▎ GLP-2 Kev Tshawb Fawb
Kev tshawb fawb keeb kwm ntawm GLP-2 yog dab tsi?
Kev txhim kho ntawm GLP-2, cov tshuaj hluavtaws polypeptide, pib los ntawm kev paub txog cov kev txwv ntawm GLP-1 receptor agonists hauv kev kho hom 2 metabolism thiab rog. Txawm hais tias GLP-1 receptor agonists ua tau zoo hauv kev tswj ntshav qabzib thiab poob phaus, cov kws tshawb fawb pom tias lawv tsis muaj zog ua rau GIP receptors txwv cov teebmeem kev kho mob. Yog li, pab pawg tshawb fawb tsom los tsim cov tshuaj tshiab uas muaj peev xwm ua rau ob qho tib si GIPR thiab GLP-1R rau kev tswj glycemic ntau dua thiab tswj qhov hnyav [1].
Kev sim ua ntej thiab kev kho mob dav dav tau ua thaum lub sijhawm txhim kho.
Preclinical tsiaj cov kev tshawb fawb soj ntsuam cov khoom pharmacodynamic, lees paub nws lub peev xwm hauv kev tswj glycemic thiab poob phaus. Phase I qhov kev sim tshuaj ntsuam xyuas feem ntau ntsuas kev nyab xeeb, kam rau ua, thiab pharmacokinetics, qhia kev nyab xeeb zoo
thiab tolerability. Phase II kev sim ntxiv tau tshawb fawb txog kev ua tau zoo thiab kev nyab xeeb ntawm cov koob tshuaj sib txawv hauv hom 2 cov neeg mob metabolism, ua ntej txiav txim siab ntau npaum li cas. Pivotal Phase III kev sim zoo li SURPASS series, suav nrog pawg loj ntawm cov neeg mob ntshav qab zib hom 2, pom GLP-2 ua tau zoo tshaj qhov uas twb muaj lawm GLP-1 receptor agonists hauv kev txo cov ntshav qabzib thiab qhov hnyav, muab cov pov thawj ruaj khov rau kev siv lag luam [1].
Tsim los ntawm 39 amino acids nrog cov qauv kev hloov kho los txhim kho kev ruaj ntseg thiab kev ua tau zoo, nws cov qauv tshwj xeeb sib xyaw ua ke ntawm GIP thiab GLP-1 rau hauv ib qho molecule, activating hormone receptors koom nrog glycemic tswj los ntawm dual mechanisms.
Ntawm ib sab tes, nws ua rau txiav txiav 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 kom ncua lub plab zom mov, ua kom satiety, thiab txo qis qab los noj mov thiab noj zaub mov kom tswj tau qhov hnyav. Qhov kev siv dual no muab GLP-2 tshwj xeeb zoo hauv kev kho hom 2 metabolism thiab rog, muab cov neeg mob ntau txoj kev kho mob [1].
GLP-2 mechanism ntawm kev txiav txim yog dab tsi?
GLP-2 txo cov ntshav qabzib los ntawm ntau yam txheej txheem:
Ua kom muaj GLP-1 Receptors: Kev khi rau GLP-1 receptors ntawm pancreatic β hlwb, nws ua raws li ntuj tsim GLP-1 los txhawb kev tsim cov tshuaj insulin, tso tawm, thiab cov piam thaj hauv cov ntshav thaum txo qis glucagon secretion los txhim kho satiety thiab suppress qab los noj mov. Hauv cov neeg mob ntshav qab zib hom 2, kev ua kom GLP-1 receptors nce insulin secretion rau kev txhim kho glycemic tswj, thaum inhibiting glucagon tso tawm ntxiv txo cov ntshav qabzib, pab tswj glycemic [2].
Kev ua kom GIP Receptors: Ua rau GIP receptors, ua kom cov tshuaj insulin rhiab heev thiab zais cia. GIP receptors feem ntau muaj nyob rau hauv cov ntaub so ntswg zoo li pancreatic β hlwb, thiab kev ua kom dhau los ntawm intracellular signaling txoj hauv kev nce insulin secretion thiab txhim kho cellular responsiveness rau insulin kom zoo dua cov ntshav qabzib [2] . Qhov no dual receptor agonism ua rau GLP-2 muaj txiaj ntsig zoo hauv kev txhawb nqa insulin secretion thiab inhibiting glucagon tso tawm dua li ib leeg GLP-1 receptor agonists [2] .
Ncua lub plab zom mov thiab ua kom satiety: Nws ua rau lub plab zom mov qeeb, ua kom cov zaub mov khaws cia hauv lub plab kom qeeb kev nqus cov zaub mov thiab tsis txhob muaj cov ntshav qabzib tom qab. Lub caij no, kev ua haujlwm ntawm lub hauv nruab nrab lub paj hlwb kom ua kom satiety txo qab los noj mov thiab noj zaub mov, tshwj xeeb tshaj yog rau kev rog rog feem ntau cuam tshuam nrog hom 2 metabolism, pab txhim kho insulin tsis kam thiab tag nrho cov txheej txheem metabolic [3].
Txhim kho Insulin Sensitivity thiab Lipid Ntshav Qab Zib: Txhim kho cov qib adiponectin-cov roj cell muaj feem cuam tshuam rau insulin rhiab heev-pab txhim kho insulin rhiab heev, ua kom cov hlwb kom muaj txiaj ntsig zoo dua thiab siv cov piam thaj kom txo cov ntshav qabzib [2] (Anonymous, 2023). Nws kuj tseem txhim kho lipid profile, nrog rau cov txiaj ntsig tiv thaiv kab mob plawv, tau pom tias txhim kho ntshav siab thiab txo qis LDL roj cholesterol thiab triglycerides [3].
Cov kev tshawb fawb cuam tshuam yog dab tsi?
GLP-2 qhia tau hais tias muaj txiaj ntsig zoo hauv kev tswj qhov hnyav rau cov neeg rog rog thiab hom 2 metabolism. Hauv SURMOUNT-2 txoj kev tshawb fawb, 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 BMI ≥27 kg / m² thiab HbA1c 7-10% tau randomized kom tau txais txhua lub lim tiam subcutaneous GLP-2 (10 mg lossis 15 mg) lossis placebo rau 72 lub lis piam. Los ntawm Lub Ob Hlis 72, qhov poob qis feem pua yog −12.8% thiab −14.7% hauv GLP-2 10 mg thiab 15 mg pawg piv rau −3.2% hauv pawg placebo, nrog kwv yees qhov sib txawv ntawm −9.6 thiab −11.6 feem pua ntawm cov ntsiab lus piv rau cov placebo (p <0.0001). Tsis tas li ntawd, ntau tus neeg mob GLP-2-kho tau ua tiav ≥5% poob phaus (79–83% vs. 32%) (Garvey WT, 2023). Nrog lub hauv paus txhais tau tias qhov hnyav 100.7 kg, BMI 36.1 kg / m², thiab HbA1c 8.02%, 72 lub lis piam ntawm kev kho mob nrog GLP-2 tsis tsuas yog txo qhov hnyav tab sis kuj txhim kho glycemic tswj [4] .
Hauv kev txhim kho cov metabolism hauv cov kab mob neuropathy, kev tshawb fawb qhia tias GLP1-RAs tuaj yeem txo qis kev pheej hmoo dementia hauv hom 2 cov neeg mob 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, GLP-2 tau kawm nyob rau hauv neuroblastoma cell kab (SHSY5Y) rau nws cov teebmeem ntawm neuronal kev loj hlob (CREB thiab BDNF), apoptosis (BAX/Bcl2 ratio), sib txawv (pAkt, MAP2, GAP43, thiab AGBL4), thiab insulin tsis kam (GLUT1., GLUT4, GLUT4, thiab GLUTOR1, GLUT4, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4, GLUT1, GLUT4. Nws tau pom tias muaj kev tiv thaiv kab mob neuroprotective los ntawm kev ua kom lub pAkt / CREB / BDNF txoj hauv kev thiab nqes dej taw qhia cascades, tiv thaiv hyperglycemia- thiab cuam tshuam txog insulin tsis kam ntawm qib neuronal. Yog li, GLP-2 tuaj yeem txhim kho hyperglycemia-induced neurodegeneration thiab kov yeej cov tshuaj insulin tsis kam, muab kev nkag siab tshiab rau kev tswj cov metabolism ntsig txog neuropathy [5].
Hauv hom 2 kev kho cov metabolism hauv kev nce qib, GLP-2, cov tshuaj hypoglycemic tshiab, tau dhau los ua thawj qhov kev pom zoo dual GIP / GLP-1R agonist rau cov metabolism hauv Teb Chaws Asmeskas Ntau qhov kev sim loj loj tau lees paub nws qhov tseem ceeb glycemic-txo thiab poob qhov hnyav, muaj peev xwm tiv thaiv kab mob plawv. Lub tswv yim ntawm hluavtaws peptides tau qhib ntau qhov kev tshawb nrhiav tsis tau rau GLP-2. Kev sim tsis tu ncua thiab pov thawj qhia tias nws yog ib qho tshuaj cog lus rau cov kab mob tsis muaj dej cawv fatty siab (NAFLD), kev tiv thaiv lub raum, thiab kev tiv thaiv neuroprotection [6].
Hais txog kev cuam tshuam mus sij hawm ntev rau kev noj qab haus huv ntawm cov hlab plawv, GLP-2 tuaj yeem txo cov kab mob plawv (CVD) los ntawm kev txhawb kev poob phaus. Ib txoj kev tshawb fawb soj ntsuam GLP-2 qhov cuam tshuam rau kev rog rog thiab CVD cov xwm txheej hauv Asmeskas cov neeg laus pom tias ntawm cov neeg tsim nyog tau txais kev kho mob GLP-2, 15 mg txoj kev kho tau kwv yees kom ua tiav ≥15% thiab ≥20% poob hauv 70.6% thiab 56.7% ntawm cov neeg laus, feem, txhais mus rau 58.8% kev txo qis dua. Hauv cov tib neeg tsis muaj CVD, kwv yees li 10-xyoo CVD qhov kev pheej hmoo poob qis los ntawm 10.1% 'kev kho ua ntej' mus rau 7.7% 'kev kho tom qab,' sawv cev rau qhov kev pheej hmoo txo qis ntawm 2.4% thiab cov txheeb ze kev pheej hmoo txo qis ntawm 23.6%, muaj peev xwm tiv thaiv 2 lab CVD txheej xwm [7].
Xaus
Hauv cov ntsiab lus, GLP-2 yog ib qho tshiab dual agonist ntawm GIP thiab GLP-1 receptors, tuav qhov tseem ceeb hauv kev kho hom 2 metabolism thiab rog. Nws muaj txiaj ntsig zoo txhawb kev tsim cov tshuaj insulin, inhibits glucagon tso tawm, thiab tswj cov ntshav qabzib, txo cov teeb meem kev pheej hmoo thaum txhim kho pancreatic β-cell muaj nuj nqi thiab ncua cov metabolism hauv kev loj hlob, nrog rau cov teebmeem cardioprotective. Hauv kev kho mob rog, nws txo qis kev noj zaub mov zoo, txo qis qab los noj mov, nce satiety, pab kom poob phaus, thiab txo qis kev rog rog cuam tshuam nrog kev txhim kho insulin tsis kam thiab lipid metabolism. Tsis tas li ntawd, nws qhia tau hais tias muaj peev xwm kho cov kab mob metabolic xws li tsis muaj cawv steatohepatitis, pw tsaug zog apnea syndrome, thiab lub plawv tsis ua hauj lwm, muab kev kho mob zoo los ntawm kev txhim kho ntau yam metabolic. Nws lub sijhawm txhaj tshuaj ib zaug ib lim piam ua kom yooj yim dua thiab ua raws li tus neeg mob. Los ntawm kev tswj cov ntshav qabzib thiab qhov hnyav, txo cov teeb meem kev pheej hmoo, thiab txhim kho lub cev nqaij daim tawv, kev ua haujlwm txhua hnub, thiab lub neej zoo, GLP-2 txhawb cov neeg mob kev ntseeg siab hauv kev tswj kab mob, txo cov teeb meem puas siab ntsws, thiab txhim kho 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 tau teev nyob rau hauv qhov kev siv ntawm cov ntaub ntawv pov thawj [4].
