Kamoo Li-Receptor tsa Insulin li Sebetsang Kateng
Insulin ke hormone ea peptide e bapalang karolo ea bohlokoa ho bolokeng maemo a tsoekere maling a leka-lekaneng le ho laola metabolism ea lik'habohaedreite, mafura le protheine. Hore insulin e sebetse, e hloka "portal" holim'a sele e lemohang le ho fetolela matšoao a insulin karabelong ea baeloji. Sebaka sena sa ho kena ke receptor ea insulin. Ho utloisisa mokhoa oa ts'ebetso ea receptor ea insulin ho thusa ho hlalosa hore na lisele li nka tsoekere joang ka mor'a lijo, hore na ke hobane'ng ha maemo a tsoekere maling a ka nyoloha ho lefu la tsoekere, le hore na ho hanyetsa insulin ho ka hlaha joang maemong a fapaneng a metabolism.
Sebopeho le Sebaka sa Li-Insulin Receptors
Seamoheli sa insulin ke sa lelapa la receptor tyrosine kinase (RTK), e leng li-receptor tsa membrane tse nang le ts'ebetso ea tyrosine kinase. Seamoheli sena se entsoe ka lipara tse peli tsa li-subunit: li-subunit tse peli tsa alpha (α) le li-subunit tse peli tsa beta (β) tse etsang motsoako oa α2β2. Li-subunit tsa α li fumaneha ka ntle ho sele (extracellular) 'me li sebetsa ho tlama insulin, ha li-subunit tsa β li kenella ka har'a lera la sele 'me li na le sebaka sa kahare ho sele se nang le ts'ebetso ea tyrosine kinase.
Li-receptor tsa insulin li fumaneha ka bongata liseleng tse arabelang insulin tse kang mesifa ea masapo, lisele tsa mafura le sebete. Boteng ba li-receptor tsena holim'a sele bo lumella 'mele ho arabela maemong a eketsehileng a insulin, mohlala ka mor'a ho ja lijo tse nang le lik'habohaedreite tse ngata.
Mothati oa 1: Ho Tlama ha Insulin ho Receptor
Ts'ebetso ena e qala ha insulin e potolohang e tlamahane le sebaka se tlamang insulin sa subunit ea α. Tlamahano ena e ikhetha, ho bolelang hore receptor ea insulin e etselitsoe ho lemoha insulin ka kamano e phahameng. Ha insulin e tlamahane, receptor e fetola sebopeho (sebopeho). Phetoho ena ea sebopeho e "kenya tšebetsong" sebaka se ka hare sa receptor, subunit ea β, e le hore receptor e be e loketse ho qala phallo ea matšoao ka har'a sele.
Ho tlama insulin ha ho sebeletse feela e le "senotlolo" sa ho notlolla lets'oao, empa hape ho khetholla matla a lets'oao: ha insulin e tlamiloe haholo, ts'ebetso ea receptor e ba matla, leha tlas'a maemo a itseng karabelo ea sele e ka fokotseha ka lebaka la ho hanyetsa insulin.
Mokhahlelo oa 2: Autophosphorylation le Ts'ebetso ea Tyrosine Kinase
Kamora hore insulin e tlamehe, sebaka sa tyrosine kinase ho β subunit se a kenngwa tshebetsong. Ts'ebetso ena e qala tshebetso ya bohlokwa e bitswang autophosphorylation, moo receptor e ipopang hodima masalla a tyrosine amino acid. Autophosphorylation e eketsa tshebetso ya enzymatic ya receptor mme e etsa "sebaka sa ho emisa" bakeng sa diprotheine tse ding tse tla fetisa letshwao.
Ho fosforila ha lisele tsa 'mele ho ka nahanoa e le mohato oa ho eketsa lets'oao: receptor, eo qalong e neng e amohela melaetsa e tsoang ho insulin feela, joale e fetoha sethala se sebetsang se ka fumanang liprotheine tse ngata ka hare ho sele.
Mothati oa 3: Ho hira le ho khelosa IRS
E 'ngoe ea lihlopha tse ka sehloohong tsa liprotheine tse hiriloeng ke Insulin Receptor Substrate (IRS), haholo-holo IRS-1 le IRS-2. Liprotheine tsa IRS li tlama ho receptor e nang le phosphorylated, ebe e etsa phosphorylated IRS holim'a masala a tyrosine. Ha IRS e na le phosphorylated, e sebetsa e le adaptara e bulang litsela tsa bohlokoa tsa ho supa ka hare ho sele.
Mohato ona o bohlokwa hobane ditlamorao tse ngata tsa insulin—ho tloha ho monyeng wa glucose ho isa ho etseng glycogen—di itshetlehile hodima ho kenngwa tshebetsong ha ditsela tse tsamaiswang ke IRS. Phosphorylation ya IRS e sitisang ke mokgwa o mong o atisang ho amahanngwa le ho hanyetsa insulin.
Mokhahlelo oa 4: Ho Kenngwa tshebetsong ha Tsela ea PI3K–Akt (Tsela ea Metabolic)
Tsela e tsebahalang haholo ea ho bontša insulin bakeng sa metabolism ke PI3K–Akt. Hang ha IRS e se e phosphorylated, e hira PI3K (phosphoinositide 3-kinase). PI3K ebe e fetola likarolo tsa lipid tsa membrane (PIP2 ho PIP3), e sebetsang e le lets'oao la ho hira liprotheine tse ling tse kang PDK1 le Akt (protein kinase B).
Akt ke ntlha ea bohlokoa e kenyang tšebetsong likarabo tse fapaneng tsa metabolism, ho kenyeletsoa:
1. Phetisetso ea GLUT4
Mesifeng ea masapo le liseleng tsa mafura, insulin e eketsa ho monngoa ha tsoekere ka ho tsamaisa sesebelisoa sa ho tsamaisa tsoekere GLUT4 ho tloha li-vesicles tse ka hare ho sele ho ea lera la sele. Ka GLUT4 e ngata holim'a metsi, tsoekere ea mali e kena habonolo seleng bakeng sa ho sebelisoa e le matla kapa polokelo.
2. Ho kopanngoa ha Glycogen
Mesifeng le sebeteng, Akt e thibela enzyme e thibelang ho thehwa ha glycogen (ka GSK3), ka hona e eketsa mosebetsi oa glycogen synthase. Ka lebaka leo, glucose e bolokoa e le glycogen.
3. Thibelo ea gluconeogenesis (haholo-holo sebeteng)
Insulin e thibela tlhahiso e ncha ea tsoekere sebeteng ka ho laola lintlha tse itseng tsa ho ngola. Sena se thusa ho thibela tsoekere maling ho nyoloha haholo.
4. Taolo ea metabolism ea mafura
Insulin e khothalletsa polokelo ea mafura 'me e thibela ho senyeha ha mafura (lipolysis) liseleng tsa mafura, e leng se tlatsetsang ho fokotseng ho lokolloa ha mafura a mafura a mahala ka har'a potoloho ea mali.
Mokhahlelo oa 5: Ho Kenngwa tshebetsong ha Tsela ea Ras–MAPK (Tsela ea Kholo)
Ntle le litlamorao tsa eona tsa metabolism, insulin receptor e boetse e kenya tšebetsong litsela tse amanang le kholo le phapang ea lisele, e leng Ras–MAPK. Tsela ena e atisa ho amahanngoa le:
– kgolo ya disele,
– karohano,
– tlhahiso ea liphatsa tse itseng tsa lefutso,
– litlamorao tsa nako e telele tsa insulin liseleng.
Tseleng ena, IRS kapa liprotheine tse ling tsa adaptara tse kang Shc li ka kenya tšebetsong Ras → Raf → MEK → ERK (MAPK) cascade. Ho kenya tšebetsong ERK ho ama khubu ea sele, ho fetola polelo ea liphatsa tsa lefutso le likarabo tsa sele tsa nako e telele.
Tekanyo pakeng tsa litsela tsa PI3K–Akt le Ras–MAPK e bohlokoa ho netefatsa hore insulin ha e laole maemo a tsoekere feela, empa hape e tšehetsa ts'ebetso e tloaelehileng ea sele.
Ho Fela ha Letšoao: Endocytosis le Desensitization
Letšoao la insulin le ke ke la qala ho sebetsa. Ka mora hore insulin e tlamehe 'me receptor e sebetse, motsoako oa insulin-receptor o ka feta endocytosis, e huloang ka seleng ka vesicle. Ka hare ho sele, insulin e ka lokolloa le ho senngoa, ha receptor e ka:
– e ka sebediswa hape ho ya bokahodimo ba sele, kapa
– e senyehile haeba ho hlokahala.
Ho phaella moo, ho na le mekgwa ya thibelo ya ho ntsha matshwao ka di-phosphatase tse tlosang phosphate ho receptor kapa IRS. Tlas'a maemo a itseng, phosphorylation ya IRS hodima masala a serine/threonine (ho ena le tyrosine) e ka fokotsa bokgoni ba IRS ba ho fetisa matshwao, e leng e nngwe ya lisosa tsa motheo tsa ho hanyetsa insulin.
Khanyetso ea Insulin Mabapi le Li-Receptors le Matšoao
Ho hanyetsa insulin ho etsahala ha lisele li sa arabele insulin haholo, e leng se hlokang insulin e ngata ho hlahisa phello e tšoanang. Mekgwa e ka kenyeletsa:
– palo ea li-receptor tsa insulin ea fokotseha (ho fokotseha ha tekanyo),
- mathata a autophosphorylation ea receptor,
– ho sitisoa ha phosphorylation ea IRS ho tyrosine,
– ho eketseha ha matšoao a ho ruruha le khatello ea oxidative e thibelang tsela ea PI3K-Akt,
– ho bokellana ha mafura (lipotoxicity) e sitisang phetisetso ea matšoao.
Ka lebaka leo, GLUT4 ha e kgone ho tsamaya ka katleho hodima lera, ho monyela ha glucose hoa fokotseha, mme tswekere ya madi e atisa ho nyoloha. Ebe manyeme a buseletsa ka ho hlahisa insulin e ngata, empa ha nako e ntse e ya puseletso ena e ka hloleha mme ya fetoha lefu la tswekere la mofuta wa 2.
Qetello
Mokhoa oa tšebetso oa insulin receptor o qala ka ho tlama insulin ho alpha subunit, e lateloa ke ho kenya tšebetsong ha tyrosine kinase ho beta subunit ka autophosphorylation, ebe ho hiroa liprotheine tsa IRS tse fetisetsang matšoao litseleng tsa bohlokoa tse kang PI3K-Akt le Ras-MAPK. Tsela ea PI3K-Akt e laola litlamorao tsa metabolism ea insulin, ho kenyeletsoa le translocation ea GLUT4 le polokelo e eketsehileng ea tsoekere, ha tsela ea Ras-MAPK e bapala karolo kholong le taolong ea liphatsa tsa lefutso. Letšoao la insulin ebe le felisoa ka endocytosis le mekhoa ea ho fokotsa kutloisiso. Tšitiso ho efe kapa efe ea mekhahlelo ena e ka lebisa ho hanyetsaneng ha insulin, e leng motheo oa bohlokoa bakeng sa mathata a fapaneng a metabolism joalo ka lefu la tsoekere la mofuta oa 2.
Haeba o lakatsa, nka eketsa chate e bonolo, kakaretso ea lintlha tsa bohlokoa, kapa ka e amahanya le mokhoa oo meriana ea antidiabetic e sebetsang ka oona tseleng ea insulin.
