Momwe Ma Insulin Receptors Amagwirira Ntchito
Insulin ndi hormone ya peptide yomwe imagwira ntchito yofunika kwambiri pakusunga shuga m'magazi moyenera komanso kuwongolera kagayidwe ka chakudya, mafuta, ndi mapuloteni. Kuti insulin igwire ntchito, imafunika "portal" pamwamba pa selo yomwe imazindikira ndikumasulira zizindikiro za insulin kukhala yankho lachilengedwe. Doko lolowera ili ndi cholandirira insulin. Kumvetsetsa momwe cholandirira insulin chimagwirira ntchito kumathandiza kufotokoza momwe maselo amatengera shuga atatha kudya, chifukwa chake shuga m'magazi angakwere mu shuga, komanso momwe kukana insulini kungakulire m'mikhalidwe yosiyanasiyana ya kagayidwe kachakudya.
Kapangidwe ndi Malo a Zolandirira Insulin
Cholandirira cha insulin chili m'gulu la receptor tyrosine kinase (RTK), zomwe ndi zolandirira za membrane zomwe zimakhala ndi ntchito ya tyrosine kinase. Cholandirirachi chimapangidwa ndi ma subunits awiri: ma subunits awiri a alpha (α) ndi ma subunits awiri a beta (β) omwe amapanga α2β2 complex. Ma subunits a α ali kunja kwa selo (kunja kwa selo) ndipo amagwira ntchito yomangirira insulin, pomwe ma subunits a β amalowa mu cell membrane ndikukhala ndi intracellular domain yomwe ili ndi ntchito ya tyrosine kinase.
Ma receptor a insulin amapezeka ambiri m'maselo omwe amayankha insulin monga minofu ya mafupa, minofu ya mafuta, ndi chiwindi. Kupezeka kwa ma receptor awa pamwamba pa selo kumathandiza thupi kuyankha kuchuluka kwa insulin, mwachitsanzo mutadya chakudya chokhala ndi chakudya chambiri.
Gawo 1: Kumangirira kwa Insulin ku Receptor
Njirayi imayamba pamene insulin yozungulira imalumikizana ndi gawo lomangirira insulin la α subunit. Kulumikizana kumeneku ndi kwapadera, kutanthauza kuti cholandirira insulin chimapangidwa kuti chizindikire insulin ndi mphamvu yayikulu. Pamene insulin imamangirira, cholandiriracho chimasintha mawonekedwe (mawonekedwe). Kusintha kumeneku "kumayatsa" gawo lamkati la cholandiriracho, β subunit, kotero kuti cholandiriracho chikhale chokonzeka kuyambitsa kufalikira kwa zizindikiro mkati mwa selo.
Kumanga insulin sikuti kumangokhala "chinsinsi" chotsegulira selo, komanso kumatsimikiza mphamvu ya chizindikiro: insulin ikamangika kwambiri, mphamvu ya receptor imayambika, ngakhale kuti pazifukwa zina, yankho la selo limatha kuchepa chifukwa cha kukana insulin.
Gawo 2: Autophosphorylation ndi Tyrosine Kinase Activation
Pambuyo poti insulin yalumikizana, chigawo cha tyrosine kinase pa β subunit chimayatsidwa. Kuyatsa kumeneku kumayambitsa njira yofunika kwambiri yotchedwa autophosphorylation, momwe receptor imadzipangira yokha pa tyrosine amino acid residue. Autophosphorylation imawonjezera ntchito ya enzyme ya receptor ndikupanga "malo oikira" mapuloteni ena omwe amatumiza chizindikirocho.
Kuchuluka kwa phosphorylation kungaganizidwe ngati gawo lokulitsa chizindikiro: cholandirira, chomwe poyamba chimalandira mauthenga ochokera ku insulin yokha, tsopano chimakhala nsanja yogwira ntchito yomwe ingathe kusonkhanitsa mapuloteni ambiri mkati mwa maselo.
Gawo 3: Kulemba Anthu Ntchito ndi Kusagwiritsa Ntchito Ma IRS
Limodzi mwa magulu akuluakulu a mapuloteni omwe amatengedwa ndi Insulin Receptor Substrate (IRS), makamaka IRS-1 ndi IRS-2. Mapuloteni a IRS amamangirira ku phosphorylated receptor, yomwe kenako imapanga phosphorylation ya IRS pa zotsalira za tyrosine. IRS ikapangidwa phosphorylated, imagwira ntchito ngati adaputala yomwe imatsegula njira zazikulu zolumikizirana mkati mwa selo.
Gawo ili ndi lofunika kwambiri chifukwa zotsatira zambiri za insulin—kuyambira kuyamwa kwa shuga mpaka kupanga glycogen—zimadalira kuyambika kwa njira zomwe zimayendetsedwa ndi IRS. Kusokonekera kwa phosphorylation ya IRS ndi njira imodzi yomwe nthawi zambiri imagwirizanitsidwa ndi kukana kwa insulin.
Gawo 4: Kuyambitsa Njira ya PI3K–Akt (Njira ya Kagayidwe ka Metabolic)
Njira yodziwika bwino yolumikizirana ndi insulin ya kagayidwe kachakudya ndi PI3K–Akt. IRS ikangosinthidwa kukhala phosphorylated, imagwiritsa ntchito PI3K (phosphoinositide 3-kinase). Kenako PI3K imasintha zigawo za lipid za membrane (PIP2 kukhala PIP3), zomwe zimagwira ntchito ngati chizindikiro chogwiritsa ntchito mapuloteni ena monga PDK1 ndi Akt (protein kinase B).
Akt ndiye mfundo yayikulu yomwe imayambitsa mayankho osiyanasiyana a kagayidwe kachakudya, kuphatikiza:
1. Kusamutsa kwa GLUT4
Mu minofu ya mafupa ndi minofu ya mafuta, insulin imawonjezera kuyamwa kwa shuga mwa kusuntha GLUT4 yonyamula shuga kuchokera ku ma vesicles mkati mwa selo kupita ku nembanemba ya selo. Ndi GLUT4 yochulukirapo pamwamba, shuga m'magazi mosavuta kulowa m'maselo kuti agwiritsidwe ntchito ngati mphamvu kapena kusungidwa.
2. Kupanga kwa Glycogen
Mu minofu ndi chiwindi, Akt imaletsa enzyme yomwe imaletsa kupangika kwa glycogen (kudzera mu GSK3), motero imawonjezera ntchito ya glycogen synthase. Zotsatira zake, shuga amasungidwa ngati glycogen.
3. Kuletsa kupanga shuga m'magazi (makamaka m'chiwindi)
Insulin imaletsa kupanga shuga watsopano m'chiwindi mwa kuwongolera zinthu zina zomwe zimapangitsa kuti shuga m'magazi asakwere kwambiri.
4. Kulamulira kagayidwe ka mafuta m'thupi
Insulin imathandizira kusunga mafuta ndikuletsa kusweka kwa mafuta (lipolysis) mu minofu yamafuta, zomwe zimapangitsa kuti mafuta acids aulere atulutsidwe m'magazi.
Gawo 5: Kuyambitsa Njira ya Ras–MAPK (Njira Yokulira)
Kuwonjezera pa zotsatira zake za kagayidwe kachakudya, cholandirira insulin chimayambitsanso njira zokhudzana ndi kukula ndi kusiyana kwa maselo, zomwe ndi Ras–MAPK. Njirayi nthawi zambiri imagwirizanitsidwa ndi:
- kukula kwa maselo,
- kugawa,
- kufotokozera majini ena,
- zotsatira za insulin kwa nthawi yayitali pa minofu.
Munjira iyi, IRS kapena mapuloteni ena a adapter monga Shc amatha kuyambitsa Ras → Raf → MEK → ERK (MAPK) cascade. Kuyambitsa kwa ERK kumakhudza nucleus ya selo, kusintha mawonekedwe a majini ndi mayankho a nthawi yayitali a maselo.
Kugwirizana pakati pa njira za PI3K–Akt ndi Ras–MAPK ndikofunikira kuti insulini isamangowongolera kuchuluka kwa shuga m'magazi, komanso imathandizira magwiridwe antchito abwinobwino a maselo.
Kutha kwa Chizindikiro: Endocytosis ndi Kuchepetsa Kuzindikira
Chizindikiro cha insulin sichingayambitsidwe nthawi zonse. Pambuyo poti insulin yalumikizana ndipo cholandiriracho chayamba kugwira ntchito, insulin-receptor complex imatha kulowa mu endocytosis, yomwe imakokedwa mu selo kudzera mu vesicle. Mkati mwa selo, insulin imatha kutulutsidwa ndikuwonongedwa, pomwe cholandiriracho chimatha:
- kubwezeretsedwanso pamwamba pa selo, kapena
- kuwonongedwa ngati pakufunika kutero.
Kuphatikiza apo, pali njira zoletsa zizindikiro kudzera mu phosphatases zomwe zimachotsa phosphate kuchokera ku receptor kapena IRS. Pazifukwa zina, phosphorylation ya IRS pa zotsalira za serine/threonine (m'malo mwa tyrosine) ingachepetse mphamvu ya IRS yotumizira zizindikiro, zomwe ndi chimodzi mwa zifukwa zazikulu za kukana insulin.
Kukana kwa Insulin Potengera Ma Receptors ndi Zizindikiro
Kukana kwa insulin kumachitika pamene maselo sakuyankha bwino ku insulin, zomwe zimafuna kuti insulin yambiri ipange zotsatira zomwezo. Njira zake zingaphatikizepo:
- kuchuluka kwa ma insulin receptors kumachepa (kuchepa kwa insulin receptors),
- matenda a autophosphorylation a receptor,
- kusokonezeka kwa phosphorylation ya IRS pa tyrosine,
- zizindikiro zotupa zomwe zimawonjezera komanso kupsinjika kwa okosijeni komwe kumalepheretsa njira ya PI3K-Akt,
- kusonkhanitsa mafuta (lipotoxicity) komwe kumasokoneza kufalikira kwa zizindikiro.
Zotsatira zake, GLUT4 singathe kuyenda bwino kudzera mu nembanemba, kuyamwa kwa shuga m'magazi kumachepa, ndipo shuga m'magazi nthawi zambiri amakwera. Kenako kapamba amapanga insulin yambiri, koma pakapita nthawi izi zimatha kulephera ndikukhala matenda a shuga amtundu wachiwiri.
Mapeto
Kagwiridwe ka ntchito ka insulin receptor kamayamba ndi insulin yomangirira ku alpha subunit, kutsatiridwa ndi kuyambitsa kwa tyrosine kinase pa beta subunit kudzera mu autophosphorylation, kenako kusonkhanitsa mapuloteni a IRS omwe amatumiza zizindikiro ku njira zazikulu monga PI3K-Akt ndi Ras-MAPK. Njira ya PI3K-Akt imalamulira zotsatira za kagayidwe ka insulin, kuphatikizapo GLUT4 translocation ndi kuchuluka kwa shuga wosungidwa, pomwe njira ya Ras-MAPK imagwira ntchito pakukula ndi kulamulira majini. Chizindikiro cha insulin chimathetsedwa kudzera mu endocytosis ndi njira zochepetsera kukhudzidwa kwa maselo. Kusokonezeka mu gawo lililonse mwa izi kungayambitse kukana kwa insulin, komwe ndi maziko ofunikira a matenda osiyanasiyana a kagayidwe ka thupi monga matenda a shuga amtundu wachiwiri.
Ngati mukufuna, nditha kuwonjezera tchati chosavuta, chidule cha mfundo zazikulu, kapena kuzigwirizanitsa ndi momwe mankhwala ochepetsa shuga amagwirira ntchito pa njira ya insulin.
