Shuɗin Methylene da Ciwon Sukari: Abin da Nazarin Ƙwayoyin Halitta da Dabbobi Ya Nuna

Tambayar da ke bayan yawan tallatawa

Wannan kammalawa tana kama da mai ma'ana, amma ta dogara ne da kuskuren fahimta. Tana ɗaukar abubuwa uku daban-daban kamar abu ɗaya: shigar glucose cikin ƙwayar halitta guda a kwanon gwaji, tafiyar da sinadaran rayuwa a cikin mitochondrion na zuciya, da sarrafa glucose a jikin mutum gaba ɗaya. Kowannensu yana da nasa ma'aunai da iyakoki. Wannan maƙala tana rarrabe su.

Amsa a taƙaice: shuɗin methylene yana kunna jigilar glucose a wani nau'in ƙwayoyin halitta da aka yi wa nazari sosai, kuma yana canza halayen sinadarai na mitochondria da wasu ma'aunan zuciya a berayen da ke da ciwon sukari. Amma a nazarin beraye mafi tsawo, bai canza glucose na lokacin azumi ko haemoglobin da glucose ya manne masa ba, kuma babu wata shaida da aka wallafa daga mutane da ta nuna cewa shuɗin methylene da ake ba wa jiki gaba ɗaya yana inganta sukarin jini, HbA1c, ko insulin a ciwon sukari.

Ƙwayoyin halitta: shigar glucose da sauri ta masu jigilar da ke cikin membrane tun da farko

Masu bincike sun yi amfani da ƙwayoyin fibroblast na L929, wani nau'i da shigar glucose cikinsa ta dogara da mai jigila guda ɗaya, GLUT1. Tunda mai jigila guda ɗaya ne kawai yake akwai, duk wani canji a shigar glucose dole ya fito daga wannan mai jigilar.

Lokacin da ƙungiyar ta sanya waɗannan ƙwayoyin halitta cikin shuɗin methylene, shigar sinadarin bin sawu ta ƙaru cikin mintuna 10, kuma ƙarin ya danganta da yawan sinadarin da aka yi amfani da shi. Ya kai kusan kashi 800 cikin ɗari na matakin farko a 50 micromolar na mintuna 45. Bayanin saurin wannan aiki yana da muhimmanci: matsakaicin sauri (Vmax) ya ƙaru, yayin da ƙarfin alaƙar ɗaurewa (Km) da adadin furotin na GLUT1 suka tsaya yadda suke. Adadin ƙofofi ɗaya ne, amma sun bar ƙarin glucose ya wuce a kowace minti. Rinin ya kunna masu jigilar da ke cikin membrane tun da farko, maimakon ƙara sababbi.

Gwaje-gwajen kwatanci sun ƙara bayyana lamarin. Nau'in da ya karɓi electrons, wanda ba shi da launi, bai yi komai ba. Wani sinadarin oksidasyon da ke wajen ƙwayoyin halitta, wanda ya hana rinin shiga cikinsu, ya toshe samun launi da motsa jigilar glucose duka. Abubuwan da ke toshe hanyoyin AMP kinase da PI kinase ba su canza komai ba, abin da ke nuna cewa waɗannan sanannun hanyoyin isar da saƙo biyu ba su ne dalilin ba.

Hasashen farko shi ne zagayawar redox: rinin yana jigilar electrons, yana jawo ɗan damuwa ga ƙwayar halitta, sannan ƙwayoyin da ke cikin damuwa su buɗe ƙofofin glucose. Wani bincike na gaba ya gwada wannan ra'ayi. Masu binciken sun yi amfani da methyl-beta-cyclodextrin, wani ƙwayar sinadari mai siffar zobe wanda yake kama shuɗin methylene a cikin haɗin da ke riƙe shi a ciki (tsayayyen ma'aunin haɗuwa kusan 310 M-1). Rinin da aka kama bai ba ƙwayoyin halitta launi ba kuma bai motsa shigar glucose ba. Wanke rinin ya kuma yi daidai sosai da ɓacewar tasirin. Kammalawarsu ta saɓa wa bayanin redox: mai yiwuwa kunna jigilar ya fito ne daga hulɗar kai tsaye tsakanin rinin da wani furotin a hanyar kunna GLUT1, ba daga damuwar oksidasyon ta gaba ɗaya ba.

Ka'idar aikin tana da takamaiman iyaka. Shuɗin methylene na iya kunna shigar glucose ta GLUT1 cikin ƙwayoyin L929 cikin ɗan lokaci, kuma ana iya juyar da tasirin, ta hanyar shigarsa cikin ƙwayar halitta da hulɗa da furotin. Wannan bai bayyana komai game da insulin, pancreas, ko sukarin jini a dabba mai rai ba. Don ƙarin bayani game da rinin a matsayin mai jigilar electrons, duba yadda shuɗin methylene yake aiki a matsayin mai jigilar electrons. Don ƙa'idojin karanta nazarin ƙwayoyin halitta, duba yadda ake karanta binciken shuɗin methylene.

Berayen da ke da ciwon sukari: zukata sun canza, sukarin jini bai canza ba

Binciken dabbobi ya koma ga wani abu dabam: zuciyar da ke fama da ciwon sukari. Nazarin berayen biyu sun yi amfani da streptozotocin, wani guba da ke lalata ƙwayoyin beta masu samar da insulin, kuma yake haifar da yanayi mai kama da ciwon sukari na nau'i na 1. Masu karatu da ke neman bayani game da shuɗin methylene da ciwon sukari na nau'i na 2 ya kamata su lura da wannan bambanci tun daga farko. Waɗannan dabbobi ba masu ciwon sukari na nau'i na 2 ba ne.

A nazarin dogon lokaci, an ba wa berayen Lewis maza 10 mg a kowace kg a kowace rana a cikin ruwan sha na makonni 11, tare da ƙananan adadin insulin don hana lalacewar jiki ba tare da mayar da glucose zuwa matakin al'ada ba. A mitochondria na zuciya, rinin ya taimaka wajen oksidasyon na NADH, ya ƙara NAD+, kuma ya ƙara aikin Sirtuin 3 na cire rukunin acetyl. Binciken furotin ya gano ƙarancin haɗewar rukunin acetyl a wurare 83 a kan furotin 34 na mitochondria, a ayyukan oksidasyon na kitse, zagayen citric acid, da jigilar electrons. Oksidasyon na kitse mai dogon sarƙa da aikin hydroxyacyl-CoA dehydrogenase sun ragu. An fassara hakan a matsayin sassauta yawan dogaron zuciyar mai ciwon sukari kan kitse. Girman ɗakunan zuciya da kaso na jinin da zuciya ke fitarwa sun inganta, kuma wata alamar ƙarin kaurin tsokar zuciya ta koma matakin al'ada, duk da cewa matsin jini da saurin matsewar zuciya sun ci gaba da kasancewa ƙasa.

Ga sakamakon da ya fi muhimmanci: matakin glucose a jini bai canza ba. Glucose na lokacin azumi da na lokacin da ba azumi ya ci gaba da kasancewa sama. HbA1c ya kasance kusa da kashi 5.6 cikin ɗari a berayen da ke da ciwon sukari, waɗanda aka yi wa magani da waɗanda ba a yi wa magani ba, ba tare da tasirin magani mai muhimmanci ta fuskar ƙididdiga ba. Rinin kuma bai gyara matsalar numfashin complex I da II a mitochondria da aka ware ba. Aikin zuciya ya inganta a wasu ma'aunai, amma sarrafa glucose da babbar matsalar numfashin mitochondria ba su inganta ba. Sakamako daban-daban sun kasance daban-daban.

Nazari na biyu ya yi aiki a ƙaramin mataki: mitochondria da aka ware daga zukata masu lafiya da waɗanda suka shafe watanni biyu da ciwon sukari, an ba su ƙaramin adadi guda ɗaya na 0.1 micromolar yayin aunawa. Amfani da oxygen ya ƙaru da sinadaran da complex I da II ke amfani da su. Amma fitowar hydrogen peroxide ta bambanta bisa sinadarin da ake amfani da shi a matsayin makamashi: ta ƙaru da glutamate tare da malate, ta ragu da succinate. Riƙe calcium bai canza ba. Wannan nazarin tasirin sinadari ne a mitochondria, ba gwajin aikin zuciya ko glucose ba. Darasinsa ita ce rinin ba sinadarin hana oksidasyon ba ne da yake aiki iri ɗaya a kowane yanayi. Ko fitowar sinadaran oksidasyon za ta ƙaru ko ta ragu ya danganta da irin sinadarin da mitochondrion yake ƙonawa. Don bayanai masu alaƙa, duba shuɗin methylene a binciken zuciya da jijiyoyin jini.

Teburin samfurin gwaji da ma'aunin sakamako: abin da aka gwada, abin da ya canza, da abin da bai canza ba

Samfurin gwaji	Abin da shuɗin methylene ya yi	Ma'aunin sakamakon da aka auna	Sakamako
Ƙwayoyin fibroblast na L929, GLUT1 kaɗai, shigar sinadarin bin sawu	Kunna masu jigilar da suke akwai cikin ɗan lokaci, Vmax ya ƙaru, Km bai canza ba, babu sabon furotin na GLUT1	Saurin shigar glucose a kwanon gwaji	Ya ƙaru har zuwa ninki ~8 a 50 micromolar, tasirin ya gushe bayan wankewa
Ƙwayoyin fibroblast na L929 tare da tarkon cyclodextrin	An riƙe rinin a wajen ƙwayoyin halitta, samun launi ya ɓace	Motsa shigar glucose	An toshe shi tare da samun launi, abin da ya fi goyon bayan hulɗar kai tsaye da furotin fiye da damuwar redox ta gaba ɗaya
Berayen da STZ ya jawo musu ciwon sukari, 10 mg/kg/day ta baki, makonni 11	Oksidasyon na NADH, ƙarin NAD+, ƙarin aikin Sirtuin 3, an cire rukunin acetyl a wurare 83 na mitochondria, oksidasyon na kitse mai dogon sarƙa ya ragu	Girman ɗakunan zuciya, kaso na jinin da zuciya ke fitarwa, alamar ƙarin kaurin tsokar zuciya	Sun inganta a wani ɓangare (girman ɗakuna, kaso na jinin da zuciya ke fitarwa, ANP sun koma matakin al'ada; matsin jini da dP/dt sun ci gaba da kasancewa ƙasa)
Nazarin beraye na dogon lokaci ɗaya	Adadin sinadarin ɗaya	Glucose na lokacin azumi, glucose na lokacin da ba azumi, HbA1c	Babu canji mai muhimmanci ta fuskar ƙididdiga; ciwon sukari ya ci gaba da kasancewa
Nazarin beraye na dogon lokaci ɗaya, mitochondria da aka ware	Ba da sinadarin ta baki na dogon lokaci, sannan auna numfashi a wajen jiki	Fosforileshon ta oksidasyon da complex I da II ke tallafawa	Ba a gyara matsalar ba
Mitochondria da aka ware daga zukata masu lafiya da masu ciwon sukari, 0.1 micromolar cikin ɗan lokaci	Sauya hanyar electrons yayin auna numfashi	Amfani da oxygen	Ya ƙaru da sinadaran da complex I da II ke amfani da su
Nazarin mitochondria na ɗan lokaci ɗaya	Adadin sinadarin ɗaya	Fitowar hydrogen peroxide	Ya danganta da sinadarin makamashi: ya ƙaru da glutamate/malate, ya ragu da succinate
Mutane, ba da sinadarin ga jiki gaba ɗaya	Babu gwajin da aka wallafa wanda babban sakamakonsa ya shafi sukarin jini kuma aka wallafa sakamakonsa	HbA1c, glucose na lokacin azumi, insulin	Ba a samu ingantawa da aka wallafa ba

Mutane: kusan babu bayanan tasiri kan sukarin jini

Gwaji na iya nazarin raunuka a mutanen da ke da ciwon sukari ba tare da nazarin sarrafa glucose ba. Haka kuma aikin haƙori na iya bayar da rahoton HbA1c a matsayin ma'aunin gefe ba tare da gwada maganin ciwon sukari ba.

Wani gwaji da aka yi wa rajista, NCT05850611, yana shirin ba da shuɗin methylene ta baki (70 mg a madara, makonni huɗu) don miki a ƙafar mai ciwon sukari. Glucose na lokacin azumi, insulin, da HbA1c suna cikin ma'aunansa, amma ba a wallafa sakamako ba. Wani ƙaramin nazarin gwaji da aka wallafa ya haɗa gel na plasma mai yalwar faranti na jini da ƙaramin adadin rinin ta baki don miki a ƙafa. Ya bayar da rahoton sakamakon rauni da samun oxygen, ba na sukarin jini ba. Gwaje-gwajen haƙori da suka shafa rinin a wurin a matsayin sinadarin yaƙi da ƙwayoyin cuta da haske ke kunnawa, a majinyata masu periodontitis da ciwon sukari, ba su gano wata fa'ida mai muhimmanci ta fuskar ƙididdiga ga HbA1c ba. Rini a aljihun dasashi abu ne dabam da maganin tafiyar da sinadaran rayuwa na jiki gaba ɗaya, don haka waɗannan sakamakon rashin tasiri ba su bayyana komai game da ba da shi ta baki ba.

Taƙaitawa ta gaskiya: babu shaida da aka wallafa daga mutane da ta nuna cewa shuɗin methylene da ake ba wa jiki gaba ɗaya yana inganta HbA1c, glucose na lokacin azumi, ko insulin a ciwon sukari. Rashin shaida ba hujja ce ta rashin tasiri ba, amma yana ƙaryata tallan da ke gabatar da shigar glucose cikin ƙwayoyin halitta ko sakamakon zuciyar bera a matsayin hujjar sarrafa glucose. Don sanin iyakokin aminci kafin kowa ya gwada, ciki har da haɗarin serotonin syndrome tare da magungunan rage damuwa da aka saba amfani da su, duba amincin shuɗin methylene da hulɗarsa da magunguna.

Yadda za ka yi amfani da wannan shaida ba tare da yaudarar kanka ba

Ka yi tunanin injuna uku. Inji na ɗaya ƙofar glucose ce a ƙwayar halitta guda da aka reno a dakin gwaji. Inji na biyu mitochondrion ne a zuciyar bera. Inji na uku mutum ne mai ciwon sukari, tare da pancreas, hanta, tsokoki, ƙododi, magunguna, da abinci. An nuna cewa rinin yana shafar injuna na ɗaya da na biyu. Ba a nuna cewa inji na uku yana amsawa da ingantaccen sarrafa glucose ba.

Wannan bambanci shi ne maƙalar gaba ɗaya a sakin layi ɗaya. Da'awar kula da ciwon sukari da shuɗin methylene wadda take nuna kunna masu jigila ko haɗewar rukunin acetyl a mitochondria maimakon ma'aunin sakamako na sukarin jini ta sauya batun. Sakamakon Sirtuin 3 da oksidasyon na kitse sun ci gaba da cancantar a sa musu ido, amma gwajin da ya kamata a jira takamaimai ne: gwaji mai rukunin kwatanci a mutanen da ke da ciwon sukari, wanda yake auna HbA1c, glucose na lokacin azumi, ko insulin a matsayin babban sakamako.