GLP-215 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 loj hlob yog 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 mellitus (T2DM) thiab rog rog. Txawm hais tias GLP-1 receptor agonists tau pom qhov ua tau zoo hauv kev tswj ntshav qabzib thiab poob phaus, cov kws tshawb fawb tau pom tias lawv qhov kev ua haujlwm ntawm GIP receptor yog qhov tsis muaj zog, uas txwv tsis pub cov tshuaj kho tau zoo. 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, txhawm rau ua kom tiav ntau dua thiab muaj txiaj ntsig zoo ntshav qabzib tswj thiab tswj qhov hnyav ^[1].

Thaum lub sijhawm tshawb fawb thiab kev tsim kho, cov kws tshawb fawb tau ua ntau qhov kev tshawb fawb txog kev tshawb fawb thiab kev sim tshuaj. Nyob rau theem kev tshawb fawb preclinical, cov tshuaj pharmacodynamic ntawm GLP-2 tau soj ntsuam kom zoo los ntawm kev sim tsiaj, txheeb xyuas nws cov peev xwm hauv kev tswj ntshav qabzib thiab poob phaus. Cov txiaj ntsig tau pom tias nws tuaj yeem txo cov ntshav qabzib ntau hauv cov qauv tsiaj thiab ua kom pom kev ua tau zoo hauv kev tswj qhov hnyav, tso lub hauv paus rau kev sim tshuaj tom ntej.

Tom qab ntawd, qhov kev sim tshuaj ntsuam xyuas suav nrog Theem I, II, thiab III kev sim. Theem I mus sib hais mas ntsuam xyuas kev nyab xeeb, kam rau ua, thiab pharmacokinetic zog ntawm cov tshuaj. Cov txiaj ntsig tau qhia tias GLP-2 muaj kev nyab xeeb thiab ua haujlwm ntev. Theem II sim ntxiv tshawb xyuas qhov ua tau zoo thiab kev nyab xeeb ntawm cov koob tshuaj sib txawv ntawm GLP-2 hauv cov neeg mob T2DM, ua ntej txiav txim siab nws cov koob tshuaj zoo. Qhov tseem ceeb tshaj plaws Phase III kev sim tshuaj, xws li SURPASS series ntawm kev tshawb fawb, koom nrog ntau tus neeg mob nrog T2DM. 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 kev lag luam daim ntawv thov ntawm GLP-2 ^[1].

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

GLP-2 txo cov ntshav qabzib los ntawm ntau lub tshuab ua haujlwm ua ke. Thaum ua kom lub GLP-1 receptor, GLP-2 khi rau GLP-1 receptor ntawm pancreatic β-hlwb, ua raws li kev ua ntawm ntuj GLP-1. GLP-1 yog ib qho tshuaj hormones tsim nyob rau hauv txoj hnyuv thiab tseem ceeb heev rau kev tswj cov piam thaj homeostasis. Nws tuaj yeem txhawb kev tsim cov tshuaj insulin, zais cia, thiab ntsuas ntshav qabzib, txo qis glucagon secretion los txhawb satiety, thiab txo qis qab los noj mov.

Qhov kev ua kom muaj zog no tuaj yeem txhawb kev tsim cov tshuaj insulin. Insulin yog lub ntsiab hypoglycemic cov tshuaj hormones hauv lub cev, uas tuaj yeem txhim kho kev noj qab haus huv thiab kev siv cov piam thaj los ntawm cov hlwb, yog li txo cov ntshav qabzib. Hauv cov neeg mob uas muaj T2DM, insulin secretion tsis txaus lossis cell rhiab heev rau insulin txo, ua rau cov ntshav qabzib nce siab. Los ntawm kev ua kom lub GLP-1 receptor, GLP-2 nce insulin secretion, uas pab txhim kho cov ntshav qabzib tswj.

Nyob rau tib lub sijhawm, kev ua haujlwm ntawm GLP-1 receptor kuj inhibits qhov tso tawm ntawm glucagon. Glucagon feem ntau txhawb nqa glycogenolysis thiab gluconeogenesis thaum yoo mov, ua kom cov ntshav qabzib ntau ntxiv. Los ntawm inhibiting qhov kev txiav txim ntawm glucagon, GLP-2 ntxiv txo cov ntshav qabzib, pab tswj ntshav qabzib ^[2].

Thaum ua rau GIP receptor, GLP-2 ua rau GIP receptor ib txhij. Tom qab ua kom tiav, nws tuaj yeem txhim kho kev nkag siab ntawm insulin thiab tso tawm. GIP receptor feem ntau muaj nyob hauv cov ntaub so ntswg xws li pancreatic β-hlwb. Tom qab ua haujlwm, los ntawm kev sib kis ntawm intracellular signaling pathways, insulin secretion yog nce, thiab lub cell lub teb rau insulin yog txhim kho, yog li ntawd zoo dua txo cov ntshav qabzib.

GLP-2 yog thawj-hauv-chav kawm dual glucagon-zoo li peptide-1 thiab cov piam thaj-dependent insulinotropic polypeptide (GIP) analog, tau pom zoo rau kev kho mob ntawm cov neeg laus nrog T2DM raws li kev noj haus thiab kev tawm dag zog. GLP-2 yog cov qauv tshuaj hluavtaws raws li GIP ib ntus, muaj li ntawm 39-amino acid peptide. Nws tsub kom insulin secretion, txo glucagon tso tawm raws li cov piam thaj-dependant, txo qis kev yoo mov thiab postprandial ntshav qabzib ntau ntau, txhawb kev satiety, txo lub cev hnyav, thiab qeeb plab hnyuv. 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].

GLP-2 kuj tseem tuaj yeem ncua lub plab zom mov thiab ua kom satiety. Nws tuaj yeem ncua kev ua pa hauv plab, ua kom lub sijhawm nyob ntawm cov zaub mov hauv lub plab thiab ua kom qeeb ntawm kev nqus ntawm cov as-ham, yog li tsis txhob muaj qhov nce siab hauv cov ntshav qabzib tom qab. Hauv cov kev tshawb fawb uas tsis yog kev kho mob thiab kev kho mob, cov nyhuv ntawm GLP-2 ntawm lub plab khoob yog piv rau cov GLP-1 receptor agonists. Hauv kev noj zaub mov kom cov nas rog rog, qhov ntsuas ntawm lub plab zom mov qeeb los ntawm GLP-2 zoo ib yam li GLP-1, tab sis cov kev cuam tshuam hnyav no ploj tom qab 2 lub lis piam ntawm kev kho mob.

Hauv cov neeg koom nrog thiab tsis muaj T2DM, ib zaug ib lub lim tiam GLP-2 (≥5 mg thiab ≥4.5 mg, feem) ncua kev ua pa ntawm plab tom qab ib koob tshuaj. Hauv cov neeg koom nrog noj qab haus huv, cov txiaj ntsig tau txo qis tom qab ntau koob tshuaj GLP-2 lossis dulaglutide (Urva S, 2020). Nyob rau tib lub sijhawm, nws tuaj yeem ua rau lub hauv nruab nrab lub paj hlwb, ua kom satiety, txo qab los noj mov, thiab noj zaub mov. Los ntawm kev tswj hwm kev noj haus, nws tsis ncaj qha los tswj cov ntshav qabzib, tshwj xeeb tshaj yog tsim nyog rau cov teeb meem rog rog feem ntau nrog cov neeg mob T2DM, thiab pab txhim kho insulin tsis kam thiab tag nrho cov txheej txheem metabolic ^[2].

GLP-2 tau pom tias nce qib ntawm adiponectin, ib qho adipocytokine ntsig txog insulin rhiab heev. Kev nce qib ntawm adiponectin pab txhim kho insulin rhiab heev, ua rau cov hlwb ua rau cov tshuaj insulin ntau dua, yog li kev noj qab haus huv zoo dua thiab txo cov ntshav qabzib ^[2] . Tsis tas li ntawd, GLP-2 tuaj yeem txhim kho lipid profile thiab muaj peev xwm tiv thaiv kab mob plawv. GLP-2 tau raug pov thawj tias tuaj yeem txhim kho cov ntshav siab, txo qis lipoprotein tsawg (LDL) cov roj cholesterol thiab triglycerides ^[3] , txhawb nqa nws cov txiaj ntsig zoo hauv kev tswj ntshav qabzib.

Source: PubMed ^[5]

Kev tshawb fawb ntsig txog

Kev ua tau zoo ntawm kev tswj qhov hnyav hauv cov neeg mob rog rog thiab hom 2 metabolism mellitus

Ntau qhov kev tshawb fawb soj ntsuam tau lees paub qhov ua tau zoo ntawm GLP-2 hauv kev tswj hwm lub cev hnyav hauv cov neeg mob rog thiab T2DM. Hauv kev tshawb fawb hu ua 'SURMOUNT-2', uas yog Theem 3, ob qhov muag tsis pom kev, randomized, cov tshuaj placebo tswj kev sim ua nyob rau hauv xya lub teb chaws. Cov neeg laus (hnub nyoog ≥18 xyoo) nrog lub cev qhov hnyav (BMI) ntawm 27 kg / m² los yog siab dua thiab glycated hemoglobin (HbA₁c) qib ntawm 7 - 10% tau muab tso rau kom tau txais kev txhaj tshuaj subcutaneous ib zaug ib lim piam 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 ​​​​ntawm cov ntsiab lus, feem, ob qho tib si tseem ceeb (p <0.0001). Tsis tas li ntawd, feem ntau ntawm cov neeg mob tau txais kev kho mob GLP-2 mus txog qhov hnyav ntawm 5% lossis ntau dua (79 - 83% vs 32%) ^[4].

Hauv kev tshawb fawb 'SURMOUNT-2', 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 cov txiaj ntsig ntawm cov metabolism cuam tshuam txog neuropathy

ome kev tshawb fawb tau taw qhia tias GLP1-RAs tuaj yeem txo qhov kev pheej hmoo ntawm dementia hauv cov neeg mob T2DM los ntawm kev txhim kho kev nco, kev kawm, thiab kov yeej kev puas hlwb. Raws li ib tug dual GIP-RA / GLP-1RA, GLP-2 tau kawm nyob rau hauv neuroblastoma cell kab (SHSY5Y) rau nws cov teebmeem ntawm cov cim ntawm neuronal kev loj hlob (CREB thiab BDNF), apoptosis (BAX / Bcl2 ratio), sib txawv (pAkt, MAP2, GAP43, thiab AGBL4), thiab insulin resistance (GLUTGL1, GLUT1, thiab GLUT1).

Cov txiaj ntsig thawj zaug 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, nrog rau nws cov txiaj ntsig neuroprotective. Nws kuj tau qhia tias GLP-2 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 kev nkag siab tshiab rau kev txhim kho cov metabolism cuam tshuam txog neuropathy ^[5].

Kev tshawb nrhiav kev nce qib hauv kev kho mob ntawm hom 2 metabolism hauv mellitus

Qee cov kev tshawb fawb tau taw qhia tias raws li hom tshuaj hypoglycemic tshiab, GLP-2 tau dhau los ua thawj ob GIP / GLP-1R agonist tau pom zoo rau kev kho cov metabolism hauv Tebchaws Meskas. Nws tau raug lees paub tias muaj cov txiaj ntsig tseem ceeb ntawm kev txo cov ntshav qabzib thiab txo lub cev hnyav hauv ntau qhov kev kuaj mob loj, thiab muaj pov thawj qhia tias nws tseem muaj peev xwm tiv thaiv kab mob plawv.

Tsis tas li ntawd, lub tswv yim ntawm hluavtaws peptides tau qhib ntau qhov tsis paub txog qhov ua tau rau GLP-2. Kev sim tsis tu ncua (NCT04166773) thiab cov pov thawj qhia tias nws zoo li yog cov tshuaj cog lus hauv thaj chaw xws li kab mob tsis muaj dej cawv fatty siab (NAFLD), kev tiv thaiv lub raum, thiab kev tiv thaiv neuroprotection ^[6].

Kev cuam tshuam ntev ntawm GLP-2 rau kev noj qab haus huv ntawm lub plawv

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 (Wong ND, 2024). 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, nws tau kwv yees tias 70.6% thiab 56.7% ntawm cov neeg laus muaj qhov hnyav ntawm ≥15% thiab ≥20%, feem, 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 kev kho', uas qhia txog qhov kev pheej hmoo txo ​​qis ntawm 2.4% thiab tus txheeb ze pheej hmoo txo ​​qis ntawm 23.6%, uas txhais tau hais tias 2 lab tus kab mob hauv lub xyoo.

Hauv kev xaus, GLP-2 yog ib qho tshiab dual agonist ntawm GIP thiab GLP-1 receptors, uas yog qhov tseem ceeb hauv kev kho T2DM 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 β-hlwb, thiab ncua kev loj hlob ntawm cov metabolism. Nws kuj muaj kev tiv thaiv zoo ntawm cov hlab plawv.

Hauv kev kho mob rog rog, nws tuaj yeem txo cov zaub mov kom tsawg, txo qis qab los noj mov, ua kom satiety, pab cov neeg rog 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 tau pom tias muaj peev xwm hauv kev kho mob ntawm cov kab mob metabolic cuam tshuam xws li tsis muaj cawv steatohepatitis, pw tsaug zog apnea syndrome, thiab lub plawv tsis ua haujlwm. Nws tuaj yeem txhim kho ntau yam ntsuas metabolic ib txhij, 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.

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.

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.