu, kitumbula okufulumya insulini era kiziyiza okufulumya glucagon, bwe kityo ne kikendeeza bulungi glucose mu musaayi; ku luuyi olulala, olw’okulwawo okufulumya amazzi mu lubuto n’okwongera okukkuta, kikendeeza ku njagala y’okulya n’okulya emmere, era bwe kityo ne kituuka ku kukendeeza ku buzito. Enkola eno ey’emirimu ebiri ewa Tirzepatid enkizo ez’enjawulo mu kujjanjaba ekika kya 2 metabolism mellitus n’omugejjo, okuwa abalwadde eky’obujjanjabi ekisingako [1]..
Enkola ya Tirzepatid ekola ki?
Tirzepatid ekkakkanya glucose mu musaayi ng’eyita mu nkola eziwera ezikolagana, nga bwe ziti: Okukola kw’ekirungo kya GLP-1: Tirzepatid yeekwata ku kirungo kya GLP-1 ku butoffaali bwa β obw’olubuto, ng’akoppa enkola ya GLP-1 ey’obutonde. GLP-1 busimu obukolebwa mu byenda era bukulu nnyo mu kukuuma glucose homeostasis 2. Busobola okutumbula okukola insulini, okufulumya insulini, n’okutegeera glucose, n’okukendeeza ku kufulumya glucagon okutumbula okukkuta n’okuziyiza apetite 2.
Okukola kuno kuyinza okutumbula okufulumya insulini. Insulin ye hormone enkulu ekendeeza glucose mu musaayi mu mubiri, eyinza okwongera okutwala n’okukozesa glucose obutoffaali, bwe kityo ne kikendeeza ku glucose mu musaayi. Mu balwadde abalina ekika kya 2 metabolism mellitus, okufulumya insulini tekumala oba obutoffaali okuwulira insulini bukendeera, ekivaako glucose mu musaayi okweyongera. Tirzepatid ayongera ku kufulumya insulini ng’akola ekirungo kya GLP-1 ekiyamba okulongoosa okufuga glucose mu musaayi. Mu kiseera kye kimu, okukola kw’ekirungo kya GLP-1 nakyo kisobola okuziyiza okufulumya kwa glucagon. Glucagon etera okutumbula glycogenolysis ne gluconeogenesis mu mbeera y’okusiiba, okwongera ku kukola glucose mu musaayi. Nga aziyiza ekikolwa kya glucagon, Tirzepatid ayongera okukendeeza ku nsibuko ya glucose mu musaayi, ekiyamba okufuga glucose mu musaayi [2] (Anonymous, 2023).
Okukola kw’ekirungo kya GIP: Tirzepatid ekola ku kikwata kya GIP mu kiseera kye kimu. Oluvannyuma lw’okukola, esobola okutumbula okuwulira kwa insulini n’okufulumya. Ekirungo kya GIP kisinga kubeera mu bitundu by’omubiri nga obutoffaali bwa β obw’olubuto. Oluvannyuma lw’okukola, okuyita mu kutambuza ekkubo ly’obubonero mu butoffaali, okufulumya insulini kweyongera, era okuddamu kw’obutoffaali eri insulini kulongoosebwa, bwe kityo ne kikendeeza bulungi ku glucose mu musaayi 2. Tirzepatid ye peptide-1 eringa glucagon ey’emirundi ebiri ne glucose-dependent insulinotropic polypeptide (GIP) analog esooka mu kibinja, ekkirizibwa okujjanjaba abalwadde abakulu abalina ekika kya 2 metabolism mellitus nga adjunct ku mmere ne dduyiro 2. Tirzepatid ye nsengekera ya kemiko ey’obutonde eyesigamiziddwa ku nsengekera ya GIP, ekoleddwa mu 39-amino acid peptide. Kyongera ku kufulumya insulini, kikendeeza ku kufulumya glucagon mu ngeri eyeesigama ku glucose, kikendeeza ku glucose mu musaayi mu kisiibo n’oluvannyuma lw’okulya, kitumbula okukkuta, kikendeeza ku buzito, n’okulwawo okufulumya amazzi mu lubuto 2.
Kino ekikolwa kya dual receptor agonist kifuula Tirzepatid okukola obulungi mu kutumbula okufulumya insulini n’okuziyiza okufulumya glucagon okusinga single GLP-1 receptor agonists [2]..
Okulwawo okufulumya amazzi mu lubuto n’okwongera okukkuta: Tirzepatid esobola okulwawo okufulumya amazzi mu lubuto, okwongera ku budde emmere gy’emala mu lubuto, okukendeeza ku sipiidi y’okunyiga ebiriisa, era bwe kityo ne yeewala okweyongera ennyo mu glucose mu musaayi oluvannyuma lw’okulya. Mu kunoonyereza okusooka n’okusooka, enkola ya Tirzepatid ku kuggyamu ebintu mu lubuto egeraageranyizibwa ku ya GLP-1 receptor agonists. Mu mbeba ezigejjulukuka ezireetebwa emmere, diguli y’okulwawo okufulumya amazzi mu lubuto nga Tirzepatid efaananako n’eya semaglutide, naye ebikolwa bino eby’okuziyiza eby’amangu bibula oluvannyuma lwa wiiki 2 nga bijjanjabiddwa. Mu beetabye mu kugezesebwa abalina n’abatalina kika kya 2 metabolism mellitus, Tirzepatid omulundi gumu buli wiiki (≥5 ne ≥4.5mg, respectively) yalwawo okufulumya amazzi mu lubuto oluvannyuma lwa ddoozi emu. Mu beetabye mu kugezesebwa abalamu, ekikolwa kino kyakendeera oluvannyuma lw’okukozesa dose eziwera eza Tirzepatid oba dulaglutide [3]. .
Mu kiseera kye kimu, era esobola okukola ku busimu obw’omu makkati, okwongera okukkuta, n’okukendeeza ku njagala y’okulya n’okulya emmere. Nga efuga emmere, eyamba mu ngeri etali butereevu okufuga emiwendo gya glucose mu musaayi naddala nga gisaanira ekizibu ky’omugejjo ekitera okuwerekerwako abalwadde abalina ekika kya 2 metabolism mellitus, era kiyamba okulongoosa obuziyiza insulini n’embeera y’enkyukakyuka mu mubiri okutwalira awamu [2]..
Okulongoosa enkola ya insulini n’enkyukakyuka y’amasavu: Tirzepatid ezuuliddwa nti eyongera ku muwendo gwa adiponectin, nga kino kye kirungo kya adipocytokine ekikwatagana n’okuwulira insulini. Okwongera ku muwendo gwa adiponectin kiyamba okulongoosa okuwuliziganya kwa insulini, okufuula obutoffaali okuwuliziganya ennyo ku insulini, era bwe kityo ne kitwala bulungi n’okukozesa glucose, okukendeeza ku glucose mu musaayi [2]..
Okugatta ku ekyo, Tirzepatid era esobola okulongoosa ensengeka y’amasavu era erina ekikolwa ekiyinza okukuuma obulamu bw’emisuwa n’emisuwa. Tirzepatid ekakasiddwa nti esobola okulongoosa puleesa, okukendeeza ku kolesterol ow’ekika kya low-density lipoprotein (LDL) ne triglycerides [4] .Kino kyongera okuwagira emigaso gyayo egy’enjawulo mu kuddukanya glucose mu musaayi.
Okunoonyereza okukwatagana
Obulung’amu ku kuddukanya obuzito mu balwadde abagejjulukuka n’ekika kya 2 metabolism mellitus:
Okunoonyereza okungi kukakasizza ebikolwa eby'amaanyi eby'okugejja: Mu kunoonyereza okwatuumiddwa 'SURMOUNT-2', okugezesebwa kuno kwali kwa mutendera gwa 3, okugezesebwa okw'emirundi ebiri, okwa randomized, okufugibwa placebo okwakolebwa mu nsi musanvu. Abantu abakulu (emyaka ≥18) nga balina body mass index (BMI) ya 27 kg/m² oba okusingawo ne glycated hemoglobin (HbA1) eya 7 - 10% zaweebwa mu ngeri ey’ekifuulannenge okufuna empiso ya Tirzepatid (10mg oba 15mg) oba placebo omulundi gumu buli wiiki wansi w’olususu okumala wiiki 72. Ebivudde mu kunoonyereza biraga nti mu wiiki 72, ebitundu by’okugejja mu kibinja kya Tirzepatid 10mg ne 15mg byali -12.8% ne -14.7%, ate mu kibinja kya placebo byali -3.2%. Enjawulo mu bujjanjabi obubalirirwamu obwa Tirzepatid 10mg ne 15mg bw’ogeraageranya n’obubonero bwa placebo bwali -9.6 ku buli 100 ne -11.6 ku buli 100, okusinziira ku, byombi byali bikulu mu bibalo (p.0.0001). Okugatta ku ekyo, abalwadde bangi abajjanjabwa ne Tirzepatid baatuuka ku kigero ky’okugejja ebitundu 5% oba okusingawo (79 - 83% vs 32%) [5] (Garvey WT, 2023). I n the 'SURMOUNT-2' study, baseline average obuzito bwali 100.7 kg, BMI yali 36.1 kg/m², ate HbA1 yali 8.02%. Oluvannyuma lwa wiiki 72 ng’ajjanjabwa, Tirzepatid teyakoma ku kukendeeza nnyo ku buzito wabula era yakola kinene mu kufuga glucose mu musaayi [5]..
Okulongoosa ekikolwa ku bulwadde bw’obusimu obukwatagana n’enkyukakyuka y’emmere:
Okunoonyereza okumu kulaga nti glucagon-like peptide 1 receptor agonists (GLP1-RAs) zisobola okukendeeza ku bulabe bw’okusannyalala mu balwadde abalina type 2 metabolism mellitus nga zitereeza okujjukira, okuyiga, n’okuvvuunuka obuzibu mu kutegeera. Nga dual glucose-dependent insulin polypeptide receptor agonist (GIP-RA)/GLP-1RA, Tirzepatid yasomesebwa ku bikolwa byayo ku bubonero bw’okukula kw’obusimu (CREB ne BDNF), apoptosis (BAX/Bcl2 ratio), okwawukana (pAkt, MAP2, GAP43, ne AGBL4), n’okuziyiza insulini (GLUT1, GLUT4, GLUT3, ne SORBS1) mu layini y’obutoffaali bw’obusimu obuyitibwa neuroblastoma cell line (SHSY5Y). Ebivuddemu omulundi ogusoose byaggumiza omulimu gwa Tirzepatid mu kukola ekkubo lya pAkt/CREB/BDNF ne downstream signaling cascades, awamu n’obulungi bwayo mu kukuuma obusimu. Era kyalaga nti Tirzepatid esobola okuziyiza ebikosa ebikwatagana ne hyperglycemia n’okuziyiza insulini ku mutendera gw’obusimu. N’olwekyo, Tirzepatid esobola okulongoosa okuvunda kw’obusimu obuva ku sukaali omungi n’okuvvuunuka okuziyiza insulini y’obusimu, okuwa amagezi amapya ku kulongoosa obulwadde bw’obusimu obukwatagana n’okukyusakyusa emmere [6]. .
Enkulaakulana y’okunoonyereza mu kujjanjaba obulwadde bwa type 2 metabolism mellitus:
Okunoonyereza okumu kulaga nti Tirzepatid, ng’ekika ekipya eky’eddagala erikendeeza sukaali, lifuuse eddagala erisooka erya dual GIP/GLP-1R agonist eryakkirizibwa okujjanjaba enkyukakyuka mu mubiri mu Amerika. Kikakasiddwa nti kirina kinene nnyo mu kukendeeza glucose mu musaayi n’okugejja mu kugezesebwa okw’amaanyi okungi, era waliwo obukakafu nti era kirina obusobozi bungi mu kukuuma emisuwa gy’omutima. Okugatta ku ekyo, endowooza ya peptides ezikolebwa egguddewo ebintu bingi ebitamanyiddwa eri Tirzepatid. Okugezesebwa okugenda mu maaso (NCT04166773) n’obujulizi biraga nti kirabika ddagala erisuubiza mu by’obulwadde bw’ekibumba ekitali kya mwenge (NAFLD), okukuuma ekibumba n’obusimu n’ebirala [7]..
Ebikolwa bya okumala ebbanga eddene T irzepatide ku bulamu bw’emisuwa n’emisuwa:
Tirzepatid eyinza okukendeeza ku bulabe bw’endwadde z’emisuwa ng’etumbula okugejja. Okunoonyereza kwekenneenya enkola ya Tirzepatid ku mugejjo n’endwadde z’emisuwa mu bantu abakulu mu Amerika [8] . Okunoonyereza kwazuula nti mu bantu abakulu mu Amerika abalina ebisaanyizo okujjanjabwa Tirzepatid, oluvannyuma lw’okujjanjabwa ne 15mg za Tirzepatid, kyabalirirwa nti 70.6% ne 56.7% ku bantu abakulu baalina okugejja ≥15% ne ≥20%, okusinziira ku, ekitegeeza nti omuwendo gwa abantu abagejjulukuka bakendedde ebitundu 58.8%. Mu bantu abatalina ndwadde za misuwa, obulabe obubalirirwamu obw’emyaka 10 obw’endwadde z’emisuwa bwakendeera okuva ku bitundu 10.1% nga tebannaba kujjanjabwa okutuuka ku bitundu 7.7% oluvannyuma lw’okujjanjabwa, ekiraga okukendeeza ku bulabe obw’enkomeredde ebitundu 2.4% n’okukendeeza ku bulabe obw’enjawulo ebitundu 23.6%, ekitegeeza nti ebiseera by’endwadde z’emisuwa obukadde 2 bisobola okuziyizibwa mu myaka 10.
Mu kumaliriza, Tirzepatid ye novel dual agonist of GIP ne GLP-1 receptors era ya makulu nnyo mu kujjanjaba type 2 metabolism mellitus n’omugejjo. Kiyinza okutumbula obulungi okufulumya insulini, okuziyiza okufulumya kwa glucagon, okulungamya obulungi glucose mu musaayi, okukendeeza ku bulabe bw’ebizibu, okulongoosa enkola y’obutoffaali bwa β obw’olubuto, n’okulwawo okukula kw’enkyukakyuka mu mubiri. Era erina ekikolwa eky’obukuumi ku nkola y’emisuwa gy’omutima. Mu kujjanjaba omugejjo, kisobola bulungi okukendeeza ku mmere gye balya, okukendeeza ku njagala y’okulya, okwongera okukkuta, okuyamba abalwadde abagejjulukuka okugejja, n’okukendeeza ku bulabe bw’ebizibu ebiva ku mugejjo. Era asobola okulongoosa obuziyiza bwa insulini n’okukyusakyusa amasavu. Okugatta ku ekyo, eraga obusobozi mu kujjanjaba endwadde ezikwatagana n’obutabeera bulungi mu nkyukakyuka y’emmere nga obulwadde bw’ekibumba obutali bwa mwenge, obulwadde bw’okusannyalala mu tulo, n’okulemererwa kw’omutima, era mu kiseera kye kimu esobola okulongoosa ebiraga enkyukakyuka y’emmere eziwera, ne kiwa enteekateeka y’obujjanjabi esingako obulungi. Enkola yaayo ey’okugikuba empiso omulundi gumu buli wiiki nnyangu okukozesa era esobola okulongoosa abalwadde okugoberera obujjanjabi. Nga tufuga bulungi glucose mu musaayi n’obuzito n’okukendeeza ku bulabe bw’ebizibu, embeera z’omubiri z’abalwadde zisobola okulongoosebwa ennyo, obusobozi bwabwe obw’okukola emirimu gya buli lunaku n’omutindo gw’obulamu bisobola okunywezebwa, obwesige bwabwe mu kufuga endwadde busobola okweyongera, omugugu gwabwe ogw’eby’omwoyo gusobola okuwummuzibwa, n’okukyusakyusa kwabwe mu mbeera z’abantu kuyinza okulongoosebwa.
Ebikwata ku Muwandiisi
Ebintu ebyogeddwako waggulu byonna binoonyerezeddwako, birongooseddwa era ne bikung’aanyizibwa kkampuni ya Cocer Peptides.
Omuwandiisi wa Scientific Journal
Dr. William T. Garvey mukenkufu era munoonyereza ow’ekitiibwa alina akakwate n’amatendekero ag’ekitiibwa agawerako, omuli Yunivasite y’e Alabama e Birmingham, Yunivasite ya Aston, ne Birmingham Veterans Affairs Medical Center. Obuyigirize bwe n’obumanyirivu bwe mu by’emikono bikwata ku bintu bingi mu by’obusawo ne ssaayansi. Dr. Garvey akoze kinene mu bitundu by’eby’omubiri n’okukyusakyusa ebiriisa, endya n’emmere, biochemistry ne molecular biology, wamu n’obusawo obw’enjawulo n’obw’omunda, ng’essira aliteeka nnyo ku nkola y’emisuwa n’omutima. Omulimu gwe gubadde gumanyiddwa nnyo era ne guweebwa ekitiibwa, naddala okulondebwa ng’Omunoonyereza Amanyiddwa ennyo mu mutendera gwa Cross-Field mu mwaka gwombi ogwa 2023 ne 2024, ekiraga enkosa ennene n’enkola y’okunoonyereza kwe ku kibiina kya ssaayansi ekigazi.
Dr. Garvey by’ayagala mu kunoonyereza n’obukugu bituuka ku bintu eby’enjawulo ebikwata ku ndwadde z’enkyukakyuka mu mubiri n’enzirukanya yazo. Abadde yeenyigira nnyo mu kusoma ku nkyukakyuka y’emmere, omugejjo, n’ebizibu ebikwatagana nabyo, ng’agenderera okuzuula enkola empya ez’obujjanjabi n’okulongoosa ebiva mu balwadde. Omulimu gwe guzingiramu okunoonyereza kwa ssaayansi okusookerwako, okugezesa mu bujjanjabi, n’okunoonyereza ku kuvvuunula, okuziba ekituli wakati w’ebizuuliddwa mu laboratory n’okukozesebwa mu by’obujjanjabi mu nsi entuufu. Okuyita mu kunoonyereza kwe okunene, Dr. Garvey ayambye okutegeera obulungi enkola ezisibukamu obuzibu mu nkyukakyuka y’emmere era ayambye okukola ebiragiro by’obujjanjabi n’enkola z’obujjanjabi mu by’endocrinology n’enkyukakyuka y’emmere. Dr. William T. Garvey awandiikiddwa mu kiwandiiko ekijuliziddwa [5]..
