By Cocer Peptides 
kwanaki 13 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da duk wani yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
Kiba yana ƙara zama matsala mai tsanani a duniya, yana shafar ba kawai lafiyar jiki ba amma kuma yana da alaƙa da cututtuka masu tsanani kamar cututtukan zuciya da cututtukan zuciya da nau'in ciwon sukari na 2. Nemo hanyoyin asara mai lafiya da inganci ya kasance mahimmin mayar da hankali kan binciken likita. Tizepatide magani ne wanda ke aiki akan masu karɓa biyu, yana ba da sabuwar hanyar kula da kiba.
Hoto 1: Tsarin da matakan farko na siginar kwayoyin ta hanyar GIPR da GLP1R a cikin GIPR-GLP1R dual agonists RG7697-NNCOO90-2746 da LY3298176.
Tizepatide's Dual Receptor Agonist Mechanism
(1) GIP Mai karɓar Agonist Mechanism
Tushen Jiki na Mai karɓar GIP
Mai karɓa na GIP ƙwararren mai karɓar tantanin halitta ne wanda aka samo a cikin gabobin da yawa, ciki har da pancreas, adipose tissue, hanta, da tsokoki. A saman sel beta na sel na pancreatic, lokacin da hormone GIP ya ɗaure ga wannan mai karɓa, yana kunna hanyoyin siginar intracellular, yana haifar da haɓaka matakan cAMP na ciki. cAMP sannan yana kunna furotin kinase A, wanda, ta hanyar jerin halayen, yana haɓaka haɓakar insulin.
A cikin adipose nama, kunna mai karɓar GIP yana daidaita metabolism na adipocyte. Yana inganta haɓakar glucose ta hanyar adipocytes, yana haɓaka haɓakar fatty acid da adanawa, kuma yana hana lipolysis. Bincike ya nuna wannan tsari na iya haɗawa da haɓakar adadin masu jigilar glucose (GLUT4), wanda ke sauƙaƙe shigar glucose cikin adipocytes, samar da albarkatun ƙasa don haɗakar mai.
Tasirin Tizepatide akan Mai karɓar GIP
Tizepatide yana da tsari mai kama da hormone na GIP kuma yana iya ɗaure musamman da kunna masu karɓar GIP. Idan aka kwatanta da GIP na endogenous, Tizepatide yana da ƙaƙƙarfan alaƙar ɗaure ga masu karɓa, yana ba da damar kunna hanyoyin sigina mafi inganci. Bincike ya nuna cewa bayan haɗawa ga masu karɓa, zai iya ƙara haɓaka matakan CAMP, ta haka ya fi inganta haɓakar insulin. A cikin adipose nama, daidaitaccen tsarin sa na metabolism na lipid bayan kunna mai karɓa yana ba da damar ɗaukar glucose ta hanyar adipocytes da daidaiton kira da adana fatty acids, yana hana tarin kitse mai yawa-mahimmin mahimmanci wajen kiyaye metabolism na lipid na al'ada.
Hoto 2: Sakamakon kwatankwacin RG7697 / NNCOO90-2746 da LY3298176 daga gwaji na asibiti, sai dai inda asterisks ya nuna (an nuna kawai a cikin rodents).
(2) GLP-1 Tsarin Rarraba Mai karɓa
Tushen Jiki na GLP-1 Masu karɓa
Mai karɓar GLP-1 kuma mai karɓar tantanin halitta ne da farko da aka rarraba a cikin ƙwayoyin β na pancreatic, sashin gastrointestinal, da kwakwalwa. A cikin ƙwayoyin β na pancreatic, GLP-1 yana ɗaure ga mai karɓa kuma yana kunna hanyoyin sigina don haɓaka ɓoyewar insulin. Ba kamar GIP ba, tasirin GLP-1 ana daidaita shi ta matakan glucose na jini: yana haɓaka haɓakar insulin lokacin da glucose na jini ya yi yawa kuma tasirin sa yana raunana lokacin da glucose na jini ya zama al'ada, yana sa ya fi aminci.
A cikin sashin gastrointestinal, kunna mai karɓar GLP-1 yana tsawaita riƙe abinci a cikin ciki, yana hana saurin hawan glucose na jini bayan cin abinci, kuma yana hana fitar da acid na ciki, yana kare mucosa na ciki. A cikin kwakwalwa, yana aiki akan yankuna masu sarrafa ci abinci, rage yunwa da karuwar koshi, wanda hakan zai haifar da rage yawan abinci.
Tasirin Tizepatide akan mai karɓar GLP-1
Tizepatide yana da alaƙa mai ƙarfi ga masu karɓar GLP-1, kuma akan kunnawa, yana haifar da sakamako kama da na GLP-1 na ƙarshe. Dangane da tsarin glucose na jini, yana haɓaka haɓakar insulin dangane da matakan glucose na jini, don haka mafi kyawun sarrafa glucose na jini. A cikin gastrointestinal tract, tasirinsa na jinkirta zubar da ciki ya fi bayyana fiye da na wasu magungunan gargajiya. A cikin kwakwalwa, tasirinta na hana ci ya fi dorewa, yana taimakawa rage nauyi yadda ya kamata.
(3) Tasirin Haɗin kai na Mai karɓar Agonism Biyu
Tasirin Haɗin kai a cikin Tsarin Glucose na Jini
Tizepatide yana aiki akan duka GIP da masu karɓar GLP-1, yana haifar da ingantaccen tsarin glucose na jini. GIP da farko yana haɓaka ƙwayar insulin cikin sauri a farkon lokacin postprandial, yana rage kololuwar glucose na jini; GLP-1 yana ci gaba da aiki a duk lokacin aikin postprandial, ba wai kawai inganta haɓakar insulin ba har ma yana jinkirta zubar da ciki, rage cin abinci, da kiyaye matakan glucose na jini. Kunna duka masu karɓa a lokaci guda yana haifar da mafi kyawun sarrafa glucose na jini bayan cin abinci. Misali, a cikin gwaje-gwajen dabbobi masu ciwon sukari, Tizepatide ya rage yawan karuwar glucose na jini bayan cin abinci fiye da ko dai GIP ko GLP-1 kwayoyi kadai, kuma glucose na jini ya dawo daidai da sauri.
Tasirin Haɗin kai akan Metabolism na Makamashi
Dangane da metabolism na makamashi, masu karɓar masu karɓa na GIP suna haɓaka haɓakar glucose ta ƙwayoyin mai, amma a ƙarƙashin tasirin Tizepatide, haɗin mai ba ya tarawa da yawa. A halin yanzu, GLP-1 agonists masu karɓa suna hana ci, ƙara yawan gamsuwa, rage yawan adadin kuzari, da haɓaka ƙona mai da kashe kuzari. Wannan aikin biyu yana daidaita yawan kuzari da kashe kuɗi. Misali, a gwaje-gwajen dabbobi masu kiba, bayan yin amfani da Tizepatide na wani lokaci, nauyin jikin dabbobin ya ragu, kitsen jikinsu ya ragu, sannan kuma ya kara habaka sinadarin basal.
Hoto na 3: Bambance-bambance tsakanin agonists na synergistic (chimeras) da tsarin haɗin peptide
Aikace-aikacen Tizepatide a cikin Maganin Kiba
(1) Illar Rage Nauyi
Shaidar Bincike na Preclinical
A cikin gwaje-gwajen dabba, berayen masu kiba da aka gudanar da Tizepatide sun nuna raguwar nauyi a hankali a kan lokaci, tare da raguwa mai ƙarfi idan aka kwatanta da ƙungiyar kulawa. Binciken kitsen jiki ya nuna cewa ba wai kawai rage yawan kitse bane amma kuma yana inganta rarraba mai, yana rage yawan kitse na visceral. Hanyoyi na farko sune nau'i biyu: na farko, kunna mai karɓar GLP-1 yana hana ci ta hanyar hana cibiyar yunwar kwakwalwa; na biyu, yana inganta ƙona kitse kuma yana ƙara kashe kuzari.
Shaidar gwaji na asibiti
A cikin gwaje-gwajen asibiti da aka yi niyya ga marasa lafiya masu kiba, Tizepatide kuma ya nuna sakamako mai kyau na asarar nauyi. Gwaje-gwajen da bazuwar da yawa sun nuna cewa bayan ɗan lokaci na jiyya, nauyin jikin marasa lafiya ya ragu sosai. Alal misali, a cikin gwaji na makonni 24, ƙungiyar kulawa ta sami asarar nauyi na kusan 10%, yayin da ƙungiyar placebo ta nuna kadan canji. Bugu da ƙari, kewayen kugu na marasa lafiya da kewayen hip suma sun ragu, wanda ke nuni da cewa ba wai yana inganta asarar nauyi ba amma yana inganta rarraba mai kuma yana rage haɗarin cututtukan da ke da alaƙa da kiba.
(2) Haɓaka Ma'anoni masu alaƙa da Ciwon Jiki
Ingantattun Tsarin Glucose na Jini
Marasa lafiya masu kiba sau da yawa suna da lamuran glucose na jini, kuma Tizepatide yana inganta sarrafa glucose na jini yayin haɓaka asarar nauyi. A cikin gwaje-gwajen asibiti, marasa lafiya sun sami raguwa mai yawa a cikin glucose na jini mai azumi, glucose na jini na postprandial, da haemoglobin A1c (alamar kula da glucose na jini na dogon lokaci) bayan jiyya. Wannan shi ne saboda yana aiki ta hanyar hanyoyin masu karɓa na dual, inganta haɓakar insulin da haɓaka haɓakar insulin, yayin da kuma yana jinkirta zubar da ciki da rage saurin sha abinci. Idan aka kwatanta da magungunan antidiabetic na gargajiya, ba wai kawai rage glucose na jini bane amma yana inganta asarar nauyi, yana ba da fa'ida mafi girma ga masu kiba masu ciwon sukari.
Haɓaka Tsarin Lipid
Kiba sau da yawa yana tare da dyslipidemia, kamar haɓakar triglycerides da ƙananan matakan lipoprotein (HDL). Tizepatide na iya daidaita lipids: bayan gudanarwa, marasa lafiya sun sami raguwar matakan triglyceride da haɓaka matakan HDL. Wannan na iya kasancewa yana da alaƙa da tsarin sa na metabolism na lipid, kamar inganta haɓakar glucose ta ƙwayoyin mai, rage sakin fatty acid, da haɓaka oxidation mai mai, ta haka inganta bayanan lipid da rage haɗarin cututtukan zuciya.
(3) Amfani mai yuwuwa ga tsarin jijiyoyin jini
Tsarin hawan jini
Kiba yana ɗaya daga cikin abubuwan haɗari ga hauhawar jini. Nazarin asibiti sun gano cewa bayan jiyya tare da Tizepatide, systolic marasa lafiya da hawan jini na diastolic duka suna raguwa. Wannan na iya kasancewa da alaƙa da asarar nauyi da haɓaka haɓakar haɓaka: asarar nauyi yana rage nauyi akan zuciya, kuma ingantaccen glucose na jini da matakan lipid yana taimakawa dawo da lafiyar jijiyoyin jini da rage juriya na jijiyoyin jini. Bugu da ƙari, tasirin sa akan sashin gastrointestinal na iya yin tasiri a kaikaice ka'idodin neuroendocrine, don haka daidaita hawan jini.
Tasirin kariya na jijiyoyin jini
Kumburi na yau da kullun da damuwa na oxidative suna da yawa a cikin marasa lafiya masu kiba, wanda zai iya lalata endothelium na jijiyoyin jini kuma yana haɓaka atherosclerosis. Tizepatide yana kare endothelium na jijiyoyin jini ta hanyar inganta metabolism, rage sakin abubuwan da ke haifar da kumburi, da rage yawan damuwa na oxidative. Nazarin ya nuna cewa bayan jiyya, alamomin kumburin marasa lafiya irin su C-reactive protein (CRP) sun ragu, kuma alamun aikin endothelial na jijiyoyi kamar sakin nitric oxide ya karu, yana nuna ingantaccen lafiyar jijiyoyin jini da kuma taimakawa wajen rigakafin cututtukan zuciya.
Kammalawa
Tizepatide yana nuna gagarumin yuwuwar a cikin maganin kiba ta hanyar aiki lokaci guda akan masu karɓar GIP da GLP-1. Ba wai kawai yana haɓaka asarar nauyi ba yadda ya kamata amma yana inganta alamun rayuwa kamar glucose na jini da matakan lipid, yayin da ke ba da kariya ta zuciya da jijiyoyin jini. Ta hanyar hanyoyin aiwatar da abubuwa da yawa, yana ba da sabon zaɓin magani don kiba da yanayin da ke da alaƙa.
Sources
[1] Boer GA, Hay DL, Tups A. Obesity pharmacotherapy: incretin mataki a cikin tsakiyar juyayi tsarin [J]. Juyawa a cikin Kimiyyar Magunguna, 2023,44 (1): 50-63.DOI: 10.1016/j.tips.2022.11.001.
[2] Jensen TL, Nden ABO, Karstoft K, et al. Tirzepatid. Dual GLP-1/GIP agonist mai karɓa, Jiyya na nau'in ciwon sukari na 2 da kiba [J]. Magunguna na gaba, 2023. DOI:10.3389/fendo.2022.1004044
[3] Willard FS, Douros JD, Gabe MB, et al. Tirzepatid shine rashin daidaituwa kuma mai son zuciya dual GIP da GLP-1 agonist mai karɓa [J]. Jci Insight, 2020,5 (17).DOI:10.1172/jci.inji.140532.
[4] Bastin M, Andreelli F. Dual GIP-GLP1-Mai karɓar Agonists A cikin Jiyya na Nau'in Ciwon Ciwon sukari na 2: Takaitaccen Bita Akan Bayyanar Bayanai da Yiwuwar warkewa [J]. Ciwon sukari Metabolic Syndrome da Kiba-Manufa da Farfa, 2019,12:1973-1985.DOI:10.2147/DMSO.S191438.
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