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1kits (Ebipipa 10) .
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▎ Enzimba ya GLP-2
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 GLP-2
Ensibuko y’okunoonyereza ku GLP-2 eri etya?
GLP-2 ddagala lya polypeptide erya synthetic, era enkulaakulana yaalwo eva mu kutegeera okw’amaanyi ku buzibu bw’ebirungo ebiziyiza GLP-1 receptor agonists ebiriwo mu kujjanjaba ekika kya 2 metabolism mellitus n’omugejjo. Wadde nga GLP-1 receptor agonists zalaga dda nti zikola bulungi nnyo 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 glucose mu musaayi n’okuddukanya obuzito mu ngeri esingako era ennungi [1]. .
Mu nkola y’okunoonyereza n’okukulaakulanya GLP-2, bannassaayansi bakoze okunoonyereza okusookerwako okungi n’okugezesa mu bujjanjabi. Okusookera ddala, mu mutendera gw’okunoonyereza nga tekunnabaawo, engeri z’eddagala lya GLP-2 zaali zeekenneenyezebwa nnyo okuyita mu kugezesa ebisolo, era obusobozi bwayo mu kufuga glucose mu musaayi n’okugejja bwakakasibwa. Ebivuddemu biraga nti GLP-2 esobola okukendeeza ennyo ku glucose mu musaayi mu bikolwa by’ebisolo era era yakola bulungi mu kuddukanya obuzito. Ebizuuliddwa bino ebirungi byassaawo omusingi omunywevu ogw’okugezesebwa okw’obujjanjabi okwaddirira.
Oluvannyuma, GLP-2 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 GLP-2 yalina obukuumi obulungi n’okugumiikiriza. Okugezesebwa okw’omutendera II kwayongera okunoonyereza ku bulungibwansi n’obukuumi bwa ddoozi ez’enjawulo eza GLP-2 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 GLP-2 yali esukkulumye nnyo ku agonists eziriwo ezikwata GLP-1, nga GLP-1, mu kukendeeza glucose mu musaayi n’obuzito. Ekivaamu kino eky’okumenyawo kyawa obujulizi obw’amaanyi obuwagizi ku nkola y’okutunda GLP-2 [1]..
GLP-2 ye polypeptide erimu amino acids 39, nga mu zo amino acids ssekinnoomu zikyusiddwa mu nsengeka okulongoosa obutebenkevu bwayo n’obulungi bwayo. Enteekateeka eno ey’enjawulo ey’enzimba esobozesa GLP-2 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 okuyita mu nkola bbiri ez’okukola. Okusingira ddala, GLP-2 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 ludda 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 GLP-2 enkizo ez’enjawulo mu kujjanjaba ekika kya 2 metabolism mellitus n’omugejjo, n’ewa abalwadde eky’obujjanjabi ekisingako [1]..
Enkola ya GLP-2 ekola ki?
GLP-2 ekkakkanya glucose mu musaayi ng’eyita mu nkola eziwera ezikolagana, nga bwe ziti: Okukola kw’ekirungo kya GLP-1: GLP-2 yeekwata ku kikwata kya GLP-1 ku butoffaali bwa β obw’olubuto, ng’ekoppa 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. GLP-2 eyongera ku kufulumya insulini ng’ekola 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 eziyiza ekikolwa kya glucagon, GLP-2 eyongera okukendeeza ku nsibuko ya glucose mu musaayi, ekiyamba okufuga glucose mu musaayi [2] (Anonymous, 2023).
Okukola kw’ekirungo kya GIP: GLP-2 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. GLP-2 ye analog esooka mu kibinja kya dual glucagon-like peptide-1 ne glucose-dependent insulinotropic polypeptide (GIP) analog, eyakkirizibwa okujjanjaba abalwadde abakulu abalina ekika kya 2 metabolism mellitus nga adjunct to diet and exercise 2. GLP-2 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 GLP-2 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: GLP-2 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’okujjanjaba, ekikolwa kya GLP-2 ku kufulumya amazzi mu lubuto kigeraageranyizibwa ku kya GLP-1 receptor agonists. Mu mbeba ezigejjulukuka ezireetebwa emmere, diguli y’okulwawo okufulumya amazzi mu lubuto nga GLP-2 efaananako n’eya GLP-1, 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, GLP-2 omulundi gumu buli wiiki (≥5 ne ≥4.5mg, okusinziira ku) yalwawo okufulumya amazzi mu lubuto oluvannyuma lwa ddoozi emu. Mu beetabye mu kugezesebwa abalamu, ekikolwa kino kyakendeezebwa oluvannyuma lw’okukozesa dose eziwera eza GLP-2 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 okulya emmere, mu ngeri etali butereevu eyamba 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’okukyusakyusa amasavu: GLP-2 kizuuliddwa nti eyongera ku muwendo gwa adiponectin, nga kino kye kirungo kya adipocytokine ekikwatagana n’okuwulira insulini. Okwongera ku mutindo gwa adiponectin kiyamba okulongoosa okuwuliziganya kwa insulini, okufuula obutoffaali okuwuliziganya ennyo ku insulini, era bwe kityo ne kikwata bulungi n’okukozesa glucose, okukendeeza ku glucose mu musaayi [2]..
Okugatta ku ekyo, GLP-2 era esobola okulongoosa enkola y’amasavu era erina ekikolwa ekiyinza okukuuma obulamu bw’emisuwa n’emisuwa. GLP-2 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 okutuumiddwa '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 (HbA2c) eya 7 - 10% zaaweebwa mu ngeri ey’ekifuulannenge okufuna empiso ya GLP-2 (10mg oba 15mg) oba placebo omulundi gumu buli wiiki wansi w’olususu okumala wiiki 72. Ebivuddemu biraga nti mu wiiki 72, ebitundu by’okugejja mu kibinja kya GLP-2 10mg ne 15mg byali -12.8% ne -14.7%, ate nga mu kibinja kya placebo byali -3.2%. Enjawulo mu bujjanjabi ebalirirwamu eza GLP-2 10mg ne 15mg bw’ogeraageranya ne placebo zaali -9.6 ku buli 100 ne -11.6 ku buli 100, okusinziira ku, byombi byali bikulu mu bibalo (p0.0001). Okugatta ku ekyo, abalwadde bangi abajjanjabwa ne GLP-2 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 ez’obujjanjabi, GLP-2 teyakoma ku kukendeeza nnyo ku buzito naye 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, GLP-2 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 GLP-2 mu kukola ekkubo lya pAkt/CREB/BDNF n’obusimu obulaga obubonero wansi, awamu n’obulungi bwayo mu kukuuma obusimu. Era kyalaga nti GLP-2 esobola okuziyiza ebikosa ebikwatagana ne hyperglycemia n’okuziyiza insulini ku mutendera gw’obusimu. N’olwekyo, GLP-2 esobola okulongoosa okuvunda kw’obusimu obuva ku sukaali omungi n’okuvvuunuka okuziyiza insulini y’obusimu, n’ewa 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 GLP-2, 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 ezikoleddwa egguddewo ebintu bingi ebitamanyiddwa ebisoboka ku GLP-2. Okugezesebwa okugenda mu maaso (NCT04166773) n’obujulizi biraga nti lirabika nga 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:
GLP-2 eyinza okukendeeza ku bulabe bw’endwadde z’emisuwa ng’etumbula okugejja. Okunoonyereza kwekenneenya enkosa ya GLP-2 ku mugejjo n’endwadde z’emisuwa mu bantu abakulu mu Amerika [8] . Okunoonyereza kwazuula nti mu bantu abakulu mu Amerika abalina ebisaanyizo okujjanjabibwa GLP-2, oluvannyuma lw’okujjanjabwa ne 15mg za GLP-2, kyabalirirwa nti 70.6% ne 56.7% ku bantu abakulu baalina okugejja kwa ≥15% ne ≥20%, okusinziira ku, ekitegeeza nti omuwendo gw’abantu abagejjulukuka yakendedde ebitundu 58.8%. Mu bantu abatalina ndwadde z’emisuwa, 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, GLP-2 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 glucagon, okutereeza obulungi glucose mu musaayi, okukendeeza ku bulabe bw’ebizibu, okulongoosa enkola y’obutoffaali bwa β mu lubuto, 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 bintu by’endwadde z’omu lubuto n’enkyukakyuka mu mubiri, endya n’endya, eby’obutonde n’ebiramu ebikola molekyu, 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 2023 ne 2024, ekiraga enkosa ennene n’enkola y’okunoonyereza kwe ku kibiina kya ssaayansi ekigazi.
Dr. Garvey okunoonyereza n’obukugu bw’alina 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 ennyo enkola ezisibukamu obuzibu mu nkyukakyuka y’emmere era ayambye okukola ebiragiro by’obujjanjabi n’enkola z’obujjanjabi mu by’endwadde z’omu lubuto n’enkyukakyuka mu mubiri. Dr. William T. Garvey awandiikiddwa mu kiwandiiko ekijuliziddwa [5]..
