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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 PubChem CID: 163285897. Enkola y’okukuuma eddagala lino Ebigambo ebifaanagana: Zepbound; Mounjaro nga bwe |
▎ Okunoonyereza ku GLP-2
Ensibuko y’okunoonyereza ku GLP-2 eri etya?
GLP-2 ddagala lya polypeptide erikolebwa mu ngeri ey’ekikugu. Enkula yaayo eva mu kutegeera okw’amaanyi ku buzibu bw’ebirungo ebiziyiza GLP-1 receptor agonists ebiriwo mu kujjanjaba ekika kya 2 metabolism mellitus (T2DM) n’omugejjo. Wadde nga GLP-1 receptor agonists ziraga nti zikola bulungi nnyo mu kufuga glucose mu musaayi n’okugejja, bannassaayansi bakizudde nti okukola kwazo ku GIP receptor kunafu nnyo, ekikoma ku bujjanjabi bw’eddagala lino. N’olwekyo, ttiimu y’abanoonyereza n’okukulaakulanya ebadde yeewaddeyo okukola ekika ky’eddagala ekipya ekiyinza okukola GIPR ne GLP-1R omulundi gumu, nga kigenderera okutuuka ku kufuga kwa glucose mu musaayi n’okuddukanya obuzito mu ngeri esingako era ennungi [1]..
Mu nkola y’okunoonyereza n’okukulaakulanya, bannassaayansi bakoze okunoonyereza okusookerwako okungi n’okugezesa mu malwaliro. Mu mutendera gw’okunoonyereza nga tegunnabaawo, eby’obugagga by’eddagala ebya GLP-2 byakeberebwa bulungi okuyita mu kugezesa ebisolo, okukakasa obusobozi bwayo mu kufuga glucose mu musaayi n’okugejja. Ebivuddemu biraga nti esobola okukendeeza ennyo ku mutindo gwa glucose mu musaayi mu bikolwa by’ebisolo era ne kiraga nti ekola bulungi nnyo mu kuddukanya obuzito, ne kiteekawo omusingi gw’okugezesebwa okw’obujjanjabi okuddirira.
Oluvannyuma, omutendera gw’okugezesebwa mu malwaliro gwalimu okugezesebwa kwa Phase I, II, ne III. Okugezesebwa kwa Phase I okusinga kwekenneenya obukuumi, okugumiikiriza, n’obulungi bw’eddagala lino. Ebivuddemu biraga nti GLP-2 yalina obukuumi obulungi n’okugumira. Okugezesebwa kwa Phase II kwayongera okunoonyereza ku bulungibwansi n’obukuumi bwa ddoozi ez’enjawulo eza GLP-2 mu balwadde abalina T2DM, nga basooka kuzuula ddoozi zaayo ezikola. Okugezesebwa okusinga obukulu okwa Phase III clinical trials, nga SURPASS series of studies, kwalimu abalwadde bangi abalina T2DM. Ebivuddemu biraga nti GLP-2 yali esukkulumye nnyo ku GLP-1 receptor agonists eziriwo, nga GLP-1, mu kukendeeza glucose mu musaayi n’obuzito, nga kiwa obujulizi obw’amaanyi ku kukozesa GLP-2 mu kutunda [1]..
Enkola ya GLP-2 ekola ki?
GLP-2 ekendeeza ku glucose mu musaayi ng’eyita mu nkola eziwera ezikolagana. Nga ekola ku GLP-1 receptor, GLP-2 esiba ku GLP-1 receptor ku pancreatic β-cells, nga ekoppa ekikolwa kya GLP-1 eky’obutonde. GLP-1 busimu obukolebwa mu byenda era nga bukulu nnyo mu kukuuma glucose homeostasis. Kiyinza okutumbula okukola insulini, okufulumya, n’okutegeera glucose, okukendeeza ku glucagon okufulumya okutumbula okukkuta, n’okuziyiza okwagala okulya.
Okukola kuno kuyinza okutumbula okufulumya insulini. Insulin ye hormone enkulu ekendeeza sukaali mu mubiri, esobola okwongera okutwala n’okukozesa glucose obutoffaali, bwe kityo ne kikendeeza ku glucose mu musaayi. Mu balwadde abalina T2DM, okufulumya insulini tekumala oba obutoffaali okuwulira insulini kukendeera, ekivaako glucose mu musaayi okulinnya. Nga ekola ku GLP-1 receptor, GLP-2 eyongera ku kufulumya insulini, ekiyamba okulongoosa okufuga glucose mu musaayi.
Mu kiseera kye kimu, okukola kw’ekirungo kya GLP-1 nakyo kiziyiza okufulumya kwa glucagon. Glucagon etera okutumbula glycogenolysis ne gluconeogenesis mu kiseera ky’okusiiba, okwongera ku kukola glucose mu musaayi. Nga eziyiza ekikolwa kya glucagon, GLP-2 eyongera okukendeeza ku nsibuko ya glucose mu musaayi, ekiyamba mu kufuga glucose mu musaayi [2]..
Nga ekola ku GIP receptor, GLP-2 ekola ku GIP receptor omulundi gumu. Oluvannyuma lw’okukola, esobola okutumbula okuwulira kwa insulini n’okufulumya. GIP receptor esinga kubeera mu bitundu by’omubiri nga pancreatic β-cells. Oluvannyuma lw’okukola, okuyita mu kutambuza amakubo g’obubonero mu butoffaali, okufulumya insulini kweyongera, era okuddamu kw’obutoffaali eri insulini kulongooka, bwe kityo ne kikendeeza bulungi glucose mu musaayi.
GLP-2 ye peptide-1 eringa glucagon emirundi ebiri ne glucose-dependent insulinotropic polypeptide (GIP) analog esooka mu mutindo, ekkiriziddwa okujjanjaba abalwadde abakulu abalina T2DM ng’ekigatta ku mmere n’okukola dduyiro. GLP-2 nsengekera ya kemiko ey’obutonde eyesigamiziddwa ku nsengekera ya GIP, ekoleddwa mu peptide ya amino asidi 39. 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 bw’omubiri, n’okulwawo okufulumya amazzi mu lubuto. Kino dual receptor agonist effect kifuula GLP-2 okukola obulungi okusinga single GLP-1 receptor agonists mu kutumbula okufulumya insulini n’okuziyiza okufulumya glucagon [2]..
GLP-2 era esobola okulwawo okufulumya amazzi mu lubuto n’okwongera okukkuta. Kiyinza okulwawo okufulumya amazzi mu lubuto, ne kiwangaaza obudde emmere gy’emala mu lubuto n’okukendeeza ku sipiidi y’okunyiga ebiriisa, bwe kityo ne kyewala okulinnya ennyo kwa glucose mu musaayi oluvannyuma lw’okulya. Mu kunoonyereza okutali kwa bujjanjabi 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 T2DM, GLP-2 omulundi gumu buli wiiki (≥5 mg ne ≥4.5 mg, mu kulondako) yalwawo okufulumya amazzi mu lubuto oluvannyuma lwa ddoozi emu. Mu beetabye abalamu, ekikolwa kyakendeera oluvannyuma lw’okukozesa dose eziwera eza GLP-2 oba dulaglutide (Urva S, 2020). Mu kiseera kye kimu, era esobola okukola ku busimu obw’omu makkati, okwongera okukkuta, okukendeeza ku njagala y’okulya n’okulya emmere. Nga efuga emmere, eyamba mu ngeri etali butereevu okufuga emiwendo gya glucose mu musaayi, naddala esaanira ekizibu ky’omugejjo ekitera okuwerekerwako abalwadde abalina T2DM, era kiyamba okulongoosa obuziyiza insulini n’embeera y’enkyukakyuka mu mubiri okutwalira awamu [2]..
GLP-2 kizuuliddwa nti eyongera ku muwendo gwa adiponectin, adipocytokine ekwatagana n’okuwulira insulini. Okwongera ku miwendo gya adiponectin kiyamba okulongoosa okuwuliziganya kwa insulini, okufuula obutoffaali okuddamu insulini, bwe kityo ne kitwala bulungi n’okukozesa glucose n’okukendeeza ku glucose mu musaayi [2] . Okugatta ku ekyo, GLP-2 era esobola okulongoosa enkola y’amasavu era erina ekikolwa ekiyinza okukuuma ku bulamu bw’emisuwa n’emisuwa. GLP-2 ekakasiddwa nti esobola okulongoosa puleesa, okukendeeza ku low-density lipoprotein (LDL) cholesterol ne triglycerides [3] , okwongera okuwagira emigaso gyayo egy’enjawulo mu kuddukanya glucose mu musaayi.
Ensibuko: PubMed [5] .
Okunoonyereza okukwatagana
Obulung’amu ku kuddukanya obuzito mu balwadde abagejjulukuka n’ekika kya 2 metabolism mellitus
Okunoonyereza kungi kukakasizza obulungi bwa GLP-2 mu kuddukanya obuzito bw’omubiri mu balwadde abagejjulukuka ne T2DM. Mu kunoonyereza okwatuumibwa 'SURMOUNT-2', okwali kwa Phase 3, okugezesebwa okw'emirundi ebiri, okwa randomized, okwakolebwa mu mawanga musanvu. Abantu abakulu (emyaka ≥18) nga balina body mass index (BMI) ya 27 kg/m² oba okusingawo n’omutindo gwa glycated hemoglobin (HbA2c) ogwa 7 - 10% baaweebwa mu ngeri ey’ekifuulannenge okufuna empiso za GLP-2 (10 mg oba 15 mg) oba placebo omulundi gumu buli wiiki wansi w’olususu okumala wiiki 72.
Ebivuddemu biraga nti mu wiiki 72, ebitundu by’okugejja mu bibinja bya GLP-2 10 mg ne 15 mg byali -12.8% ne -14.7%, okusinziira ku -3.2% mu kibinja kya placebo. Enjawulo mu bujjanjabi ebalirirwamu eza GLP-2 10 mg ne 15 mg bw’ogeraageranya ne placebo zaali -9.6 ku buli 100 ne -11.6 ku buli 100, okusinziira ku, byombi byali bikulu mu bibalo (p < 0.0001). Okugatta ku ekyo, ekitundu ekinene eky’abalwadde abafuna obujjanjabi bwa GLP-2 baatuuka ku kigero ky’okugejja ebitundu 5% oba okusingawo (79 - 83% vs 32%) [4]..
Mu kunoonyereza kwa 'SURMOUNT-2', obuzito obw'omusingi bwali 100.7 kg, BMI yali 36.1 kg/m², ate HbA1 yali 8.02%. Oluvannyuma lwa wiiki 72 nga bajjanjabwa, GLP-2 teyakoma ku kukendeeza nnyo ku buzito bw’omubiri naye era yalina akakwate akalungi ku kufuga glucose mu musaayi [4]..
Okulongoosa effect ku metabolism-related neuropathy
ome okunoonyereza kulaga nti GLP1-RAs zisobola okukendeeza ku bulabe bw’okusannyalala mu balwadde abalina T2DM nga zilongoosa okujjukira, okuyiga, n’okuvvuunuka obuzibu mu kutegeera. Nga GIP-RA/GLP-1RA ey’emirundi ebiri, GLP-2 yasomesebwa mu layini y’obutoffaali bwa neuroblastoma (SHSY5Y) olw’ebikolwa 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).
Ebivuddemu omulundi ogusoose byaggumiza omulimu gwa GLP-2 mu kukola ekkubo lya pAkt/CREB/BDNF n’obusimu obulaga obubonero wansi, awamu n’obulungi bwayo obw’okukuuma obusimu. Era kyalaga nti GLP-2 yasobola okuziyiza ebikosa ebikwatagana ne hyperglycemia n’okuziyiza insulini ku mutendera gw’obusimu. Nolwekyo, GLP-2 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 [5]..
Enkulaakulana y’okunoonyereza mu kujjanjaba obulwadde bwa type 2 metabolism mellitus
Okunoonyereza okumu kulaga nti ng’ekika ekipya eky’eddagala erikendeeza sukaali mu musaayi, GLP-2 efuuse eddagala ery’emirundi ebiri erya GIP/GLP-1R erisoose okukkirizibwa okujjanjaba enkyukakyuka mu mubiri mu Amerika. Kikakasiddwa nti kirina kinene kye kikola ku kukendeeza glucose mu musaayi n’okukendeeza ku buzito bw’omubiri mu kugezesebwa okw’amaanyi okungi, era waliwo obujulizi obulaga 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 bintu nga obulwadde bw’ekibumba obutali bwa masavu (NAFLD), okukuuma ekibumba, n’okukuuma obusimu [6]..
Ebikolwa bya GLP-2 eby’ekiseera ekiwanvu ku bulamu bw’emisuwa
GLP-2 eyinza okukendeeza ku bulabe bw’endwadde z’emisuwa ng’etumbula okugejja. Okunoonyereza kwekenneenya enkola ya GLP-2 ku mugejjo n’endwadde z’emisuwa mu bantu abakulu mu Amerika (Wong ND, 2024). Okunoonyereza kuno kwazuula nti mu bantu abakulu mu Amerika abalina ebisaanyizo okujjanjabibwa GLP-2, oluvannyuma lw’okujjanjabwa n’eddagala lya GLP-2 15 mg, kyabalirirwa nti abantu abakulu 70.6% ne 56.7% baali bakendedde ku buzito bwa ≥15% ne ≥20%, ekitegeeza nti omuwendo gw’abantu abagejjulukuka gwakendeera ebitundu 58.8%.
Mu abo abatalina ndwadde za misuwa, obulabe obubalirirwamu obw'emyaka 10 obw'endwadde z'emisuwa bwakendeera okuva ku 10.1% 'nga tebannaba kujjanjabwa' okutuuka ku 7.7% 'oluvannyuma lw'okujjanjabwa', ekiraga okukendeeza ku bulabe obw'enkomeredde ebitundu 2.4% n'okukendeeza ku bulabe obw'enjawulo okwa 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, nga kino kya makulu nnyo mu kujjanjaba T2DM n’omugejjo. Kiyinza okutumbula obulungi okufulumya insulini, okuziyiza okufulumya kwa glucagon, okutereeza 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 esobola okulongoosa obuziyiza bwa insulini n’okukyusakyusa amasavu. Okugatta ku ekyo, eraga nti erina obusobozi mu kujjanjaba endwadde ezeekuusa ku buzibu bw’enkyukakyuka mu mubiri nga non-alcoholic steatohepatitis, sleep apnea syndrome, n’okulemererwa kw’omutima. Kiyinza okulongoosa ebipimo by’enkyukakyuka y’emmere ebingi omulundi gumu, ne kiwa enteekateeka y’obujjanjabi enzijuvu.
Enkola yaayo ey’okukuba empiso omulundi gumu buli wiiki nnyangu okukozesa era esobola okulongoosa mu kugoberera obujjanjabi bw’abalwadde.
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 [4]..
