GLP-210 mg

▎ GLP-2 Structure

Source: PubChem

Ib ntus: Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{diacid-C20-gamm a-Glu-(AEEA)2-Lys}-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-NH2 Molecular Formula: C 225H 348N 48O68 Molecular Luj: 4813 g / mol CAS Nr .: 2023788-19-2 PubChem CID: 163285897 Synonyms: Zepbound; Mounjaro

▎ GLP-2 Kev Tshawb Fawb

Kev tshawb fawb keeb kwm ntawm GLP-2 yog dab tsi?

GLP-2 yog cov tshuaj hluavtaws polypeptide. Nws txoj kev tshawb fawb thiab kev loj hlob los ntawm kev nkag siab tob txog cov kev txwv ntawm GLP-1 receptor agonists uas twb muaj lawm hauv kev kho mob ntawm hom 2 metabolism thiab rog thaum lub sijhawm ntawd. Txawm hais tias GLP-1 receptor agonists tau pom qhov ua tau zoo hauv kev tswj cov ntshav qabzib thiab poob phaus, cov kws tshawb fawb pom tias lawv qhov kev ua haujlwm ntawm GIP receptor yog qhov tsis muaj zog, uas txwv qhov kev ua tau zoo ntawm cov tshuaj rau qee yam. Yog li ntawd, pab pawg tshawb fawb thiab kev tsim kho tau cog lus los tsim cov tshuaj tshiab uas tuaj yeem ua rau ob qho tib si GIPR thiab GLP-1R ib txhij kom ua tiav cov ntshav qabzib ntau dua thiab muaj txiaj ntsig zoo tswj ntshav qab zib thiab tswj qhov hnyav ^[1].

Thaum lub sij hawm tshawb fawb thiab kev loj hlob ntawm GLP-2, cov kws tshawb fawb tau ua ntau qhov kev tshawb fawb thiab kev sim tshuaj. Hauv theem kev tshawb fawb preclinical, kev sim tsiaj tau siv los ntsuas cov tshuaj pharmacodynamic ntawm GLP-2. Cov txiaj ntsig tau lees paub nws lub peev xwm hauv kev tswj ntshav qabzib thiab poob phaus, tso lub hauv paus rau kev sim tshuaj tom ntej. Tom qab ntawd, GLP-2 tau nkag mus rau theem kev sim tshuaj, suav nrog theem I, II, thiab III. Phase I feem ntau tau soj ntsuam kev nyab xeeb, kam rau ua, thiab cov tshuaj pharmacokinetic ntawm cov tshuaj, thiab cov txiaj ntsig tau pom tias muaj kev nyab xeeb zoo thiab ua haujlwm ntev. Phase II tau tshawb fawb ntxiv txog kev ua tau zoo thiab kev nyab xeeb ntawm cov koob tshuaj sib txawv hauv cov neeg mob uas muaj hom 2 metabolism, ua ntej txiav txim siab qhov koob tshuaj zoo. Cov theem tseem ceeb III kev sim tshuaj, xws li SURPASS series ntawm kev tshawb fawb, koom nrog ntau tus neeg mob nrog hom 2 metabolism. Cov txiaj ntsig tau pom tias GLP-2 tau zoo dua rau GLP-1 receptor agonists uas twb muaj lawm, xws li GLP-1, hauv kev txo cov ntshav qabzib thiab qhov hnyav, muab pov thawj muaj zog rau daim ntawv thov kev lag luam ^[1].

GLP-2 yog polypeptide uas muaj 39 amino acids, thiab nws cov qauv tau raug hloov kho los txhim kho nws cov stability thiab pharmacodynamics. Nws cov qauv tsim tshwj xeeb tso cai rau nws los ua ke cov teebmeem ntawm ob lub incretins, GIP thiab GLP-1, rau hauv ib lub molecule, ua rau cov tshuaj hormones receptors koom nrog hauv cov ntshav qabzib tswj los ntawm ob lub tswv yim. Tshwj xeeb, ntawm ib sab, nws ua haujlwm ntawm pancreas los txhawb cov insulin secretion thiab inhibit glucagon tso tawm kom txo cov ntshav qabzib; Ntawm qhov tod tes, nws ua rau lub hauv nruab nrab lub paj hlwb, ncua lub plab zom mov, ua kom satiety, txo qab los noj mov thiab noj zaub mov, thiab ua tiav kev tswj qhov hnyav. Qhov kev siv ob npaug no muab GLP-2 tshwj xeeb zoo hauv kev kho mob ntawm hom 2 metabolism thiab rog, muab cov neeg mob nrog kev xaiv kev kho mob ntau dua ^[1].

GLP-2 mechanism ntawm kev txiav txim yog dab tsi?

GLP-2 txo cov ntshav qabzib los ntawm ntau cov txheej txheem hauv qab no:

Ua kom cov GLP-1 Receptors: GLP-2 khi rau GLP-1 receptors ntawm pancreatic beta hlwb, ua raws li kev ua ntawm ntuj GLP-1. GLP-1 yog cov tshuaj hormones tsim los ntawm txoj hnyuv uas yog qhov tseem ceeb rau kev tswj cov piam thaj hauv tsev. Nws tuaj yeem txhawb kev tsim cov tshuaj insulin, zais cia, thiab ntsuas ntshav qabzib, thiab txo qis glucagon secretion los txhawb satiety thiab suppress qab los noj mov. Hauv cov neeg mob uas muaj hom 2 metabolism, kev tso tawm insulin tsis txaus lossis txo qis cellular rhiab heev rau insulin ua rau cov ntshav qabzib nce siab. GLP-2 nce insulin secretion los ntawm activating GLP-1 receptors, txhim kho cov ntshav qabzib tswj. Nyob rau tib lub sijhawm, kev ua haujlwm ntawm GLP-1 receptors tuaj yeem cuam tshuam kev tso tawm ntawm glucagon, ntxiv txo cov ntshav qabzib thiab pab txhawb kev tswj ntshav qabzib ^[2].

Kev ua haujlwm ntawm GIP Receptors: GLP-2 ua rau GIP receptors, thiab nws qhov kev ua kom muaj peev xwm txhim kho insulin rhiab heev thiab zais cia. GIP receptors feem ntau muaj nyob hauv cov ntaub so ntswg xws li pancreatic beta hlwb. Tom qab ua kom muaj zog, los ntawm kev hloov pauv ntawm cov teeb liab hauv lub cev, kev tso tawm ntawm cov tshuaj insulin yog nce, thiab lub cell lub teb rau insulin yog txhim kho, txo cov ntshav qabzib ntau dua ^[2] . Qhov no dual receptor agonist nyhuv ua rau GLP-2 zoo dua li ib leeg GLP-1 receptor agonists hauv kev txhawb nqa insulin secretion thiab inhibiting glucagon tso tawm ^[2].

Kev ncua lub plab zom mov thiab nce satiety: GLP-2 tuaj yeem ncua lub plab zom mov, ua kom lub sijhawm nyob ntawm cov zaub mov hauv plab, ua rau qeeb ntawm kev nqus ntawm cov as-ham, thiab tiv thaiv kev nce siab hauv cov ntshav qabzib tom qab. Nws cov nyhuv ntawm lub plab khoob yog piv rau cov GLP-1 receptor agonists. Nyob rau tib lub sijhawm, nws ua haujlwm ntawm lub hauv nruab nrab lub paj hlwb, ua kom satiety, txo qab los noj mov thiab noj zaub mov, tshwj xeeb tshaj yog rau cov teeb meem rog rog feem ntau nrog cov neeg mob uas muaj hom 2 metabolism, pab txhim kho insulin tsis kam thiab tag nrho cov metabolic mob ^[2].

Txhim kho Insulin Sensitivity thiab Lipid Ntshav Qab Zib: GLP-2 tuaj yeem nce qib ntawm adiponectin, ib qho adipocytokine cuam tshuam nrog insulin rhiab heev, pab txhim kho insulin rhiab heev, ua kom cov hlwb ua kom zoo dua thiab siv cov piam thaj, thiab txo cov ntshav qabzib (Anonymous, 2023). Tsis tas li ntawd, nws tuaj yeem txhim kho lipid profile, muaj peev xwm tiv thaiv kab mob plawv. Nws tau raug pov thawj tias tuaj yeem txhim kho ntshav siab, txo qis LDL roj cholesterol thiab triglycerides ^[3].

Source: PubMed ^[5]

Cov kev tshawb fawb ntsig txog dab tsi?

Kev ua tau zoo ntawm kev tswj qhov hnyav hauv cov neeg mob rog rog thiab hom 2 mob ntshav qab zib

Ntau qhov kev tshawb fawb soj ntsuam tau lees paub tias GLP-2 muaj qhov cuam tshuam loj heev. Hauv 'SURMOUNT-2' txoj kev tshawb no, theem 3 no, ob qhov muag tsis pom kev, randomized, cov placebo-tswj sim tau ua nyob rau hauv xya lub teb chaws. Cov neeg laus (hnub nyoog ≥ 18 xyoo) nrog BMI ntawm 27 kg / m² los yog siab dua thiab HbA₁c ntawm 7 - 10% tau tso npe thiab muab tso rau hauv ib lub lim tiam kom tau txais kev txhaj tshuaj subcutaneous ntawm GLP-2 (10 mg lossis 15 mg) lossis placebo rau 72 lub lis piam. Cov txiaj ntsig tau pom tias nyob rau lub lim tiam 72, qhov feem pua ​​​​ntawm qhov hnyav hauv GLP-2 10 mg thiab 15 mg pawg yog -12.8% thiab -14.7% feem, piv nrog -3.2% hauv pawg placebo. Kev kwv yees qhov sib txawv ntawm kev kho mob ntawm GLP-2 10 mg thiab 15 mg piv nrog cov placebo yog -9.6 feem pua ​​​​cov ntsiab lus thiab -11.6 feem pua ​​​​cov ntsiab lus feem, uas yog qhov tseem ceeb (p <0.0001). Tsis tas li ntawd, ntau tus neeg mob tau txais kev kho GLP-2 mus txog qhov pib ntawm 5% lossis ntau dua qhov hnyav (79 - 83% vs 32%) (Garvey WT, 2023). Hauv txoj kev tshawb no, qhov nruab nrab qhov hnyav yog 100.7 kg, BMI yog 36.1 kg / m² thiab HbA₁c yog 8.02%. Tom qab 72 lub lis piam ntawm kev kho mob, GLP-2 tsis tsuas yog txo lub cev hnyav xwb tab sis kuj muaj txiaj ntsig zoo rau kev tswj ntshav qabzib ^[4].

Kev txhim kho ntawm Diabetic Neuropathy

Cov kev tshawb fawb tau taw qhia tias GLP1-RAs tuaj yeem txo qhov kev pheej hmoo ntawm dementia hauv cov neeg mob uas muaj hom 2 metabolism los ntawm kev txhim kho kev nco, kev kawm, thiab kov yeej kev puas hlwb. Raws li ib tug dual GIP-RA / GLP-1RA, nyob rau hauv lub neuroblastoma cell kab (SHSY5Y), kev tshawb fawb tau pom tias GLP-2 muaj kev cuam tshuam rau cov cim ntawm neuronal loj hlob (CREB thiab BDNF), apoptosis (BAX / Bcl2 piv), sib txawv (pAkt, MAP2, GAP43, thiab AGBL4), thiab insulin tsis kam (SGL4, GLUT1, BSGL4, thiab AGBL4). Cov txiaj ntsig tau hais txog lub luag haujlwm ntawm GLP-2 hauv kev ua kom lub pAkt / CREB / BDNF txoj hauv kev thiab cov kev taw qhia qis qis thiab nws cov kev tiv thaiv neuroprotective, qhia tias nws tuaj yeem tiv thaiv cov teebmeem cuam tshuam nrog hyperglycemia thiab insulin tsis kam ntawm qib neuronal. Yog li, GLP-2 tuaj yeem txhim kho cov neurodegeneration tshwm sim los ntawm hyperglycemia thiab kov yeej cov tshuaj insulin tsis kam, muab cov kev nkag siab tshiab rau kev txhim kho cov metabolism hauv neuropathy ^[5].

Kev Tshawb Fawb Kev Txhim Kho hauv Kev Kho Mob Ntshav Qab Zib Hom 2

Raws li hom tshuaj hypoglycemic tshiab, GLP-2 tau dhau los ua thawj ob GIP / GLP-1R agonist pom zoo rau kev kho cov metabolism hauv Tebchaws Meskas. Ntau qhov kev sim tshuaj loj loj tau lees paub tias nws cov ntshav qabzib tseem ceeb txo qis thiab txo qhov hnyav, thiab nws muaj peev xwm tiv thaiv kab mob plawv. Lub tswv yim ntawm hluavtaws peptides tau qhib ntau qhov tsis paub muaj peev xwm rau GLP-2. Kev sim tsis tu ncua (NCT04166773) thiab cov pov thawj qhia tias nws yog ib qho tshuaj cog lus nyob rau hauv thaj chaw ntawm cov kab mob uas tsis yog-alcoholic fatty siab (NAFLD), lub raum thiab neuroprotection ^[6] (Ma Z, 2023).

Kev cuam tshuam ntev ntev ntawm GLP-2 ntawm Kev Noj Qab Haus Huv Kab Mob

GLP-2 tuaj yeem txo qhov kev pheej hmoo ntawm cov kab mob plawv los ntawm kev txhawb nqa qhov hnyav. Ib txoj kev tshawb fawb tau tshuaj xyuas qhov cuam tshuam ntawm GLP-2 ntawm kev rog rog thiab kab mob plawv hauv Asmeskas cov neeg laus ^[7] . Txoj kev tshawb nrhiav pom tias cov neeg laus Asmeskas tau txais kev kho mob GLP-2, tom qab kev kho mob nrog 15 mg ntawm GLP-2, kwv yees li 70.6% thiab 56.7% ntawm cov neeg laus poob ≥ 15% thiab ≥ 20% ntawm lawv lub cev hnyav raws li, uas txhais tau tias txo qis ntawm 58.8% ntawm cov neeg rog. Ntawm cov uas tsis muaj kab mob plawv, kwv yees li 10-xyoo kab mob plawv txo qis los ntawm 10.1% 'ua ntej kho' mus rau 7.7% 'tom qab kho', nrog rau qhov kev pheej hmoo txo ​​qis ntawm 2.4% thiab tus txheeb ze pheej hmoo txo ​​qis ntawm 23.6%, tiv thaiv 2 lab kab mob plawv.

Hauv kev xaus, GLP-2 yog ib hom tshiab ntawm dual agonist ntawm GIP thiab GLP-1 receptors, uas yog qhov tseem ceeb hauv kev kho mob ntawm hom 2 metabolism thiab rog. Nws tuaj yeem txhawb kev tsim cov tshuaj insulin ntau dua, inhibit glucagon secretion, tswj cov ntshav qabzib, txo cov kev pheej hmoo ntawm cov teeb meem, txhim kho kev ua haujlwm ntawm pancreatic beta hlwb, ncua kev loj hlob ntawm cov metabolism, thiab muaj cov nyhuv cardioprotective. Hauv kev kho mob rog rog, nws tuaj yeem txo cov khoom noj kom tsawg, txo qis qab los noj mov, ua kom satiety, pab cov neeg mob rog rog, thiab txo cov kev pheej hmoo ntawm kev rog rog. Nws kuj tseem tuaj yeem txhim kho insulin tsis kam thiab lipid metabolism. Tsis tas li ntawd, nws qhia tau hais tias muaj peev xwm hauv kev kho cov kab mob metabolic txawv txav xws li tsis muaj cawv steatohepatitis, pw tsaug zog apnea syndrome, thiab lub plawv tsis ua hauj lwm, thiab tuaj yeem txhim kho ntau yam kev ntsuas metabolic, muab cov phiaj xwm kev kho mob ntau dua. Nws txoj kev txhaj tshuaj ib zaug ib lub lim tiam yog qhov yooj yim rau siv thiab tuaj yeem txhim kho cov neeg mob kev ua raws li kev kho mob. Los ntawm kev tswj cov ntshav qabzib thiab qhov hnyav thiab txo qhov kev pheej hmoo ntawm cov teeb meem, nws tuaj yeem txhim kho cov neeg mob lub cev zoo, txhim kho lawv txoj haujlwm niaj hnub muaj peev xwm thiab lub neej zoo, ua kom lawv muaj kev ntseeg siab hauv kev tswj kab mob, txo lawv lub nra ntawm lub hlwb, thiab txhim kho lawv cov kev sib raug zoo.

Hais Txog Tus Sau

Cov ntaub ntawv hais saum toj no yog txhua yam tshawb fawb, kho thiab sau los ntawm Cocer Peptides.

Scientific Journal Author

Dr. William T. Garvey yog ib tug kws tshaj lij thiab kws tshawb fawb koom nrog ntau lub tsev kawm ntawv muaj koob npe, suav nrog University of Alabama ntawm Birmingham, Aston University, thiab Birmingham Veterans Affairs Medical Center. Nws keeb kwm kev kawm thiab kev paub dhau los nthuav dav ntau yam kev qhuab qhia hauv kev kho mob thiab kev tshawb fawb. Dr. Garvey tau ua haujlwm tseem ceeb rau kev ua haujlwm ntawm endocrinology thiab metabolism, khoom noj khoom haus thiab kev noj haus, biochemistry thiab molecular biology, nrog rau cov tshuaj dav dav thiab sab hauv, nrog rau kev tsom mus rau cov hlab plawv thiab cov hlab plawv. Nws txoj haujlwm tau txais kev lees paub dav dav thiab tau txais txiaj ntsig, tshwj xeeb tshaj yog raug hu ua Tus Kws Tshawb Fawb Tshaj Lij Tshaj Lij Tshaj Lij rau ob qho tib si 2023 thiab 2024, qhia txog qhov cuam tshuam loj heev thiab cuam tshuam ntawm nws txoj kev tshawb fawb hauv zej zog kev tshawb fawb dav dav.

Dr. Garvey txoj kev tshawb fawb txog kev txaus siab thiab kev txawj ntse txuas mus rau ntau yam ntawm cov kab mob metabolic thiab lawv txoj kev tswj hwm. Nws tau koom tes nrog kev kawm txog cov metabolism hauv kev rog, rog rog, thiab lawv cov teeb meem cuam tshuam, txhawm rau nthuav tawm cov tswv yim kho tshiab thiab txhim kho cov txiaj ntsig ntawm tus neeg mob. Nws txoj haujlwm suav nrog kev tshawb fawb txog kev tshawb fawb, kev sim tshuaj kho mob, thiab kev tshawb fawb kev txhais lus, cuam tshuam qhov sib txawv ntawm kev kuaj pom thiab daim ntawv thov kev kho mob tiag tiag. Los ntawm nws txoj kev tshawb fawb dav dav, Dr. Garvey tau pab txhawb kom nkag siab tob txog cov txheej txheem hauv qab ntawm cov kab mob metabolic thiab tau pab kho cov txheej txheem kho mob thiab cov txheej txheem kho mob hauv thaj chaw endocrinology thiab cov metabolism. Dr. William T. Garvey muaj npe nyob rau hauv qhov kev siv ntawm cov ntaub ntawv pov thawj ^[4 ].

▎ Cov Lus Qhia Tseem Ceeb

[1] Nowak M, Nowak W, Grzeszczak W. GLP-2 - ib tug dual GIP / GLP-1 receptor agonist - ib tug tshiab antidiabetic tshuaj uas muaj peev xwm metabolic kev ua si nyob rau hauv kev kho mob ntawm hom 2 metabolism[J]. Endokrynologia Polska, 2022,73(4):745-755.DOI:10.5603/EP.a2022.0029.

[2] Tsis qhia npe. GLP-2: Dual Glucose-Dependent Insulinotropic Polypeptide thiab Glucagon-Like Peptide-1 Agonist rau Kev Tswj Xyuas Hom 2 Mob Ntshav Qab Zib: Erratum.[J]. American Journal of Therapeutics, 2023,30(3):e311.DOI:10.1097/MJT.0000000000001634.

[3] Forzano I, Varzideh F, Avvisato R, et al. GLP-2: A Systematic Update[J]. International Journal of Molecular Sciences, 2022,23(23).DOI:10.3390/ijms232314631.

[4] Garvey WT, Frias JP, Jastreboff AM, et al. GLP-2 ib zaug ib lub lim tiam rau kev kho mob rog rog hauv cov neeg uas muaj hom 2 metabolism (SURMOUNT-2): ob qhov muag tsis pom kev, randomised, multicentre, placebo-tswj, theem 3 sim [J]. Lancet, 2023,402(10402):613-626.DOI:10.1016/S0140-6736(23)01200-X.

[5] Fontanella RA, Ghosh P, Pesapane A, et al. GLP-2 tiv thaiv neurodegeneration los ntawm ntau txoj hauv kev molecular [J]. Phau ntawv Journal of Translational Medicine, 2024,22(1).DOI:10.1186/s12967-024-04927-z.

[6] Ma Z, Jin K, Yue M, et al. Kev Tshawb Fawb Txog Kev Tshawb Fawb ntawm GIP / GLP-1 Receptor Coagonist GLP-2, Rising Star in Type 2 Diabetes [J]. Phau ntawv Journal of Diabetes Research, 2023,2023.DOI:10.1155/2023/5891532.

[7] Wong ND, Karthikeyan H, Ntxuam W. Teb Chaws Asmeskas Kev Tsim Nyog Kev Tsim Nyog thiab kwv yees qhov cuam tshuam ntawm GLP-2 Kev Kho Mob ntawm Obesity Prevalence thiab Kab Mob plawv[J]. Tshuaj thiab kho mob plawv, 2024.DOI:10.1007/s10557-024-07583-z.

Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.  

Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.